Neurology

Dr. Crain’s excellent review, “Breaking the cycle of medication overuse headache” (J Fam Pract. 2021;70:20-28) provides an approach to the diagnosis and treatment of this common disorder that is consistent with most expert opinion and published guidelines. However, like most articles on this subject, it is missing a critical review of the evidence that supports the existence of this condition and the recommended treatments. 

The strong association between intractable headaches and quantity of medication used makes the diagnosis of medication overuse headache (MOH) attractive with plausible (if unproven) pathophysiological mechanisms. However, reversing the direction of causation (intractable headaches lead to more medication) seems just as likely. While MOH is taken as an article of faith by most headache experts, high-quality studies in support of this theory have not yet been performed.¹

On the other hand, fear of MOH often leads to rigid, arbitrary limitations of abortive medications, blaming of the patient for their symptoms, and the substitution of a host of pharmacologic and nonpharmacologic interventions that similarly lack evidence of efficacy. Patients with chronic migraine are told to take abortive medications early in the headache but not to take them more than twice per week. They hoard their medications while trying to decide if each daily headache is the “big one” that merits depleting their limited supply of medication.

Avoiding medication “overuse” and prescribing from our growing armamentarium of effective preventive medications remain important strategies. However, until we have better evidence, we need to be a little more flexible in prescribing abortive medications and avoid accepting the MOH paradigm as gospel.

David A. Silverstein, MD
Buffalo, NY

Dr. Crain’s excellent review, “Breaking the cycle of medication overuse headache” (J Fam Pract. 2021;70:20-28) provides an approach to the diagnosis and treatment of this common disorder that is consistent with most expert opinion and published guidelines. However, like most articles on this subject, it is missing a critical review of the evidence that supports the existence of this condition and the recommended treatments. 

The strong association between intractable headaches and quantity of medication used makes the diagnosis of medication overuse headache (MOH) attractive with plausible (if unproven) pathophysiological mechanisms. However, reversing the direction of causation (intractable headaches lead to more medication) seems just as likely. While MOH is taken as an article of faith by most headache experts, high-quality studies in support of this theory have not yet been performed.¹

On the other hand, fear of MOH often leads to rigid, arbitrary limitations of abortive medications, blaming of the patient for their symptoms, and the substitution of a host of pharmacologic and nonpharmacologic interventions that similarly lack evidence of efficacy. Patients with chronic migraine are told to take abortive medications early in the headache but not to take them more than twice per week. They hoard their medications while trying to decide if each daily headache is the “big one” that merits depleting their limited supply of medication.

Avoiding medication “overuse” and prescribing from our growing armamentarium of effective preventive medications remain important strategies. However, until we have better evidence, we need to be a little more flexible in prescribing abortive medications and avoid accepting the MOH paradigm as gospel.

David A. Silverstein, MD
Buffalo, NY

Dr. Crain’s excellent review, “Breaking the cycle of medication overuse headache” (J Fam Pract. 2021;70:20-28) provides an approach to the diagnosis and treatment of this common disorder that is consistent with most expert opinion and published guidelines. However, like most articles on this subject, it is missing a critical review of the evidence that supports the existence of this condition and the recommended treatments. 

The strong association between intractable headaches and quantity of medication used makes the diagnosis of medication overuse headache (MOH) attractive with plausible (if unproven) pathophysiological mechanisms. However, reversing the direction of causation (intractable headaches lead to more medication) seems just as likely. While MOH is taken as an article of faith by most headache experts, high-quality studies in support of this theory have not yet been performed.¹

On the other hand, fear of MOH often leads to rigid, arbitrary limitations of abortive medications, blaming of the patient for their symptoms, and the substitution of a host of pharmacologic and nonpharmacologic interventions that similarly lack evidence of efficacy. Patients with chronic migraine are told to take abortive medications early in the headache but not to take them more than twice per week. They hoard their medications while trying to decide if each daily headache is the “big one” that merits depleting their limited supply of medication.

Avoiding medication “overuse” and prescribing from our growing armamentarium of effective preventive medications remain important strategies. However, until we have better evidence, we need to be a little more flexible in prescribing abortive medications and avoid accepting the MOH paradigm as gospel.

David A. Silverstein, MD
Buffalo, NY

THE CASE

A 23-year-old woman with past medical history of bipolar II disorder and a REM-specific seizure disorder that resolved at age 9 presented after a syncopal episode. The patient reported an initial sensation of lightheadedness while at work, which was followed by a syncopal episode with brief (1-2 min) loss of consciousness and a minor head injury.

She denied other prodromal symptoms including chest pain, shortness of breath, ­palpitations, and nausea. She also did not experience convulsions, urinary/bowel incontinence, or confusion upon regaining consciousness.

She denied previous syncopal episodes. However, she reported that, 2 weeks prior, there had been an event similar to that of her presenting complaint. During that episode, she experienced lightheadedness and a fall without loss of consciousness.

The patient had been prescribed a regimen of sertraline 100 mg/d and aripiprazole 10 mg/d to maintain mood stability. She had self-discontinued these medications about 8 months prior to presentation. A recent return of her depressive features had prompted a restart of this regimen 1 week before her first fall, without an initial taper upward.

While in the emergency department, she became bradycardic (heart rate, 38 beats/min) and hypotensive (blood pressure, 70/40 mm Hg). She subsequently became increasingly somnolent and had 1 episode of emesis. An electrocardiogram (EKG) revealed sinus bradycardia without other acute abnormalities (FIGURE).

Blood work including a basic metabolic panel, complete blood count, and cardiac enzymes were all within normal limits. Computed tomography of the head revealed no intracranial pathology. Her vitals were initially unresponsive to a fluid bolus but improved and stabilized after administration of intravenous atropine 0.5 mg.

Aripiprazole was held and sertraline was decreased to 75 mg on hospital Day 1, with close monitoring of her mood. Cardiology was consulted and followed the patient ­during her stay. The patient was monitored on telemetry for 3 days, exhibiting only sinus ­bradycardia with a stable heart rate of 45-55 beats/min. Systolic blood pressures were ­stable within 120 to 130 mm Hg. Transthoracic echocardiogram performed on hospital Day 2 was unremarkable, revealing a normal left ventricular ejection fraction of 65% and no wall motion abnormalities. She had no recurrence of the syncope or emesis.

Continue to: THE DIAGNOSIS

 

 

THE DIAGNOSIS

Given her benign cardiac work-up and symptom onset coinciding with the abrupt resumption of high doses of aripiprazole after an 8-month abstinence, the patient’s presentation was attributed to a rather uncommon adverse drug reaction to aripiprazole. This has only been described in a few case reports.

DISCUSSION

Aripiprazole (Abilify) is an atypical antipsychotic frequently used in the treatment of psychiatric conditions, including bipolar disorder and schizophrenia. While the specific therapeutic mechanism is unknown, it is believed that drug efficacy is related to partial agonism at dopamine D₂, serotonin 5-HT_1A, and serotonin 5-HT_2A.¹ As aripiprazole works on a variety of receptors involved in other physiologic processes, clinical adverse effects have been reported, most of which are associated with the adrenergic alpha₁ receptors.¹ These include cognitive impairment and seizures. Cardiovascular adverse effects of aripiprazole include orthostatic hypotension, cardiac arrhythmia, prolonged QT interval, and syncope.^1-5

Family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms.

Selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft) have also been shown to cause cardiac arrhythmia and syncope.⁶ Although sertraline may have contributed to the patient’s cardiac symptoms, it is more likely that the aripiprazole was the direct cause, as she remained asymptomatic while on a therapeutic dose of sertraline. Furthermore, aripiprazole is primarily metabolized though hepatic CYP2D6, which sertraline has been shown to inhibit.^1,7 Therefore, the concomitant use of sertraline with no initial taper of either medication likely led to an increased effective dose of aripiprazole in our patient and subsequently to her presentation.

Few prior cases have identified aripiprazole as a cause of antipsychotic-associated bradycardic response.⁸ Based on the Adverse Drug Reaction Probability Scale, often referred to as the Naranjo Scale, we believe this to be a probable adverse response in our patient.⁹ Bradycardia followed a reasonable temporal sequence after aripiprazole use with a response previously described in the literature. Symptoms also improved after discontinuation of the drug and other etiologies of the bradycardia were ruled out.

Our patient was discharged with a 30-day cardiac event monitor and a scheduled appointment with Cardiology.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

As this case suggests, there may be an association between aripiprazole and symptomatic bradycardia. Therefore, family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms and consider tapering this medication if other causes cannot be identified. Additionally, given the potential cardiac adverse effects of atypical antipsychotics, physicians may consider ordering baseline and follow-up EKGs to monitor for arrhythmias in patients prescribed aripiprazole. This may be especially prudent when an atypical antipsychotic is combined with an SSRI, as potential cardiac adverse effects may occur more frequently.

CORRESPONDENCE
Kyle Fletke, MD, Department of Family and Community Medicine, University of Maryland School of Medicine, 29 South Paca Street, Baltimore, MD 21201; kfletke@som.umaryland.edu

THE CASE

A 23-year-old woman with past medical history of bipolar II disorder and a REM-specific seizure disorder that resolved at age 9 presented after a syncopal episode. The patient reported an initial sensation of lightheadedness while at work, which was followed by a syncopal episode with brief (1-2 min) loss of consciousness and a minor head injury.

She denied other prodromal symptoms including chest pain, shortness of breath, ­palpitations, and nausea. She also did not experience convulsions, urinary/bowel incontinence, or confusion upon regaining consciousness.

She denied previous syncopal episodes. However, she reported that, 2 weeks prior, there had been an event similar to that of her presenting complaint. During that episode, she experienced lightheadedness and a fall without loss of consciousness.

The patient had been prescribed a regimen of sertraline 100 mg/d and aripiprazole 10 mg/d to maintain mood stability. She had self-discontinued these medications about 8 months prior to presentation. A recent return of her depressive features had prompted a restart of this regimen 1 week before her first fall, without an initial taper upward.

While in the emergency department, she became bradycardic (heart rate, 38 beats/min) and hypotensive (blood pressure, 70/40 mm Hg). She subsequently became increasingly somnolent and had 1 episode of emesis. An electrocardiogram (EKG) revealed sinus bradycardia without other acute abnormalities (FIGURE).

Blood work including a basic metabolic panel, complete blood count, and cardiac enzymes were all within normal limits. Computed tomography of the head revealed no intracranial pathology. Her vitals were initially unresponsive to a fluid bolus but improved and stabilized after administration of intravenous atropine 0.5 mg.

Aripiprazole was held and sertraline was decreased to 75 mg on hospital Day 1, with close monitoring of her mood. Cardiology was consulted and followed the patient ­during her stay. The patient was monitored on telemetry for 3 days, exhibiting only sinus ­bradycardia with a stable heart rate of 45-55 beats/min. Systolic blood pressures were ­stable within 120 to 130 mm Hg. Transthoracic echocardiogram performed on hospital Day 2 was unremarkable, revealing a normal left ventricular ejection fraction of 65% and no wall motion abnormalities. She had no recurrence of the syncope or emesis.

Continue to: THE DIAGNOSIS

 

 

THE DIAGNOSIS

Given her benign cardiac work-up and symptom onset coinciding with the abrupt resumption of high doses of aripiprazole after an 8-month abstinence, the patient’s presentation was attributed to a rather uncommon adverse drug reaction to aripiprazole. This has only been described in a few case reports.

DISCUSSION

Aripiprazole (Abilify) is an atypical antipsychotic frequently used in the treatment of psychiatric conditions, including bipolar disorder and schizophrenia. While the specific therapeutic mechanism is unknown, it is believed that drug efficacy is related to partial agonism at dopamine D₂, serotonin 5-HT_1A, and serotonin 5-HT_2A.¹ As aripiprazole works on a variety of receptors involved in other physiologic processes, clinical adverse effects have been reported, most of which are associated with the adrenergic alpha₁ receptors.¹ These include cognitive impairment and seizures. Cardiovascular adverse effects of aripiprazole include orthostatic hypotension, cardiac arrhythmia, prolonged QT interval, and syncope.^1-5

Family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms.

Selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft) have also been shown to cause cardiac arrhythmia and syncope.⁶ Although sertraline may have contributed to the patient’s cardiac symptoms, it is more likely that the aripiprazole was the direct cause, as she remained asymptomatic while on a therapeutic dose of sertraline. Furthermore, aripiprazole is primarily metabolized though hepatic CYP2D6, which sertraline has been shown to inhibit.^1,7 Therefore, the concomitant use of sertraline with no initial taper of either medication likely led to an increased effective dose of aripiprazole in our patient and subsequently to her presentation.

Few prior cases have identified aripiprazole as a cause of antipsychotic-associated bradycardic response.⁸ Based on the Adverse Drug Reaction Probability Scale, often referred to as the Naranjo Scale, we believe this to be a probable adverse response in our patient.⁹ Bradycardia followed a reasonable temporal sequence after aripiprazole use with a response previously described in the literature. Symptoms also improved after discontinuation of the drug and other etiologies of the bradycardia were ruled out.

Our patient was discharged with a 30-day cardiac event monitor and a scheduled appointment with Cardiology.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

As this case suggests, there may be an association between aripiprazole and symptomatic bradycardia. Therefore, family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms and consider tapering this medication if other causes cannot be identified. Additionally, given the potential cardiac adverse effects of atypical antipsychotics, physicians may consider ordering baseline and follow-up EKGs to monitor for arrhythmias in patients prescribed aripiprazole. This may be especially prudent when an atypical antipsychotic is combined with an SSRI, as potential cardiac adverse effects may occur more frequently.

CORRESPONDENCE
Kyle Fletke, MD, Department of Family and Community Medicine, University of Maryland School of Medicine, 29 South Paca Street, Baltimore, MD 21201; kfletke@som.umaryland.edu

THE CASE

A 23-year-old woman with past medical history of bipolar II disorder and a REM-specific seizure disorder that resolved at age 9 presented after a syncopal episode. The patient reported an initial sensation of lightheadedness while at work, which was followed by a syncopal episode with brief (1-2 min) loss of consciousness and a minor head injury.

She denied other prodromal symptoms including chest pain, shortness of breath, ­palpitations, and nausea. She also did not experience convulsions, urinary/bowel incontinence, or confusion upon regaining consciousness.

She denied previous syncopal episodes. However, she reported that, 2 weeks prior, there had been an event similar to that of her presenting complaint. During that episode, she experienced lightheadedness and a fall without loss of consciousness.

The patient had been prescribed a regimen of sertraline 100 mg/d and aripiprazole 10 mg/d to maintain mood stability. She had self-discontinued these medications about 8 months prior to presentation. A recent return of her depressive features had prompted a restart of this regimen 1 week before her first fall, without an initial taper upward.

While in the emergency department, she became bradycardic (heart rate, 38 beats/min) and hypotensive (blood pressure, 70/40 mm Hg). She subsequently became increasingly somnolent and had 1 episode of emesis. An electrocardiogram (EKG) revealed sinus bradycardia without other acute abnormalities (FIGURE).

Blood work including a basic metabolic panel, complete blood count, and cardiac enzymes were all within normal limits. Computed tomography of the head revealed no intracranial pathology. Her vitals were initially unresponsive to a fluid bolus but improved and stabilized after administration of intravenous atropine 0.5 mg.

Aripiprazole was held and sertraline was decreased to 75 mg on hospital Day 1, with close monitoring of her mood. Cardiology was consulted and followed the patient ­during her stay. The patient was monitored on telemetry for 3 days, exhibiting only sinus ­bradycardia with a stable heart rate of 45-55 beats/min. Systolic blood pressures were ­stable within 120 to 130 mm Hg. Transthoracic echocardiogram performed on hospital Day 2 was unremarkable, revealing a normal left ventricular ejection fraction of 65% and no wall motion abnormalities. She had no recurrence of the syncope or emesis.

Continue to: THE DIAGNOSIS

 

 

THE DIAGNOSIS

Given her benign cardiac work-up and symptom onset coinciding with the abrupt resumption of high doses of aripiprazole after an 8-month abstinence, the patient’s presentation was attributed to a rather uncommon adverse drug reaction to aripiprazole. This has only been described in a few case reports.

DISCUSSION

Aripiprazole (Abilify) is an atypical antipsychotic frequently used in the treatment of psychiatric conditions, including bipolar disorder and schizophrenia. While the specific therapeutic mechanism is unknown, it is believed that drug efficacy is related to partial agonism at dopamine D₂, serotonin 5-HT_1A, and serotonin 5-HT_2A.¹ As aripiprazole works on a variety of receptors involved in other physiologic processes, clinical adverse effects have been reported, most of which are associated with the adrenergic alpha₁ receptors.¹ These include cognitive impairment and seizures. Cardiovascular adverse effects of aripiprazole include orthostatic hypotension, cardiac arrhythmia, prolonged QT interval, and syncope.^1-5

Family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms.

Selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft) have also been shown to cause cardiac arrhythmia and syncope.⁶ Although sertraline may have contributed to the patient’s cardiac symptoms, it is more likely that the aripiprazole was the direct cause, as she remained asymptomatic while on a therapeutic dose of sertraline. Furthermore, aripiprazole is primarily metabolized though hepatic CYP2D6, which sertraline has been shown to inhibit.^1,7 Therefore, the concomitant use of sertraline with no initial taper of either medication likely led to an increased effective dose of aripiprazole in our patient and subsequently to her presentation.

Few prior cases have identified aripiprazole as a cause of antipsychotic-associated bradycardic response.⁸ Based on the Adverse Drug Reaction Probability Scale, often referred to as the Naranjo Scale, we believe this to be a probable adverse response in our patient.⁹ Bradycardia followed a reasonable temporal sequence after aripiprazole use with a response previously described in the literature. Symptoms also improved after discontinuation of the drug and other etiologies of the bradycardia were ruled out.

Our patient was discharged with a 30-day cardiac event monitor and a scheduled appointment with Cardiology.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

As this case suggests, there may be an association between aripiprazole and symptomatic bradycardia. Therefore, family physicians should inquire about aripiprazole use in patients who present with cardiac symptoms and consider tapering this medication if other causes cannot be identified. Additionally, given the potential cardiac adverse effects of atypical antipsychotics, physicians may consider ordering baseline and follow-up EKGs to monitor for arrhythmias in patients prescribed aripiprazole. This may be especially prudent when an atypical antipsychotic is combined with an SSRI, as potential cardiac adverse effects may occur more frequently.

CORRESPONDENCE
Kyle Fletke, MD, Department of Family and Community Medicine, University of Maryland School of Medicine, 29 South Paca Street, Baltimore, MD 21201; kfletke@som.umaryland.edu

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease.¹ Age-standardized incidence rates of PD in population-based studies in Europe and the United States range from 8.6 to 19.0 per 100,000 individuals, using a strict diagnostic criterion for PD.² The negative impact of PD on health-related quality of life imposes a heavy burden on veterans. According to the US Department of Veterans Affairs (VA) National Parkinson’s Disease Consortium, the VA has as many as 50,000 patients with PD under its care. Because of this demand, the VA has strived to revolutionize available services for veterans with PD and related movement disorders.³

The classic motor symptoms of resting tremors, bradykinesia, postural instability, and rigidity of this progressive neurodegenerative disorder is a significant cause of functional limitations that lead to increased falls and inability to perform activities of daily living that challenges the individual and caregiver. ⁴ Rehabilitation has been considered as an adjuvant to surgical and medical treatments for PD to maximize function and minimize complications. High-intensity multimodal exercise boot camps and therapy that focuses on intensely exercising high-amplitude movements, have been shown to improve motor performance in PD.^5,6 Available evidence has shown that exercise-dependent plasticity is the main mechanism underlying the effects of physiotherapy because it increases synaptic strength and affects neurotransmission.⁷ Although there is no consensus on the optimal approach for rehabilitation, innovative techniques have been proposed and studied. One such approach involves virtual reality (VR), which has begun to attract attention for its potential use during rehabilitation.⁸

VR is a simulated experience created by computer-based technology that grants users access to a virtual environment. There are 2 categories of VR: immersive and nonimmersive. Immersive VR is the most direct experience of virtual environments and usually is implemented through a head-mounted display. These displays have monitors in front of each eye, which can provide monocular or biocular imaging with the most common display being small liquid crystal display (LCD) panels.

Nonimmersive VR typically allows a participant to view a virtual environment by using standard high-resolution monitors rather than a headset or an immersive screen room. Many systems are readily available to the general public as electronic interactive entertainment (ie, video games). Interaction with the virtual world happens through interfaces such as keyboards and controllers while viewing a television or computer monitor. These systems often are more accessible and affordable when compared with immersive VR, although this is changing rapidly.

VR therapy is a noninvasive therapeutic alternative modality for PD. This review aims to study the use of VR to treat PD from a rehabilitative standpoint. Although not the only review on the topic, this systematic review is the first to examine the differences between immersive and nonimmersive VR rehabilitation for PD. VR technology is evolving rapidly and the research behind its clinical applications is steadily growing, especially as accessibility improves. This review also is an updated summary of the current literature on the effectiveness of VR therapy during PD rehabilitation.

Methods

Starting in July 2019, the authors searched several databases (PubMed, Google Scholar, Cochrane, and the Physiotherapy Evidence Database [PEDro]) for articles by using the keyword “Parkinson’s disease” combined with either “virtual reality” or “video games.” To find studies specific to rehabilitation, searches included the additional keyword: “rehabilitation.” After compiling an initial set of 89 articles, titles were reviewed to eliminate duplicates. The authors then read the abstracts to exclude study protocols, systematic reviews, and studies that used VR but did not focus on PD or any therapeutic outcome.

Articles were sorted into immersive or nonimmersive virtual reality categories. To be included as immersive VR, studies had to use any type of VR headset or full-scale VR room. Anything less immersive or similar to a traditional video game was included in the nonimmersive VR category. Articles that met inclusion criteria were selected for the systematic review. Criteria for inclusion in this review were: (1) English language; (2) included a study population focused on PD; (3) used some form of VR therapy; and (4) assessed potential rehabilitation by quantitative outcome measures. Only articles published in peer-reviewed journals were included.

Data were extracted into 2 tables specifically modified for this review: immersive and nonimmersive VR. Extracted data included study author name and publication date, study design, methodologic quality, sample size and group allocation, symptom progression via the Hoehn and Yahr Scale (1 to 5), VR modality, presence of control groups, primary outcomes, and primary findings.

Results

This review is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA).¹⁰ After screening and assessment, 28 articles met inclusion criteria for this review: 7 using immersive VR and 21 using nonimmersive VR (Figure). The immersive studies included 2 RCTs (both with PEDro scores of 5), 1 controlled study with a PEDro score of 5, 1 pre-post pilot study, and 3 cohort studies (Table 2). The nonimmersive studies included 13 RCTs with an average PEDro score of 5.8; 2 pre-post pilot studies, 1 repeated measures study with a historic control, 1 non-RCT, 2 pre-post prospective studies, and 2 cohort studies (1 retrospective and 1 prospective) (Table 3).

Several outcome and assessment tools were used; the most common measures were related to gait, balance, kinematics, and VR feasibility. Studies varied in VR modalities and protocol, ranging from 21 sessions of Nintendo Wii Fit gaming for 7 weeks to 1 session of VR headset use.

Immersive VR

There were fewer immersive VR studies and these studies had lower mean PEDro scores when compared with nonimmersive VR studies. The VR modalities in the immersive studies used a VR headset or a multisensory immersive system that included polarized glasses. All the studies showed positive improvement in primary outcomes with the exception of Ma and colleagues,which showed no difference in success rates or kinematics with moving balls, and only showed improvement in reaching for stationary balls.¹¹ The mean number of participants in the studies was 18.4.

All 7 studies had each participant complete tasks without VR then with the VR therapy. None of the studies compared immersive VR therapy with more conventional therapies. Robles-Garcia and colleagues compared 2 VR groups where the experimental group imitated an avatar’s finger tapping in the VR system while the control group lacked this imitation.¹² The authors found that adding that imitation to the VR group lead to an increase in movement amplitude.

Among the immersive VR studies, only Janeh and colleagues commented on possible adverse effects (AEs) and found that VR was a safe method without AEs of discomfort or simulator sickness.¹³ The other 6 studies did not make any mention or discussion of AEs related to the training.

Nonimmersive VR

VR modalities used in nonimmersive studies included consumer video gaming systems. Nintendo Wii and Microsoft Xbox Kinect were most commonly used. Among the 21 studies, 14 compared VR therapy with a type of traditional exercise (eg, treadmill training, stretching exercises, balance training). The mean number of participants of the studies was 28.3.

Five studies showed a difference between the VR and traditional training groups.^14-18 However, 9 studies showed positive improvement in both groups and found no between-group differences.^19-25 Among the remaining 7 studies, all showed improvement in primary outcomes after adding VR interventional therapy. In 1 RCT, 3 groups were compared (no intervention, Nintendo Wii, and Xbox Kinect) for gait tests, anxiety levels, memory, and attention.²⁶ The authors found that only the Nintendo Wii group showed improvement in outcomes. A prospective cohort study was the only one to compare different doses of VR therapy (10 sessions vs 15 sessions of Nintendo Wii Fit).²⁷ The authors found that both groups demonstrated the same amount of improvement on balance performances with no group effect.

Ten studiesreported no AEs during the training, but also did not define what was considered an AE.^{15,16,19,22-25,27-29} Eight studies did not make any mention of AEs.^{14,17,21,26,27,30-32} Yen and colleagues reported no AEs during training except for the patients’ tendency to fall.²⁰ However, therapists supervised the patients to avoid falls and no falls occurred. Nuic and colleaguesreported 3 serious AEs, unrelated to the training: severe pneumonia (n = 1) and deep-brain stimulation generator replacement (n = 2).³³ During the video game training sessions no specific AEs occurred. Only Pompeu and colleagues defined an AE as any untoward medical occurrence such as convulsion, syncope, dizziness, vertigo, falls, or any medical condition that required hospitalization or disability.³⁴ One researcher registered the occurrence of any AE; however, none occurred during the study period.

Discussion

This systematic review demonstrates that VR therapy is a promising addition to rehabilitation for PD. Evidence supporting VR therapy is limited, but is continually expanding, and current evidence has shown improvement in assessments and rehabilitative outcomes involving PD. Most nonimmersive studies have shown that VR therapy does not lead to better outcomes when compared with traditional therapy but also is not harmful and does provide similar improvement. Immersive VR studies, on the other hand, have not compared therapy with conventional training extensively, and tend to focus more on time for task completion or movement.

There were fewer immersive VR studies than nonimmersive VR studies. This could be because of the increased technological difficulty and demand to correctly execute immersive VR modalities, as well as the—until recently—substantial expense. This might be another reason why the mean PEDro scores for immersive VR RCTs were lower than the mean scores found in nonimmersive RCTs.

Limitations

This review was limited by several factors related to the included studies. A variety of rating scales were used in the immersive and nonimmersive VR studies. Although there was some general overlap with common measurements such as gait, balance, kinematics, and VR feasibility, no studies had the same primary and secondary outcomes. Such heterogeneity in protocols and outcomes limited our ability to draw conclusions from these differing studies. Additionally, the average number of participants of both immersive and nonimmersive studies were small and the statistical significance of findings should be interpreted with caution. Finally, VR devices and systems differed between studies, further limiting comparisons. Although these factors limit this systematic review, we can still identify treatment and research implications. Adequately powered future studies with standardized protocols would further improve the available evidence and support for VR as an intervention.

Conclusions

VR therapy is a promising rehabilitation modality for PD. Additional investigations of VR therapy and PD should include direct comparisons between immersive and nonimmersive VR therapies. It could be hypothesized that the greater immersion and engagement potential of immersive VR would demonstrate greater functional improvement compared with nonimmersive VR, but there is no data to support this for PD. VR therapy for PD appears to be a relatively safe alternative or adjunct to traditional therapy with a potentially positive impact on a variety of symptoms and is growing as an innovative therapeutic approach for PD patients.

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease.¹ Age-standardized incidence rates of PD in population-based studies in Europe and the United States range from 8.6 to 19.0 per 100,000 individuals, using a strict diagnostic criterion for PD.² The negative impact of PD on health-related quality of life imposes a heavy burden on veterans. According to the US Department of Veterans Affairs (VA) National Parkinson’s Disease Consortium, the VA has as many as 50,000 patients with PD under its care. Because of this demand, the VA has strived to revolutionize available services for veterans with PD and related movement disorders.³

The classic motor symptoms of resting tremors, bradykinesia, postural instability, and rigidity of this progressive neurodegenerative disorder is a significant cause of functional limitations that lead to increased falls and inability to perform activities of daily living that challenges the individual and caregiver. ⁴ Rehabilitation has been considered as an adjuvant to surgical and medical treatments for PD to maximize function and minimize complications. High-intensity multimodal exercise boot camps and therapy that focuses on intensely exercising high-amplitude movements, have been shown to improve motor performance in PD.^5,6 Available evidence has shown that exercise-dependent plasticity is the main mechanism underlying the effects of physiotherapy because it increases synaptic strength and affects neurotransmission.⁷ Although there is no consensus on the optimal approach for rehabilitation, innovative techniques have been proposed and studied. One such approach involves virtual reality (VR), which has begun to attract attention for its potential use during rehabilitation.⁸

VR is a simulated experience created by computer-based technology that grants users access to a virtual environment. There are 2 categories of VR: immersive and nonimmersive. Immersive VR is the most direct experience of virtual environments and usually is implemented through a head-mounted display. These displays have monitors in front of each eye, which can provide monocular or biocular imaging with the most common display being small liquid crystal display (LCD) panels.

Nonimmersive VR typically allows a participant to view a virtual environment by using standard high-resolution monitors rather than a headset or an immersive screen room. Many systems are readily available to the general public as electronic interactive entertainment (ie, video games). Interaction with the virtual world happens through interfaces such as keyboards and controllers while viewing a television or computer monitor. These systems often are more accessible and affordable when compared with immersive VR, although this is changing rapidly.

VR therapy is a noninvasive therapeutic alternative modality for PD. This review aims to study the use of VR to treat PD from a rehabilitative standpoint. Although not the only review on the topic, this systematic review is the first to examine the differences between immersive and nonimmersive VR rehabilitation for PD. VR technology is evolving rapidly and the research behind its clinical applications is steadily growing, especially as accessibility improves. This review also is an updated summary of the current literature on the effectiveness of VR therapy during PD rehabilitation.

Methods

Starting in July 2019, the authors searched several databases (PubMed, Google Scholar, Cochrane, and the Physiotherapy Evidence Database [PEDro]) for articles by using the keyword “Parkinson’s disease” combined with either “virtual reality” or “video games.” To find studies specific to rehabilitation, searches included the additional keyword: “rehabilitation.” After compiling an initial set of 89 articles, titles were reviewed to eliminate duplicates. The authors then read the abstracts to exclude study protocols, systematic reviews, and studies that used VR but did not focus on PD or any therapeutic outcome.

Articles were sorted into immersive or nonimmersive virtual reality categories. To be included as immersive VR, studies had to use any type of VR headset or full-scale VR room. Anything less immersive or similar to a traditional video game was included in the nonimmersive VR category. Articles that met inclusion criteria were selected for the systematic review. Criteria for inclusion in this review were: (1) English language; (2) included a study population focused on PD; (3) used some form of VR therapy; and (4) assessed potential rehabilitation by quantitative outcome measures. Only articles published in peer-reviewed journals were included.

Data were extracted into 2 tables specifically modified for this review: immersive and nonimmersive VR. Extracted data included study author name and publication date, study design, methodologic quality, sample size and group allocation, symptom progression via the Hoehn and Yahr Scale (1 to 5), VR modality, presence of control groups, primary outcomes, and primary findings.

Results

This review is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA).¹⁰ After screening and assessment, 28 articles met inclusion criteria for this review: 7 using immersive VR and 21 using nonimmersive VR (Figure). The immersive studies included 2 RCTs (both with PEDro scores of 5), 1 controlled study with a PEDro score of 5, 1 pre-post pilot study, and 3 cohort studies (Table 2). The nonimmersive studies included 13 RCTs with an average PEDro score of 5.8; 2 pre-post pilot studies, 1 repeated measures study with a historic control, 1 non-RCT, 2 pre-post prospective studies, and 2 cohort studies (1 retrospective and 1 prospective) (Table 3).

Several outcome and assessment tools were used; the most common measures were related to gait, balance, kinematics, and VR feasibility. Studies varied in VR modalities and protocol, ranging from 21 sessions of Nintendo Wii Fit gaming for 7 weeks to 1 session of VR headset use.

Immersive VR

There were fewer immersive VR studies and these studies had lower mean PEDro scores when compared with nonimmersive VR studies. The VR modalities in the immersive studies used a VR headset or a multisensory immersive system that included polarized glasses. All the studies showed positive improvement in primary outcomes with the exception of Ma and colleagues,which showed no difference in success rates or kinematics with moving balls, and only showed improvement in reaching for stationary balls.¹¹ The mean number of participants in the studies was 18.4.

All 7 studies had each participant complete tasks without VR then with the VR therapy. None of the studies compared immersive VR therapy with more conventional therapies. Robles-Garcia and colleagues compared 2 VR groups where the experimental group imitated an avatar’s finger tapping in the VR system while the control group lacked this imitation.¹² The authors found that adding that imitation to the VR group lead to an increase in movement amplitude.

Among the immersive VR studies, only Janeh and colleagues commented on possible adverse effects (AEs) and found that VR was a safe method without AEs of discomfort or simulator sickness.¹³ The other 6 studies did not make any mention or discussion of AEs related to the training.

Nonimmersive VR

VR modalities used in nonimmersive studies included consumer video gaming systems. Nintendo Wii and Microsoft Xbox Kinect were most commonly used. Among the 21 studies, 14 compared VR therapy with a type of traditional exercise (eg, treadmill training, stretching exercises, balance training). The mean number of participants of the studies was 28.3.

Five studies showed a difference between the VR and traditional training groups.^14-18 However, 9 studies showed positive improvement in both groups and found no between-group differences.^19-25 Among the remaining 7 studies, all showed improvement in primary outcomes after adding VR interventional therapy. In 1 RCT, 3 groups were compared (no intervention, Nintendo Wii, and Xbox Kinect) for gait tests, anxiety levels, memory, and attention.²⁶ The authors found that only the Nintendo Wii group showed improvement in outcomes. A prospective cohort study was the only one to compare different doses of VR therapy (10 sessions vs 15 sessions of Nintendo Wii Fit).²⁷ The authors found that both groups demonstrated the same amount of improvement on balance performances with no group effect.

Ten studiesreported no AEs during the training, but also did not define what was considered an AE.^{15,16,19,22-25,27-29} Eight studies did not make any mention of AEs.^{14,17,21,26,27,30-32} Yen and colleagues reported no AEs during training except for the patients’ tendency to fall.²⁰ However, therapists supervised the patients to avoid falls and no falls occurred. Nuic and colleaguesreported 3 serious AEs, unrelated to the training: severe pneumonia (n = 1) and deep-brain stimulation generator replacement (n = 2).³³ During the video game training sessions no specific AEs occurred. Only Pompeu and colleagues defined an AE as any untoward medical occurrence such as convulsion, syncope, dizziness, vertigo, falls, or any medical condition that required hospitalization or disability.³⁴ One researcher registered the occurrence of any AE; however, none occurred during the study period.

Discussion

This systematic review demonstrates that VR therapy is a promising addition to rehabilitation for PD. Evidence supporting VR therapy is limited, but is continually expanding, and current evidence has shown improvement in assessments and rehabilitative outcomes involving PD. Most nonimmersive studies have shown that VR therapy does not lead to better outcomes when compared with traditional therapy but also is not harmful and does provide similar improvement. Immersive VR studies, on the other hand, have not compared therapy with conventional training extensively, and tend to focus more on time for task completion or movement.

There were fewer immersive VR studies than nonimmersive VR studies. This could be because of the increased technological difficulty and demand to correctly execute immersive VR modalities, as well as the—until recently—substantial expense. This might be another reason why the mean PEDro scores for immersive VR RCTs were lower than the mean scores found in nonimmersive RCTs.

Limitations

This review was limited by several factors related to the included studies. A variety of rating scales were used in the immersive and nonimmersive VR studies. Although there was some general overlap with common measurements such as gait, balance, kinematics, and VR feasibility, no studies had the same primary and secondary outcomes. Such heterogeneity in protocols and outcomes limited our ability to draw conclusions from these differing studies. Additionally, the average number of participants of both immersive and nonimmersive studies were small and the statistical significance of findings should be interpreted with caution. Finally, VR devices and systems differed between studies, further limiting comparisons. Although these factors limit this systematic review, we can still identify treatment and research implications. Adequately powered future studies with standardized protocols would further improve the available evidence and support for VR as an intervention.

Conclusions

VR therapy is a promising rehabilitation modality for PD. Additional investigations of VR therapy and PD should include direct comparisons between immersive and nonimmersive VR therapies. It could be hypothesized that the greater immersion and engagement potential of immersive VR would demonstrate greater functional improvement compared with nonimmersive VR, but there is no data to support this for PD. VR therapy for PD appears to be a relatively safe alternative or adjunct to traditional therapy with a potentially positive impact on a variety of symptoms and is growing as an innovative therapeutic approach for PD patients.

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease.¹ Age-standardized incidence rates of PD in population-based studies in Europe and the United States range from 8.6 to 19.0 per 100,000 individuals, using a strict diagnostic criterion for PD.² The negative impact of PD on health-related quality of life imposes a heavy burden on veterans. According to the US Department of Veterans Affairs (VA) National Parkinson’s Disease Consortium, the VA has as many as 50,000 patients with PD under its care. Because of this demand, the VA has strived to revolutionize available services for veterans with PD and related movement disorders.³

The classic motor symptoms of resting tremors, bradykinesia, postural instability, and rigidity of this progressive neurodegenerative disorder is a significant cause of functional limitations that lead to increased falls and inability to perform activities of daily living that challenges the individual and caregiver. ⁴ Rehabilitation has been considered as an adjuvant to surgical and medical treatments for PD to maximize function and minimize complications. High-intensity multimodal exercise boot camps and therapy that focuses on intensely exercising high-amplitude movements, have been shown to improve motor performance in PD.^5,6 Available evidence has shown that exercise-dependent plasticity is the main mechanism underlying the effects of physiotherapy because it increases synaptic strength and affects neurotransmission.⁷ Although there is no consensus on the optimal approach for rehabilitation, innovative techniques have been proposed and studied. One such approach involves virtual reality (VR), which has begun to attract attention for its potential use during rehabilitation.⁸

VR is a simulated experience created by computer-based technology that grants users access to a virtual environment. There are 2 categories of VR: immersive and nonimmersive. Immersive VR is the most direct experience of virtual environments and usually is implemented through a head-mounted display. These displays have monitors in front of each eye, which can provide monocular or biocular imaging with the most common display being small liquid crystal display (LCD) panels.

Nonimmersive VR typically allows a participant to view a virtual environment by using standard high-resolution monitors rather than a headset or an immersive screen room. Many systems are readily available to the general public as electronic interactive entertainment (ie, video games). Interaction with the virtual world happens through interfaces such as keyboards and controllers while viewing a television or computer monitor. These systems often are more accessible and affordable when compared with immersive VR, although this is changing rapidly.

VR therapy is a noninvasive therapeutic alternative modality for PD. This review aims to study the use of VR to treat PD from a rehabilitative standpoint. Although not the only review on the topic, this systematic review is the first to examine the differences between immersive and nonimmersive VR rehabilitation for PD. VR technology is evolving rapidly and the research behind its clinical applications is steadily growing, especially as accessibility improves. This review also is an updated summary of the current literature on the effectiveness of VR therapy during PD rehabilitation.

Methods

Starting in July 2019, the authors searched several databases (PubMed, Google Scholar, Cochrane, and the Physiotherapy Evidence Database [PEDro]) for articles by using the keyword “Parkinson’s disease” combined with either “virtual reality” or “video games.” To find studies specific to rehabilitation, searches included the additional keyword: “rehabilitation.” After compiling an initial set of 89 articles, titles were reviewed to eliminate duplicates. The authors then read the abstracts to exclude study protocols, systematic reviews, and studies that used VR but did not focus on PD or any therapeutic outcome.

Articles were sorted into immersive or nonimmersive virtual reality categories. To be included as immersive VR, studies had to use any type of VR headset or full-scale VR room. Anything less immersive or similar to a traditional video game was included in the nonimmersive VR category. Articles that met inclusion criteria were selected for the systematic review. Criteria for inclusion in this review were: (1) English language; (2) included a study population focused on PD; (3) used some form of VR therapy; and (4) assessed potential rehabilitation by quantitative outcome measures. Only articles published in peer-reviewed journals were included.

Data were extracted into 2 tables specifically modified for this review: immersive and nonimmersive VR. Extracted data included study author name and publication date, study design, methodologic quality, sample size and group allocation, symptom progression via the Hoehn and Yahr Scale (1 to 5), VR modality, presence of control groups, primary outcomes, and primary findings.

Results

This review is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA).¹⁰ After screening and assessment, 28 articles met inclusion criteria for this review: 7 using immersive VR and 21 using nonimmersive VR (Figure). The immersive studies included 2 RCTs (both with PEDro scores of 5), 1 controlled study with a PEDro score of 5, 1 pre-post pilot study, and 3 cohort studies (Table 2). The nonimmersive studies included 13 RCTs with an average PEDro score of 5.8; 2 pre-post pilot studies, 1 repeated measures study with a historic control, 1 non-RCT, 2 pre-post prospective studies, and 2 cohort studies (1 retrospective and 1 prospective) (Table 3).

Several outcome and assessment tools were used; the most common measures were related to gait, balance, kinematics, and VR feasibility. Studies varied in VR modalities and protocol, ranging from 21 sessions of Nintendo Wii Fit gaming for 7 weeks to 1 session of VR headset use.

Immersive VR

There were fewer immersive VR studies and these studies had lower mean PEDro scores when compared with nonimmersive VR studies. The VR modalities in the immersive studies used a VR headset or a multisensory immersive system that included polarized glasses. All the studies showed positive improvement in primary outcomes with the exception of Ma and colleagues,which showed no difference in success rates or kinematics with moving balls, and only showed improvement in reaching for stationary balls.¹¹ The mean number of participants in the studies was 18.4.

All 7 studies had each participant complete tasks without VR then with the VR therapy. None of the studies compared immersive VR therapy with more conventional therapies. Robles-Garcia and colleagues compared 2 VR groups where the experimental group imitated an avatar’s finger tapping in the VR system while the control group lacked this imitation.¹² The authors found that adding that imitation to the VR group lead to an increase in movement amplitude.

Among the immersive VR studies, only Janeh and colleagues commented on possible adverse effects (AEs) and found that VR was a safe method without AEs of discomfort or simulator sickness.¹³ The other 6 studies did not make any mention or discussion of AEs related to the training.

Nonimmersive VR

VR modalities used in nonimmersive studies included consumer video gaming systems. Nintendo Wii and Microsoft Xbox Kinect were most commonly used. Among the 21 studies, 14 compared VR therapy with a type of traditional exercise (eg, treadmill training, stretching exercises, balance training). The mean number of participants of the studies was 28.3.

Five studies showed a difference between the VR and traditional training groups.^14-18 However, 9 studies showed positive improvement in both groups and found no between-group differences.^19-25 Among the remaining 7 studies, all showed improvement in primary outcomes after adding VR interventional therapy. In 1 RCT, 3 groups were compared (no intervention, Nintendo Wii, and Xbox Kinect) for gait tests, anxiety levels, memory, and attention.²⁶ The authors found that only the Nintendo Wii group showed improvement in outcomes. A prospective cohort study was the only one to compare different doses of VR therapy (10 sessions vs 15 sessions of Nintendo Wii Fit).²⁷ The authors found that both groups demonstrated the same amount of improvement on balance performances with no group effect.

Ten studiesreported no AEs during the training, but also did not define what was considered an AE.^{15,16,19,22-25,27-29} Eight studies did not make any mention of AEs.^{14,17,21,26,27,30-32} Yen and colleagues reported no AEs during training except for the patients’ tendency to fall.²⁰ However, therapists supervised the patients to avoid falls and no falls occurred. Nuic and colleaguesreported 3 serious AEs, unrelated to the training: severe pneumonia (n = 1) and deep-brain stimulation generator replacement (n = 2).³³ During the video game training sessions no specific AEs occurred. Only Pompeu and colleagues defined an AE as any untoward medical occurrence such as convulsion, syncope, dizziness, vertigo, falls, or any medical condition that required hospitalization or disability.³⁴ One researcher registered the occurrence of any AE; however, none occurred during the study period.

Discussion

This systematic review demonstrates that VR therapy is a promising addition to rehabilitation for PD. Evidence supporting VR therapy is limited, but is continually expanding, and current evidence has shown improvement in assessments and rehabilitative outcomes involving PD. Most nonimmersive studies have shown that VR therapy does not lead to better outcomes when compared with traditional therapy but also is not harmful and does provide similar improvement. Immersive VR studies, on the other hand, have not compared therapy with conventional training extensively, and tend to focus more on time for task completion or movement.

There were fewer immersive VR studies than nonimmersive VR studies. This could be because of the increased technological difficulty and demand to correctly execute immersive VR modalities, as well as the—until recently—substantial expense. This might be another reason why the mean PEDro scores for immersive VR RCTs were lower than the mean scores found in nonimmersive RCTs.

Limitations

This review was limited by several factors related to the included studies. A variety of rating scales were used in the immersive and nonimmersive VR studies. Although there was some general overlap with common measurements such as gait, balance, kinematics, and VR feasibility, no studies had the same primary and secondary outcomes. Such heterogeneity in protocols and outcomes limited our ability to draw conclusions from these differing studies. Additionally, the average number of participants of both immersive and nonimmersive studies were small and the statistical significance of findings should be interpreted with caution. Finally, VR devices and systems differed between studies, further limiting comparisons. Although these factors limit this systematic review, we can still identify treatment and research implications. Adequately powered future studies with standardized protocols would further improve the available evidence and support for VR as an intervention.

Conclusions

VR therapy is a promising rehabilitation modality for PD. Additional investigations of VR therapy and PD should include direct comparisons between immersive and nonimmersive VR therapies. It could be hypothesized that the greater immersion and engagement potential of immersive VR would demonstrate greater functional improvement compared with nonimmersive VR, but there is no data to support this for PD. VR therapy for PD appears to be a relatively safe alternative or adjunct to traditional therapy with a potentially positive impact on a variety of symptoms and is growing as an innovative therapeutic approach for PD patients.

Surgical treatment of degenerative lumbar spine disease has been rising steadily in the United States, and an increasing fraction of surgery involves lumbar fusion.^1,2 Various techniques are used to accomplish a lumbar fusion, including noninstrumented fusion, anterior lumbar interbody fusion (ALIF), lateral lumbar interbody fusion (XLIF, OLIF), posterior pedicle screw fusion, posterior cortical screw fusion, posterior interbody fusion (TLIF, PLIF), and interspinous process fusion. Rigid, metallic fusion hardware provides high stability and fusion rates, but it likely leads to stress shielding and adjacent segment disease.³ There is interest in less rigid and dynamic stabilization techniques to reduce the risk of adjacent segment disease, such as polyetheretherketone (PEEK) rods, which have been available since 2007. However, literature regarding PEEK rod utility is sparse and of mixed outcomes.^3,4 Additional patient reported outcome (PRO) information would be useful to both surgeons and patients. Using institutional data, this review was designed to examine our experience with PEEK rod lumbar fusion and to document PROs.

Methods

The study was approved by the institutional review board at the US Department of Veterans Affairs (VA) Portland Health Care System (VAPHCS) in Oregon with a waiver of authorization. In this retrospective, single center study, data were queried from the senior author’s (DAR) case logs from VA Computerized Patient Record System (CPRS). Electronic medical records, imaging, and PROs of all consecutive patients undergoing lumbar fusion at 1 or 2 levels with PEEK rods for degenerative disease were retrospectively reviewed. Cases of trauma, malignancy, or infection were excluded. From March 2011 through October 2019, 108 patients underwent lumbar fusion with PEEK rods.

Surgeries were conducted on a Mizuho OSI Jackson Table via bilateral 3 to 4 cm Wiltse incisions using the Medtronic Quadrant retractor system. Medtronic O-Arm images were acquired and delivered to a Medtronic Stealth Station for navigation of the screws. Monopolar coagulation was not used. PEEK pedicle screws were placed and verified with a second O-Arm spin before placing lordotic PEEK rods in the screw heads. No attempt was made to reduce any spondylolisthesis, but distraction was used to open the foramina and indirectly decompress the canal. An interbody device was placed only in treatment of multiply recurrent disc protrusion. After decortication of the transverse processes and facets, intertransverse fusion constructs consisting of calcium hydroxyapatite soaked in autologous bone marrow blood and wrapped in 6-mg bone morphogenetic protein-soaked sponges were placed on the bone. If canal decompression was indicated, a Medtronic Metrx retractor tube was then placed through one of the incisions and decompression carried out. Wounds were closed with absorbable suture. No bracing was used postoperatively. Figure 1 shows a typical single level PEEK rod fusion construct.

Statistical Analysis

Pre- and postoperative pairwise t tests were completed for patients with a complete data, using SAS 9.2 statistical package. Data are presented as standard deviation (SD) of the mean.

Results

Following application of the inclusion/exclusion criteria, 108 patients had undergone lumbar fusion with PEEK rods. Mean (SD) patient age was 60.2 (10.3) years and 88 patients were male (Table 1). Most surgeries were at L5-S1 and L4-5. There were 97 single-level fusions and 11 bilevel fusions. Seventy-four procedures were for spondylolisthesis, 23 for foraminal stenosis, 5 for degenerative disc disease, 3 for coronal imbalance with foraminal stenosis, 2 for pseudarthrosis after surgery elsewhere, and 1 for multiple recurrent disc herniation (Table 2). Twenty-five patients (23.1%) were current tobacco users and 28 (25.9%) were former smokers, 26 (24.1%) had diabetes mellitus (DM), 16 (14.8%) had low bone density by dual energy X-ray absorptiometry (DEXA) imaging, 35 (32.4%) had depression, and 7 (6.5%) were taking an immunosuppressive agent (chronic steroids, biological response modifiers, or methotrexate). Mean body mass index was 30.1.

Surgical Procedure

Of the 108 patients, the first 18 underwent a procedure with fluoroscopic guidance and the Medtronic FluoroNav and Stealth Systems. The next 90 patients underwent a procedure with O-Arm intraoperative CT scanning and Stealth frameless stereotactic navigation. The mean (SD) length of stay was 1.7 (1.3) days. There were no wound infections and no new neurologic deficits. Mean (SD) follow up time was 30.3 (21.8) months.

Imaging

Final imaging was by radiograph in 73 patients, CT in 31, and magnetic resonance imaging (MRI) in 3 (1 patient had no imaging). Sixty-seven patients (62.0%) had a bilateral arthrodesis, and 15 (13.9%) had at least a unilateral arthrodesis. MRI was not used to assess arthrodesis. Eight patients (7.4%) had no definite arthrodesis. Seventeen patients had inadequate or early imaging from which a fusion determination could not be made. Of 81 patients with > 11 months of follow up, 58 (71.6%) had a bilateral arthrodesis, 12 (14.8%) had a unilateral arthrodesis, 8 (9.9%) had no arthrodesis, and 3 (3.7%) were indeterminate.

No patient had any revision fusion surgery at the index level during follow up. Two patients had adjacent level fusions at 27 and 60 months after the index procedure. One patient had a laminectomy at an adjacent segment at 18 months postfusion, and 1 had a foraminotomy at an adjacent segment 89 months post fusion (Figure 3). Overall, there were 4 (3.7%) adjacent segment surgeries at a mean of 48.5 months after surgery. One patient had a sacro-iliac joint fusion below an L5-S1 fusion 17 months prior for persisting pain after the fusion procedure.

Patient Reported Outcomes

Preoperative SF-36 PF and ODI scores were available for 81 patients (Table 3). Postoperative SF-36 PF scores were obtained at 3 months for 65 of these patients, and at 1 year for 63 patients. Postoperative ODI scores were obtained at 3 months for 65 patients, and at 1 year for 55 patients. Among the 65 patients with completed SF-36 scores at 3 months, a mean increase of 22.4 (95% CI, 17-27; P < .001) was noted, and for the 63 patients at 1 year a mean increase of 30.3 (95% CI, 25-35; P < .001) was noted. Among the 65 patients with completed ODI scores at 3 months, a mean decrease of 6.8 (95% CI, 4.9-8.6; P < .001) was noted, and for the 55 patients with completed ODI scores at 1 year a mean decrease of 10.3 (n = 55; 95% CI, 8.4-12.2; P < .001) was noted.

Cost

We compared the hardware cost of a single level construct consisting of 4 pedicle screws, 4 locking caps, and 2 rods using a PEEK system with that of 2 other titanium construct systems. At VAPHCS, the PEEK system cost was about 71% of the cost of 2 other titanium construct systems and 62% of the cost when compared with Medtronic titanium rods.

Discussion

PEEK is useful for spine and cranial implants. It is inert and fully biocompatible with a modulus of elasticity between that of cortical and cancellous bone, and much lower than that of titanium, and is therefore considered to be semirigid.^3,4,6 PEEK rods are intermediate in stiffness between titanium rods (110 Gigapascals) and dynamic devices such as the Zimmer Biomet DYNESYS dynamic stabilization system or the Premia Spine TOPS system.³ Carbon fiber rods and carbon fiber reinforced PEEK implants are other semirigid rod alternatives.^7,8 PEEK rods for posterior lumbar fusion surgery were introduced in 2007. Li and colleagues provide a thorough review of the biomechanical properties of PEEK rods.³

PEEK is thought to have several advantages when compared with titanium. These advantages include more physiologic load sharing and reduction in stress shielding, improved durability, reduced risk of failure in osteoporotic bone, less wear debris, no change in bone forming environment, and imaging radiolucency.^4,9 Spinal PEEK cages have been reported to allow more uniform radiation dose distribution compared with metal constructs, an advantage that also may pertain to PEEK rods.¹⁰ Disadvantages of PEEK rods include an inability to detect rod breakage easily, lack of data on the use in more than minimally unstable clinical situations, and greater expense, although this was not the authors’ observation.^3,4,11

Importantly, it has been reported that PEEK rods permit a greater range of motion in all planes when compared with titanium rods.⁹ Polyetheretherketone rods unload the bone screw interface and increased the anterior column load to a more physiologic 75% when compared with titanium rods.^6,9 However, in another biomechanical study that compared titanium rods, PEEK rods, and a dynamic stabilization device, it was reported that anterior load sharing was 55%, 59%, and 75%, respectively.¹² This indicated that PEEK rods are closer to metal rods than truly dynamic devices for anterior load sharing. The endurance limit of a PEEK rod construct was similar to that of clinically useful metal systems.⁹ PEEK rods resulted in no increase in postfatigue motion compared with titanium rods in a biomechanical model.¹³ Intradiscal pressures at PEEK instrumented segments were similar to uninstrumented segments and greater than those with titanium rod constructs.¹⁴ Intradiscal pressures at adjacent segments were highest with dynamic devices, intermediate with semirigid rods, and lowest with rigid constructs; however, stress values at adjacent segments were lower in PEEK than titanium constructs in any direction of motion.^15,16

Fusion Rates

The use of PEEK rods in lumbar fusion has been reported previously.^3,4,17,18 However, these studies featured small sample sizes, short follow up times, and contradictory results.⁴ Of 8 outcome reports found in a systematic review, 2 studies reported on procedures designed to create nonfusion outcomes (a third similar trial from 2013 was not included in the systematic review), and 1 study reported only on the condition of PEEK rods removed at subsequent surgery.^3,19-21 Reported fusion rates varied from 86 to 100%.

In 42 patients with PEEK rod fusions who were followed for a mean of 31.4 months, 5 patients required adjacent segment surgery and 3 patients were treated for interbody cage migration and nonunion.¹⁷ Radiographic fusion rate was 86%. These authors concluded that PEEK rod fusion results were similar to those of other constructs, but not better, or perhaps worse than, metal rods.

Other studies have reported better results with PEEK.^{11,18,19,22-24} Highsmith and colleagues reported on 3 successful example cases of the use of PEEK rods.¹¹ De Iure and colleagues reported on 30 cases up to 5 levels (mean, 2.9) using autograft bone, with a mean follow up of 18 months.²³ Results were reported as satisfactory. Three patients had radiographic nonunions, 1 of which required revision for asymptomatic screw loosening at the cranial end of the construct. Qi and colleagues, reported on 20 patients with PEEK rods compared to 21 patients with titanium alloy rods.²⁴ Both groups had similar clinical outcomes, structural parameters, and 100% fusion rates. Athanasakopoulos and colleagues reported on 52 patients with up to 3 level fusions followed for a mean of 3 years.²² There were significant improvements in PROs: at 1 year 96% had radiographic union. Two patients had screw breakage, 1 of whom required revision to a metal rod construct. Colangeli and colleagues reported on 12 patients treated with PEEK rods compared with 12 who were treated with a dynamic system.¹⁸ They reported significant improvements, no complications, and 100% fusion at 6 months. Huang and colleagues reported on 38 patients intended to undergo a nonfusion procedure with 2 years of follow up.¹⁹ They reported good outcomes and 1 case of screw loosening. As no fusion was intended, no fusion outcomes were reported. All these studies suggested that longer follow up and more patients would be needed to assess the role of PEEK rods in lumbar fusion.³

Our results show a radiographic fusion rate of 86.4% and a radiographic nonunion rate of 9.9% in patients followed for at least 12 months. There was no clinical need for revision fusion at the index level. In our retrospective review, patients had high levels of smoking, DM, depression, immunosuppression, and obesity, which may negatively influence radiographic fusion rates when compared with other studies with 100% reported fusion rates. There was no instance of construct breakage or screw breakout, indicating that PEEK rods may allow enough flexibility to avoid construct failure under stress as in a fall.

Patient Reported Outcomes

Recent large studies were reviewed to assess the pre- and postoperative patient PROs reported in comparison with our study population (Table 4). In the Swedish Spine Registry analysis of 765 patients with 3 different types of lumbar fusion, the mean preoperative ODI score was 37 and mean SF-36 physical component score (PCS) was 35 for the most similar approach (posterolateral fusion with instrumentation).²⁵ At 1 year postoperation, the mean ODI was 26 and mean SF-36 PCS was 43. In the Spine Patient Outcomes Research Trial (SPORT) spondylolisthesis trial of 3 fusion types, the mean preoperative ODI was 41.2 and mean SF-36 PF score was 31.2 for the most similar approach (posterolateral instrumented fusion with pedicle screws).²⁶ Postoperative ODI scores at 1 year decreased by a mean 20.9 points and mean SF-36 PF scores increased by 29.9.

We report a mean preoperative SF-36 PF score of 28.9, which is lower than the SPORT study score for posterolateral fusion with instrumentation and the Swedish Study score for posterolateral instrumented fusion with pedicle screws. Similarly, our mean ODI score of 24.8 was better than the scores reported in the Swedish and SPORT studies. Our mean SF-36 PF score at 1 year postoperation was 59.3, compared with 58.5 for the SPORT study group and 46.0 in the Swedish study group. Mean ODI score at 1 year postoperatively was 14.5, which is better than the scores reported in the Swedish and SPORT studies.

Minimally clinically important difference (MCID) is a parameter used to gauge the efficacy of spine surgery. The utility of the MCID based upon PROs has been questioned in lumbar fusion surgery, as it has been thought to measure if the patient is “feeling” rather than “doing” better, the latter of which can be better measured by functional performance measures and objective, external socioeconomic anchors such as return to work and health care costs.²⁷ Nevertheless, validated PROs are reported widely in the spine surgery literature. The MCID in the SF-36 is not well established and can depend upon whether the scores are at the extremes or more in the central range and whether there is large variability in the scores.²⁸ Rheumatoid arthritis was estimated to be 7.1 points on the PF scale and 7.2 on the physical component summary (PCS).²⁹ For total knee replacement, it has been estimated to be 10 points on the SF-36 PCS.³⁰ Lumbar surgery was estimated to be 4.9 points for the SF-36 PCS and 12.8 points for the ODI.³¹ And the SPORT trial it has been estimated that a 30% change in the possible gain (or loss) may be an appropriate criterion.²⁸

With a preoperative mean SF-36 PF of 28.9, a 30% improvement in the available range (70.1) would be 21 points, making our data mean improvement of 30 points above the MCID. With a mean preoperative ODI of 24.6, a 30% improvement in the available range (25.4) would be 7.6 points, making our data mean improvement of 10.3 points better than the MCID. Therefore, our outcome results are comparable with other lumbar fusion outcome studies in terms of degree of disability prior to surgery and amount of improvement from surgery.

Adjacent Segment Disease

The precise factors resulting in adjacent segment disease are not fully defined.^3,32 In reviews of lumbar adjacent segment disease, reported rates ranged from 2.5% at 1 year up to 80 to 100% at 10 years, with lower rates with noninstrumented fusions.^4,32-34 Annual incidence of symptomatic adjacent segment disease following lumbar fusion ranges from 0.6 to 3.9% per year.^32,35,36 Mismatch between lumbar lordosis and pelvic incidence after fusion is thought to lead to higher rates of adjacent segment disease, as can a laminectomy at an adjacent segment.^32,36 Percutaneous fusion techniques or use of the Wiltse approach may lower the risk of adjacent segment disease due to avoidance of facet capsule disruption.^37,38

Dynamic stabilization techniques do not appear be clearly protective against adjacent segment disease, although biomechanical models suggest that they may do so.^33,39,40 A review by Wang and colleagues pooled studies to assess the risk of lumbar adjacent segment disease in spinal fusion to compare to disc arthroplasty and concluded that fusion carried a higher risk of adjacent segment disease.⁴¹ Definitive data on other types of motion preservation devices is lacking.³We show 3 adjacent segment fusions and 1 laminectomy have been needed in 108 patients and at a mean of 46 months after the index procedure and over 2.5 years of mean overall follow up. This is a low adjacent segment surgery rate compared to the historical data cited above, and may suggest some advantage for PEEK rods over more rigid constructs.

Strengths and Limitations

Strengths of this study include larger numbers than prior series of PEEK rod use and use in a population with high comorbidities linked to poor results without reduction in good outcomes. PEEK rods as used at the VAPHCS do not result in higher instrumentation costs than all metal constructs.

Study limitations include the retrospective nature with loss of follow up on some patients and incomplete radiographic and PROs in some patients. The use of 100% stereotactic guidance, the avoidance of interbody devices, and the off-label use of bone morphogenetic protein as part of the fusion construct introduce additional variables that may influence comparison to other studies. To avoid unnecessary radiation exposure, flexion extension films or CT scans were not routinely obtained if patients were doing well.⁴² Additionally, the degree of motion on dynamic views that would differentiate pseudarthrosis from arthrodesis has not been defined.⁵

Conclusions

The results presented show that lumbar fusion with PEEK rods can be undertaken with short hospitalization times and low complication rates, produce satisfactory clinical improvements, and result in radiographic fusion rates similar to metal constructs. Low rates of hardware failure or need for revision surgery were found. Preliminarily results of low rates of adjacent segment surgery are comparable with previously published metal construct rates. Longer follow up is needed to confirm these findings and to investigate whether semirigid constructs truly offer some protection from adjacent segment disease when compared to all metal constructs.

Acknowledgments
The authors thank Shirley McCartney, PhD, for editorial assistance.

Surgical treatment of degenerative lumbar spine disease has been rising steadily in the United States, and an increasing fraction of surgery involves lumbar fusion.^1,2 Various techniques are used to accomplish a lumbar fusion, including noninstrumented fusion, anterior lumbar interbody fusion (ALIF), lateral lumbar interbody fusion (XLIF, OLIF), posterior pedicle screw fusion, posterior cortical screw fusion, posterior interbody fusion (TLIF, PLIF), and interspinous process fusion. Rigid, metallic fusion hardware provides high stability and fusion rates, but it likely leads to stress shielding and adjacent segment disease.³ There is interest in less rigid and dynamic stabilization techniques to reduce the risk of adjacent segment disease, such as polyetheretherketone (PEEK) rods, which have been available since 2007. However, literature regarding PEEK rod utility is sparse and of mixed outcomes.^3,4 Additional patient reported outcome (PRO) information would be useful to both surgeons and patients. Using institutional data, this review was designed to examine our experience with PEEK rod lumbar fusion and to document PROs.

Methods

The study was approved by the institutional review board at the US Department of Veterans Affairs (VA) Portland Health Care System (VAPHCS) in Oregon with a waiver of authorization. In this retrospective, single center study, data were queried from the senior author’s (DAR) case logs from VA Computerized Patient Record System (CPRS). Electronic medical records, imaging, and PROs of all consecutive patients undergoing lumbar fusion at 1 or 2 levels with PEEK rods for degenerative disease were retrospectively reviewed. Cases of trauma, malignancy, or infection were excluded. From March 2011 through October 2019, 108 patients underwent lumbar fusion with PEEK rods.

Surgeries were conducted on a Mizuho OSI Jackson Table via bilateral 3 to 4 cm Wiltse incisions using the Medtronic Quadrant retractor system. Medtronic O-Arm images were acquired and delivered to a Medtronic Stealth Station for navigation of the screws. Monopolar coagulation was not used. PEEK pedicle screws were placed and verified with a second O-Arm spin before placing lordotic PEEK rods in the screw heads. No attempt was made to reduce any spondylolisthesis, but distraction was used to open the foramina and indirectly decompress the canal. An interbody device was placed only in treatment of multiply recurrent disc protrusion. After decortication of the transverse processes and facets, intertransverse fusion constructs consisting of calcium hydroxyapatite soaked in autologous bone marrow blood and wrapped in 6-mg bone morphogenetic protein-soaked sponges were placed on the bone. If canal decompression was indicated, a Medtronic Metrx retractor tube was then placed through one of the incisions and decompression carried out. Wounds were closed with absorbable suture. No bracing was used postoperatively. Figure 1 shows a typical single level PEEK rod fusion construct.

Statistical Analysis

Pre- and postoperative pairwise t tests were completed for patients with a complete data, using SAS 9.2 statistical package. Data are presented as standard deviation (SD) of the mean.

Results

Following application of the inclusion/exclusion criteria, 108 patients had undergone lumbar fusion with PEEK rods. Mean (SD) patient age was 60.2 (10.3) years and 88 patients were male (Table 1). Most surgeries were at L5-S1 and L4-5. There were 97 single-level fusions and 11 bilevel fusions. Seventy-four procedures were for spondylolisthesis, 23 for foraminal stenosis, 5 for degenerative disc disease, 3 for coronal imbalance with foraminal stenosis, 2 for pseudarthrosis after surgery elsewhere, and 1 for multiple recurrent disc herniation (Table 2). Twenty-five patients (23.1%) were current tobacco users and 28 (25.9%) were former smokers, 26 (24.1%) had diabetes mellitus (DM), 16 (14.8%) had low bone density by dual energy X-ray absorptiometry (DEXA) imaging, 35 (32.4%) had depression, and 7 (6.5%) were taking an immunosuppressive agent (chronic steroids, biological response modifiers, or methotrexate). Mean body mass index was 30.1.

Surgical Procedure

Of the 108 patients, the first 18 underwent a procedure with fluoroscopic guidance and the Medtronic FluoroNav and Stealth Systems. The next 90 patients underwent a procedure with O-Arm intraoperative CT scanning and Stealth frameless stereotactic navigation. The mean (SD) length of stay was 1.7 (1.3) days. There were no wound infections and no new neurologic deficits. Mean (SD) follow up time was 30.3 (21.8) months.

Imaging

Final imaging was by radiograph in 73 patients, CT in 31, and magnetic resonance imaging (MRI) in 3 (1 patient had no imaging). Sixty-seven patients (62.0%) had a bilateral arthrodesis, and 15 (13.9%) had at least a unilateral arthrodesis. MRI was not used to assess arthrodesis. Eight patients (7.4%) had no definite arthrodesis. Seventeen patients had inadequate or early imaging from which a fusion determination could not be made. Of 81 patients with > 11 months of follow up, 58 (71.6%) had a bilateral arthrodesis, 12 (14.8%) had a unilateral arthrodesis, 8 (9.9%) had no arthrodesis, and 3 (3.7%) were indeterminate.

No patient had any revision fusion surgery at the index level during follow up. Two patients had adjacent level fusions at 27 and 60 months after the index procedure. One patient had a laminectomy at an adjacent segment at 18 months postfusion, and 1 had a foraminotomy at an adjacent segment 89 months post fusion (Figure 3). Overall, there were 4 (3.7%) adjacent segment surgeries at a mean of 48.5 months after surgery. One patient had a sacro-iliac joint fusion below an L5-S1 fusion 17 months prior for persisting pain after the fusion procedure.

Patient Reported Outcomes

Preoperative SF-36 PF and ODI scores were available for 81 patients (Table 3). Postoperative SF-36 PF scores were obtained at 3 months for 65 of these patients, and at 1 year for 63 patients. Postoperative ODI scores were obtained at 3 months for 65 patients, and at 1 year for 55 patients. Among the 65 patients with completed SF-36 scores at 3 months, a mean increase of 22.4 (95% CI, 17-27; P < .001) was noted, and for the 63 patients at 1 year a mean increase of 30.3 (95% CI, 25-35; P < .001) was noted. Among the 65 patients with completed ODI scores at 3 months, a mean decrease of 6.8 (95% CI, 4.9-8.6; P < .001) was noted, and for the 55 patients with completed ODI scores at 1 year a mean decrease of 10.3 (n = 55; 95% CI, 8.4-12.2; P < .001) was noted.

Cost

We compared the hardware cost of a single level construct consisting of 4 pedicle screws, 4 locking caps, and 2 rods using a PEEK system with that of 2 other titanium construct systems. At VAPHCS, the PEEK system cost was about 71% of the cost of 2 other titanium construct systems and 62% of the cost when compared with Medtronic titanium rods.

Discussion

PEEK is useful for spine and cranial implants. It is inert and fully biocompatible with a modulus of elasticity between that of cortical and cancellous bone, and much lower than that of titanium, and is therefore considered to be semirigid.^3,4,6 PEEK rods are intermediate in stiffness between titanium rods (110 Gigapascals) and dynamic devices such as the Zimmer Biomet DYNESYS dynamic stabilization system or the Premia Spine TOPS system.³ Carbon fiber rods and carbon fiber reinforced PEEK implants are other semirigid rod alternatives.^7,8 PEEK rods for posterior lumbar fusion surgery were introduced in 2007. Li and colleagues provide a thorough review of the biomechanical properties of PEEK rods.³

PEEK is thought to have several advantages when compared with titanium. These advantages include more physiologic load sharing and reduction in stress shielding, improved durability, reduced risk of failure in osteoporotic bone, less wear debris, no change in bone forming environment, and imaging radiolucency.^4,9 Spinal PEEK cages have been reported to allow more uniform radiation dose distribution compared with metal constructs, an advantage that also may pertain to PEEK rods.¹⁰ Disadvantages of PEEK rods include an inability to detect rod breakage easily, lack of data on the use in more than minimally unstable clinical situations, and greater expense, although this was not the authors’ observation.^3,4,11

Importantly, it has been reported that PEEK rods permit a greater range of motion in all planes when compared with titanium rods.⁹ Polyetheretherketone rods unload the bone screw interface and increased the anterior column load to a more physiologic 75% when compared with titanium rods.^6,9 However, in another biomechanical study that compared titanium rods, PEEK rods, and a dynamic stabilization device, it was reported that anterior load sharing was 55%, 59%, and 75%, respectively.¹² This indicated that PEEK rods are closer to metal rods than truly dynamic devices for anterior load sharing. The endurance limit of a PEEK rod construct was similar to that of clinically useful metal systems.⁹ PEEK rods resulted in no increase in postfatigue motion compared with titanium rods in a biomechanical model.¹³ Intradiscal pressures at PEEK instrumented segments were similar to uninstrumented segments and greater than those with titanium rod constructs.¹⁴ Intradiscal pressures at adjacent segments were highest with dynamic devices, intermediate with semirigid rods, and lowest with rigid constructs; however, stress values at adjacent segments were lower in PEEK than titanium constructs in any direction of motion.^15,16

Fusion Rates

The use of PEEK rods in lumbar fusion has been reported previously.^3,4,17,18 However, these studies featured small sample sizes, short follow up times, and contradictory results.⁴ Of 8 outcome reports found in a systematic review, 2 studies reported on procedures designed to create nonfusion outcomes (a third similar trial from 2013 was not included in the systematic review), and 1 study reported only on the condition of PEEK rods removed at subsequent surgery.^3,19-21 Reported fusion rates varied from 86 to 100%.

In 42 patients with PEEK rod fusions who were followed for a mean of 31.4 months, 5 patients required adjacent segment surgery and 3 patients were treated for interbody cage migration and nonunion.¹⁷ Radiographic fusion rate was 86%. These authors concluded that PEEK rod fusion results were similar to those of other constructs, but not better, or perhaps worse than, metal rods.

Other studies have reported better results with PEEK.^{11,18,19,22-24} Highsmith and colleagues reported on 3 successful example cases of the use of PEEK rods.¹¹ De Iure and colleagues reported on 30 cases up to 5 levels (mean, 2.9) using autograft bone, with a mean follow up of 18 months.²³ Results were reported as satisfactory. Three patients had radiographic nonunions, 1 of which required revision for asymptomatic screw loosening at the cranial end of the construct. Qi and colleagues, reported on 20 patients with PEEK rods compared to 21 patients with titanium alloy rods.²⁴ Both groups had similar clinical outcomes, structural parameters, and 100% fusion rates. Athanasakopoulos and colleagues reported on 52 patients with up to 3 level fusions followed for a mean of 3 years.²² There were significant improvements in PROs: at 1 year 96% had radiographic union. Two patients had screw breakage, 1 of whom required revision to a metal rod construct. Colangeli and colleagues reported on 12 patients treated with PEEK rods compared with 12 who were treated with a dynamic system.¹⁸ They reported significant improvements, no complications, and 100% fusion at 6 months. Huang and colleagues reported on 38 patients intended to undergo a nonfusion procedure with 2 years of follow up.¹⁹ They reported good outcomes and 1 case of screw loosening. As no fusion was intended, no fusion outcomes were reported. All these studies suggested that longer follow up and more patients would be needed to assess the role of PEEK rods in lumbar fusion.³

Our results show a radiographic fusion rate of 86.4% and a radiographic nonunion rate of 9.9% in patients followed for at least 12 months. There was no clinical need for revision fusion at the index level. In our retrospective review, patients had high levels of smoking, DM, depression, immunosuppression, and obesity, which may negatively influence radiographic fusion rates when compared with other studies with 100% reported fusion rates. There was no instance of construct breakage or screw breakout, indicating that PEEK rods may allow enough flexibility to avoid construct failure under stress as in a fall.

Patient Reported Outcomes

Recent large studies were reviewed to assess the pre- and postoperative patient PROs reported in comparison with our study population (Table 4). In the Swedish Spine Registry analysis of 765 patients with 3 different types of lumbar fusion, the mean preoperative ODI score was 37 and mean SF-36 physical component score (PCS) was 35 for the most similar approach (posterolateral fusion with instrumentation).²⁵ At 1 year postoperation, the mean ODI was 26 and mean SF-36 PCS was 43. In the Spine Patient Outcomes Research Trial (SPORT) spondylolisthesis trial of 3 fusion types, the mean preoperative ODI was 41.2 and mean SF-36 PF score was 31.2 for the most similar approach (posterolateral instrumented fusion with pedicle screws).²⁶ Postoperative ODI scores at 1 year decreased by a mean 20.9 points and mean SF-36 PF scores increased by 29.9.

We report a mean preoperative SF-36 PF score of 28.9, which is lower than the SPORT study score for posterolateral fusion with instrumentation and the Swedish Study score for posterolateral instrumented fusion with pedicle screws. Similarly, our mean ODI score of 24.8 was better than the scores reported in the Swedish and SPORT studies. Our mean SF-36 PF score at 1 year postoperation was 59.3, compared with 58.5 for the SPORT study group and 46.0 in the Swedish study group. Mean ODI score at 1 year postoperatively was 14.5, which is better than the scores reported in the Swedish and SPORT studies.

Minimally clinically important difference (MCID) is a parameter used to gauge the efficacy of spine surgery. The utility of the MCID based upon PROs has been questioned in lumbar fusion surgery, as it has been thought to measure if the patient is “feeling” rather than “doing” better, the latter of which can be better measured by functional performance measures and objective, external socioeconomic anchors such as return to work and health care costs.²⁷ Nevertheless, validated PROs are reported widely in the spine surgery literature. The MCID in the SF-36 is not well established and can depend upon whether the scores are at the extremes or more in the central range and whether there is large variability in the scores.²⁸ Rheumatoid arthritis was estimated to be 7.1 points on the PF scale and 7.2 on the physical component summary (PCS).²⁹ For total knee replacement, it has been estimated to be 10 points on the SF-36 PCS.³⁰ Lumbar surgery was estimated to be 4.9 points for the SF-36 PCS and 12.8 points for the ODI.³¹ And the SPORT trial it has been estimated that a 30% change in the possible gain (or loss) may be an appropriate criterion.²⁸

With a preoperative mean SF-36 PF of 28.9, a 30% improvement in the available range (70.1) would be 21 points, making our data mean improvement of 30 points above the MCID. With a mean preoperative ODI of 24.6, a 30% improvement in the available range (25.4) would be 7.6 points, making our data mean improvement of 10.3 points better than the MCID. Therefore, our outcome results are comparable with other lumbar fusion outcome studies in terms of degree of disability prior to surgery and amount of improvement from surgery.

Adjacent Segment Disease

The precise factors resulting in adjacent segment disease are not fully defined.^3,32 In reviews of lumbar adjacent segment disease, reported rates ranged from 2.5% at 1 year up to 80 to 100% at 10 years, with lower rates with noninstrumented fusions.^4,32-34 Annual incidence of symptomatic adjacent segment disease following lumbar fusion ranges from 0.6 to 3.9% per year.^32,35,36 Mismatch between lumbar lordosis and pelvic incidence after fusion is thought to lead to higher rates of adjacent segment disease, as can a laminectomy at an adjacent segment.^32,36 Percutaneous fusion techniques or use of the Wiltse approach may lower the risk of adjacent segment disease due to avoidance of facet capsule disruption.^37,38

Dynamic stabilization techniques do not appear be clearly protective against adjacent segment disease, although biomechanical models suggest that they may do so.^33,39,40 A review by Wang and colleagues pooled studies to assess the risk of lumbar adjacent segment disease in spinal fusion to compare to disc arthroplasty and concluded that fusion carried a higher risk of adjacent segment disease.⁴¹ Definitive data on other types of motion preservation devices is lacking.³We show 3 adjacent segment fusions and 1 laminectomy have been needed in 108 patients and at a mean of 46 months after the index procedure and over 2.5 years of mean overall follow up. This is a low adjacent segment surgery rate compared to the historical data cited above, and may suggest some advantage for PEEK rods over more rigid constructs.

Strengths and Limitations

Strengths of this study include larger numbers than prior series of PEEK rod use and use in a population with high comorbidities linked to poor results without reduction in good outcomes. PEEK rods as used at the VAPHCS do not result in higher instrumentation costs than all metal constructs.

Study limitations include the retrospective nature with loss of follow up on some patients and incomplete radiographic and PROs in some patients. The use of 100% stereotactic guidance, the avoidance of interbody devices, and the off-label use of bone morphogenetic protein as part of the fusion construct introduce additional variables that may influence comparison to other studies. To avoid unnecessary radiation exposure, flexion extension films or CT scans were not routinely obtained if patients were doing well.⁴² Additionally, the degree of motion on dynamic views that would differentiate pseudarthrosis from arthrodesis has not been defined.⁵

Conclusions

The results presented show that lumbar fusion with PEEK rods can be undertaken with short hospitalization times and low complication rates, produce satisfactory clinical improvements, and result in radiographic fusion rates similar to metal constructs. Low rates of hardware failure or need for revision surgery were found. Preliminarily results of low rates of adjacent segment surgery are comparable with previously published metal construct rates. Longer follow up is needed to confirm these findings and to investigate whether semirigid constructs truly offer some protection from adjacent segment disease when compared to all metal constructs.

Acknowledgments
The authors thank Shirley McCartney, PhD, for editorial assistance.

Surgical treatment of degenerative lumbar spine disease has been rising steadily in the United States, and an increasing fraction of surgery involves lumbar fusion.^1,2 Various techniques are used to accomplish a lumbar fusion, including noninstrumented fusion, anterior lumbar interbody fusion (ALIF), lateral lumbar interbody fusion (XLIF, OLIF), posterior pedicle screw fusion, posterior cortical screw fusion, posterior interbody fusion (TLIF, PLIF), and interspinous process fusion. Rigid, metallic fusion hardware provides high stability and fusion rates, but it likely leads to stress shielding and adjacent segment disease.³ There is interest in less rigid and dynamic stabilization techniques to reduce the risk of adjacent segment disease, such as polyetheretherketone (PEEK) rods, which have been available since 2007. However, literature regarding PEEK rod utility is sparse and of mixed outcomes.^3,4 Additional patient reported outcome (PRO) information would be useful to both surgeons and patients. Using institutional data, this review was designed to examine our experience with PEEK rod lumbar fusion and to document PROs.

Methods

The study was approved by the institutional review board at the US Department of Veterans Affairs (VA) Portland Health Care System (VAPHCS) in Oregon with a waiver of authorization. In this retrospective, single center study, data were queried from the senior author’s (DAR) case logs from VA Computerized Patient Record System (CPRS). Electronic medical records, imaging, and PROs of all consecutive patients undergoing lumbar fusion at 1 or 2 levels with PEEK rods for degenerative disease were retrospectively reviewed. Cases of trauma, malignancy, or infection were excluded. From March 2011 through October 2019, 108 patients underwent lumbar fusion with PEEK rods.

Surgeries were conducted on a Mizuho OSI Jackson Table via bilateral 3 to 4 cm Wiltse incisions using the Medtronic Quadrant retractor system. Medtronic O-Arm images were acquired and delivered to a Medtronic Stealth Station for navigation of the screws. Monopolar coagulation was not used. PEEK pedicle screws were placed and verified with a second O-Arm spin before placing lordotic PEEK rods in the screw heads. No attempt was made to reduce any spondylolisthesis, but distraction was used to open the foramina and indirectly decompress the canal. An interbody device was placed only in treatment of multiply recurrent disc protrusion. After decortication of the transverse processes and facets, intertransverse fusion constructs consisting of calcium hydroxyapatite soaked in autologous bone marrow blood and wrapped in 6-mg bone morphogenetic protein-soaked sponges were placed on the bone. If canal decompression was indicated, a Medtronic Metrx retractor tube was then placed through one of the incisions and decompression carried out. Wounds were closed with absorbable suture. No bracing was used postoperatively. Figure 1 shows a typical single level PEEK rod fusion construct.

Statistical Analysis

Pre- and postoperative pairwise t tests were completed for patients with a complete data, using SAS 9.2 statistical package. Data are presented as standard deviation (SD) of the mean.

Results

Following application of the inclusion/exclusion criteria, 108 patients had undergone lumbar fusion with PEEK rods. Mean (SD) patient age was 60.2 (10.3) years and 88 patients were male (Table 1). Most surgeries were at L5-S1 and L4-5. There were 97 single-level fusions and 11 bilevel fusions. Seventy-four procedures were for spondylolisthesis, 23 for foraminal stenosis, 5 for degenerative disc disease, 3 for coronal imbalance with foraminal stenosis, 2 for pseudarthrosis after surgery elsewhere, and 1 for multiple recurrent disc herniation (Table 2). Twenty-five patients (23.1%) were current tobacco users and 28 (25.9%) were former smokers, 26 (24.1%) had diabetes mellitus (DM), 16 (14.8%) had low bone density by dual energy X-ray absorptiometry (DEXA) imaging, 35 (32.4%) had depression, and 7 (6.5%) were taking an immunosuppressive agent (chronic steroids, biological response modifiers, or methotrexate). Mean body mass index was 30.1.

Surgical Procedure

Of the 108 patients, the first 18 underwent a procedure with fluoroscopic guidance and the Medtronic FluoroNav and Stealth Systems. The next 90 patients underwent a procedure with O-Arm intraoperative CT scanning and Stealth frameless stereotactic navigation. The mean (SD) length of stay was 1.7 (1.3) days. There were no wound infections and no new neurologic deficits. Mean (SD) follow up time was 30.3 (21.8) months.

Imaging

Final imaging was by radiograph in 73 patients, CT in 31, and magnetic resonance imaging (MRI) in 3 (1 patient had no imaging). Sixty-seven patients (62.0%) had a bilateral arthrodesis, and 15 (13.9%) had at least a unilateral arthrodesis. MRI was not used to assess arthrodesis. Eight patients (7.4%) had no definite arthrodesis. Seventeen patients had inadequate or early imaging from which a fusion determination could not be made. Of 81 patients with > 11 months of follow up, 58 (71.6%) had a bilateral arthrodesis, 12 (14.8%) had a unilateral arthrodesis, 8 (9.9%) had no arthrodesis, and 3 (3.7%) were indeterminate.

No patient had any revision fusion surgery at the index level during follow up. Two patients had adjacent level fusions at 27 and 60 months after the index procedure. One patient had a laminectomy at an adjacent segment at 18 months postfusion, and 1 had a foraminotomy at an adjacent segment 89 months post fusion (Figure 3). Overall, there were 4 (3.7%) adjacent segment surgeries at a mean of 48.5 months after surgery. One patient had a sacro-iliac joint fusion below an L5-S1 fusion 17 months prior for persisting pain after the fusion procedure.

Patient Reported Outcomes

Preoperative SF-36 PF and ODI scores were available for 81 patients (Table 3). Postoperative SF-36 PF scores were obtained at 3 months for 65 of these patients, and at 1 year for 63 patients. Postoperative ODI scores were obtained at 3 months for 65 patients, and at 1 year for 55 patients. Among the 65 patients with completed SF-36 scores at 3 months, a mean increase of 22.4 (95% CI, 17-27; P < .001) was noted, and for the 63 patients at 1 year a mean increase of 30.3 (95% CI, 25-35; P < .001) was noted. Among the 65 patients with completed ODI scores at 3 months, a mean decrease of 6.8 (95% CI, 4.9-8.6; P < .001) was noted, and for the 55 patients with completed ODI scores at 1 year a mean decrease of 10.3 (n = 55; 95% CI, 8.4-12.2; P < .001) was noted.

Cost

We compared the hardware cost of a single level construct consisting of 4 pedicle screws, 4 locking caps, and 2 rods using a PEEK system with that of 2 other titanium construct systems. At VAPHCS, the PEEK system cost was about 71% of the cost of 2 other titanium construct systems and 62% of the cost when compared with Medtronic titanium rods.

Discussion

PEEK is useful for spine and cranial implants. It is inert and fully biocompatible with a modulus of elasticity between that of cortical and cancellous bone, and much lower than that of titanium, and is therefore considered to be semirigid.^3,4,6 PEEK rods are intermediate in stiffness between titanium rods (110 Gigapascals) and dynamic devices such as the Zimmer Biomet DYNESYS dynamic stabilization system or the Premia Spine TOPS system.³ Carbon fiber rods and carbon fiber reinforced PEEK implants are other semirigid rod alternatives.^7,8 PEEK rods for posterior lumbar fusion surgery were introduced in 2007. Li and colleagues provide a thorough review of the biomechanical properties of PEEK rods.³

PEEK is thought to have several advantages when compared with titanium. These advantages include more physiologic load sharing and reduction in stress shielding, improved durability, reduced risk of failure in osteoporotic bone, less wear debris, no change in bone forming environment, and imaging radiolucency.^4,9 Spinal PEEK cages have been reported to allow more uniform radiation dose distribution compared with metal constructs, an advantage that also may pertain to PEEK rods.¹⁰ Disadvantages of PEEK rods include an inability to detect rod breakage easily, lack of data on the use in more than minimally unstable clinical situations, and greater expense, although this was not the authors’ observation.^3,4,11

Importantly, it has been reported that PEEK rods permit a greater range of motion in all planes when compared with titanium rods.⁹ Polyetheretherketone rods unload the bone screw interface and increased the anterior column load to a more physiologic 75% when compared with titanium rods.^6,9 However, in another biomechanical study that compared titanium rods, PEEK rods, and a dynamic stabilization device, it was reported that anterior load sharing was 55%, 59%, and 75%, respectively.¹² This indicated that PEEK rods are closer to metal rods than truly dynamic devices for anterior load sharing. The endurance limit of a PEEK rod construct was similar to that of clinically useful metal systems.⁹ PEEK rods resulted in no increase in postfatigue motion compared with titanium rods in a biomechanical model.¹³ Intradiscal pressures at PEEK instrumented segments were similar to uninstrumented segments and greater than those with titanium rod constructs.¹⁴ Intradiscal pressures at adjacent segments were highest with dynamic devices, intermediate with semirigid rods, and lowest with rigid constructs; however, stress values at adjacent segments were lower in PEEK than titanium constructs in any direction of motion.^15,16

Fusion Rates

The use of PEEK rods in lumbar fusion has been reported previously.^3,4,17,18 However, these studies featured small sample sizes, short follow up times, and contradictory results.⁴ Of 8 outcome reports found in a systematic review, 2 studies reported on procedures designed to create nonfusion outcomes (a third similar trial from 2013 was not included in the systematic review), and 1 study reported only on the condition of PEEK rods removed at subsequent surgery.^3,19-21 Reported fusion rates varied from 86 to 100%.

In 42 patients with PEEK rod fusions who were followed for a mean of 31.4 months, 5 patients required adjacent segment surgery and 3 patients were treated for interbody cage migration and nonunion.¹⁷ Radiographic fusion rate was 86%. These authors concluded that PEEK rod fusion results were similar to those of other constructs, but not better, or perhaps worse than, metal rods.

Other studies have reported better results with PEEK.^{11,18,19,22-24} Highsmith and colleagues reported on 3 successful example cases of the use of PEEK rods.¹¹ De Iure and colleagues reported on 30 cases up to 5 levels (mean, 2.9) using autograft bone, with a mean follow up of 18 months.²³ Results were reported as satisfactory. Three patients had radiographic nonunions, 1 of which required revision for asymptomatic screw loosening at the cranial end of the construct. Qi and colleagues, reported on 20 patients with PEEK rods compared to 21 patients with titanium alloy rods.²⁴ Both groups had similar clinical outcomes, structural parameters, and 100% fusion rates. Athanasakopoulos and colleagues reported on 52 patients with up to 3 level fusions followed for a mean of 3 years.²² There were significant improvements in PROs: at 1 year 96% had radiographic union. Two patients had screw breakage, 1 of whom required revision to a metal rod construct. Colangeli and colleagues reported on 12 patients treated with PEEK rods compared with 12 who were treated with a dynamic system.¹⁸ They reported significant improvements, no complications, and 100% fusion at 6 months. Huang and colleagues reported on 38 patients intended to undergo a nonfusion procedure with 2 years of follow up.¹⁹ They reported good outcomes and 1 case of screw loosening. As no fusion was intended, no fusion outcomes were reported. All these studies suggested that longer follow up and more patients would be needed to assess the role of PEEK rods in lumbar fusion.³

Our results show a radiographic fusion rate of 86.4% and a radiographic nonunion rate of 9.9% in patients followed for at least 12 months. There was no clinical need for revision fusion at the index level. In our retrospective review, patients had high levels of smoking, DM, depression, immunosuppression, and obesity, which may negatively influence radiographic fusion rates when compared with other studies with 100% reported fusion rates. There was no instance of construct breakage or screw breakout, indicating that PEEK rods may allow enough flexibility to avoid construct failure under stress as in a fall.

Patient Reported Outcomes

Recent large studies were reviewed to assess the pre- and postoperative patient PROs reported in comparison with our study population (Table 4). In the Swedish Spine Registry analysis of 765 patients with 3 different types of lumbar fusion, the mean preoperative ODI score was 37 and mean SF-36 physical component score (PCS) was 35 for the most similar approach (posterolateral fusion with instrumentation).²⁵ At 1 year postoperation, the mean ODI was 26 and mean SF-36 PCS was 43. In the Spine Patient Outcomes Research Trial (SPORT) spondylolisthesis trial of 3 fusion types, the mean preoperative ODI was 41.2 and mean SF-36 PF score was 31.2 for the most similar approach (posterolateral instrumented fusion with pedicle screws).²⁶ Postoperative ODI scores at 1 year decreased by a mean 20.9 points and mean SF-36 PF scores increased by 29.9.

We report a mean preoperative SF-36 PF score of 28.9, which is lower than the SPORT study score for posterolateral fusion with instrumentation and the Swedish Study score for posterolateral instrumented fusion with pedicle screws. Similarly, our mean ODI score of 24.8 was better than the scores reported in the Swedish and SPORT studies. Our mean SF-36 PF score at 1 year postoperation was 59.3, compared with 58.5 for the SPORT study group and 46.0 in the Swedish study group. Mean ODI score at 1 year postoperatively was 14.5, which is better than the scores reported in the Swedish and SPORT studies.

Minimally clinically important difference (MCID) is a parameter used to gauge the efficacy of spine surgery. The utility of the MCID based upon PROs has been questioned in lumbar fusion surgery, as it has been thought to measure if the patient is “feeling” rather than “doing” better, the latter of which can be better measured by functional performance measures and objective, external socioeconomic anchors such as return to work and health care costs.²⁷ Nevertheless, validated PROs are reported widely in the spine surgery literature. The MCID in the SF-36 is not well established and can depend upon whether the scores are at the extremes or more in the central range and whether there is large variability in the scores.²⁸ Rheumatoid arthritis was estimated to be 7.1 points on the PF scale and 7.2 on the physical component summary (PCS).²⁹ For total knee replacement, it has been estimated to be 10 points on the SF-36 PCS.³⁰ Lumbar surgery was estimated to be 4.9 points for the SF-36 PCS and 12.8 points for the ODI.³¹ And the SPORT trial it has been estimated that a 30% change in the possible gain (or loss) may be an appropriate criterion.²⁸

With a preoperative mean SF-36 PF of 28.9, a 30% improvement in the available range (70.1) would be 21 points, making our data mean improvement of 30 points above the MCID. With a mean preoperative ODI of 24.6, a 30% improvement in the available range (25.4) would be 7.6 points, making our data mean improvement of 10.3 points better than the MCID. Therefore, our outcome results are comparable with other lumbar fusion outcome studies in terms of degree of disability prior to surgery and amount of improvement from surgery.

Adjacent Segment Disease

The precise factors resulting in adjacent segment disease are not fully defined.^3,32 In reviews of lumbar adjacent segment disease, reported rates ranged from 2.5% at 1 year up to 80 to 100% at 10 years, with lower rates with noninstrumented fusions.^4,32-34 Annual incidence of symptomatic adjacent segment disease following lumbar fusion ranges from 0.6 to 3.9% per year.^32,35,36 Mismatch between lumbar lordosis and pelvic incidence after fusion is thought to lead to higher rates of adjacent segment disease, as can a laminectomy at an adjacent segment.^32,36 Percutaneous fusion techniques or use of the Wiltse approach may lower the risk of adjacent segment disease due to avoidance of facet capsule disruption.^37,38

Dynamic stabilization techniques do not appear be clearly protective against adjacent segment disease, although biomechanical models suggest that they may do so.^33,39,40 A review by Wang and colleagues pooled studies to assess the risk of lumbar adjacent segment disease in spinal fusion to compare to disc arthroplasty and concluded that fusion carried a higher risk of adjacent segment disease.⁴¹ Definitive data on other types of motion preservation devices is lacking.³We show 3 adjacent segment fusions and 1 laminectomy have been needed in 108 patients and at a mean of 46 months after the index procedure and over 2.5 years of mean overall follow up. This is a low adjacent segment surgery rate compared to the historical data cited above, and may suggest some advantage for PEEK rods over more rigid constructs.

Strengths and Limitations

Strengths of this study include larger numbers than prior series of PEEK rod use and use in a population with high comorbidities linked to poor results without reduction in good outcomes. PEEK rods as used at the VAPHCS do not result in higher instrumentation costs than all metal constructs.

Study limitations include the retrospective nature with loss of follow up on some patients and incomplete radiographic and PROs in some patients. The use of 100% stereotactic guidance, the avoidance of interbody devices, and the off-label use of bone morphogenetic protein as part of the fusion construct introduce additional variables that may influence comparison to other studies. To avoid unnecessary radiation exposure, flexion extension films or CT scans were not routinely obtained if patients were doing well.⁴² Additionally, the degree of motion on dynamic views that would differentiate pseudarthrosis from arthrodesis has not been defined.⁵

Conclusions

The results presented show that lumbar fusion with PEEK rods can be undertaken with short hospitalization times and low complication rates, produce satisfactory clinical improvements, and result in radiographic fusion rates similar to metal constructs. Low rates of hardware failure or need for revision surgery were found. Preliminarily results of low rates of adjacent segment surgery are comparable with previously published metal construct rates. Longer follow up is needed to confirm these findings and to investigate whether semirigid constructs truly offer some protection from adjacent segment disease when compared to all metal constructs.

Acknowledgments
The authors thank Shirley McCartney, PhD, for editorial assistance.

THE CASE

A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.

Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.

During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.

A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.

THE DIAGNOSIS

The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.

DISCUSSION

Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.^1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.⁴

Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.⁵ Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.⁵

Continue to: With a primary lung abscess...

With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.² The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.^1,2

Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).⁶ Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.⁷

What to rule out

The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.^1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.^1,4

Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.⁸

Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.⁹

Continue to: Excavating bronchogenic carcinomas

Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.¹⁰

Treatment

When antibiotics first became available, penicillin was used to treat lung abscess.¹¹ Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.^12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.¹⁴

Current therapy includes beta-lactam with beta-lactamase inhibitors.¹⁴ Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.^15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.⁷ Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.⁴

Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).

THE TAKEAWAY

All patients with lung abscesses should have sputum culture with gram stain done—­ideally prior to starting antibiotics.^3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.³

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; morteza.khodaee@cuanschutz.edu

THE CASE

A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.

Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.

During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.

A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.

THE DIAGNOSIS

The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.

DISCUSSION

Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.^1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.⁴

Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.⁵ Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.⁵

Continue to: With a primary lung abscess...

With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.² The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.^1,2

Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).⁶ Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.⁷

What to rule out

The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.^1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.^1,4

Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.⁸

Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.⁹

Continue to: Excavating bronchogenic carcinomas

Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.¹⁰

Treatment

When antibiotics first became available, penicillin was used to treat lung abscess.¹¹ Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.^12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.¹⁴

Current therapy includes beta-lactam with beta-lactamase inhibitors.¹⁴ Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.^15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.⁷ Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.⁴

Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).

THE TAKEAWAY

All patients with lung abscesses should have sputum culture with gram stain done—­ideally prior to starting antibiotics.^3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.³

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; morteza.khodaee@cuanschutz.edu

THE CASE

A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.

Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.

During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.

A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.

THE DIAGNOSIS

The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.

DISCUSSION

Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.^1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.⁴

Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.⁵ Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.⁵

Continue to: With a primary lung abscess...

With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.² The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.^1,2

Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).⁶ Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.⁷

What to rule out

The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.^1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.^1,4

Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.⁸

Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.⁹

Continue to: Excavating bronchogenic carcinomas

Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.¹⁰

Treatment

When antibiotics first became available, penicillin was used to treat lung abscess.¹¹ Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.^12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.¹⁴

Current therapy includes beta-lactam with beta-lactamase inhibitors.¹⁴ Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.^15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.⁷ Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.⁴

Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).

THE TAKEAWAY

All patients with lung abscesses should have sputum culture with gram stain done—­ideally prior to starting antibiotics.^3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.³

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; morteza.khodaee@cuanschutz.edu

This article has been updated to reflect new US Food and Drug Administration and Centers for Disease Control and Prevention recommendations to pause administration of the Johnson and Johnson Jansen (JNJ-78436735) COVID-19 vaccine.¹

Since the outbreak of the pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2),a plethora of studies have been performed to increase our knowledge of its associated illness COVID-19.² There is no cure for COVID-19, which can be lethal. In the absence of a cure, preventive measures are of vital importance. In order to help prevent the spread of the virus, the Centers for Diseases Control and Prevention (CDC) advocates for: (1) the use of a face mask over the mouth and nose; (2) a minimum of 6-foot distance between individuals; and (3) avoidance of gatherings.As of March 2021, the US Food and Drug Administration (FDA) approved 3 vaccines for the prevention of COVID-19, under an emergency use authorization (EUA).^3-5

COVID-19 and Multiple Sclerosis

Since the beginning of the pandemic, neurologists have faced a new challenge—determining whether persons with multiple sclerosis (pwMS) were more at risk than others of becoming ill from COVID-19 or were destined for a worse outcome. The National MS Society has advised a personalized approach in relation to particularly vulnerable persons when needed and has also initiated worldwide registries to collect information regarding incidence and outcome of COVID-19 in pwMS. Accordingly, through the MS Center of Excellence (MSCoE), the Veterans Health Administration (VHA) has established a national registry assembling data regarding COVID-19 in veterans with MS.

A recent descriptive literature review summarized the outcomes of 873 persons with both MS and COVID-19 and reported that about 36% of COVID-19 cases were treated with B-cell depleting therapies (ocrelizumab or rituximab).⁶ This proportion was relatively higher when compared with other disease modifying agents. Of those who became infected with SARS-CoV-2, death from COVID-19 occurred in about 4%, and an additional 3% required assisted invasive or noninvasive ventilation. Persons reported to have passed away from COVID-19 generally were older; had progressive MS; or had associated comorbidities such as obesity, hypertension, heart or lung conditions, or cancers. Of these, 50% were not on any disease modifying agent, 25% were on B-cell depleting therapies (ocrelizumab or rituximab), and the remaining 25% were on various medications for MS. It is important to highlight that no formal statistical analyses were performed in this review. On the contrary, in the recently published Italian report on 844 pwMS who had suspected or confirmed COVID-19, the authors used univariate and multivariate models to analyze their findings and noted that the use of ocrelizumab was significantly associated with a worse clinical outcome.⁷ These authors also identified age, sex, disability score, and recent (within 1 month) use of steroids as risk factors for a severe COVID-19 outcome. The incidence of death from COVID-19 in this cohort was 1.54%.

The recently published data from the North American Registry of the National MS Society based on 1,626 patients reported a 3.3% incidence of death from COVID-19.⁸ The following factors were identified as risks for worse outcome: male sex, nonambulatory status, age, Black race, and cardiovascular disease. The use of rituximab, ocrelizumab, and steroids (the latter medication over the preceding 2 months) increased the risks of hospitalization for COVID-19.

COVID-19 Vaccines

Of the 3 available vaccines, the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine is approved for individuals aged ≥ 16 years, while the Moderna COVID-19 (mRNA-1273) and the Johnson and Johnson/Jannsen COVID-19 (JNJ-78436735) vaccines are approved for individuals aged ≥ 18 years, though the latter vaccine has been temporarily suspended.^1,3-5 The EUAs were released following the disclosure of the results of 3 phase 3 clinical trials and several phase 1 and 2 clinical trials.^9-16

The BNT162b2 vaccine from Pfizer-BioNTech encodes the SARS-CoV-2 full-length spike protein (S) in prefusion conformation locked by the mutation in 2 prolines.⁹ Differently from the BNT162b2 vaccine, the BNT162b1 vaccine encodes a secreted trimerized SARS-CoV-2 receptor–binding domain. The S-glycoprotein is required for viral entry, as implicated in host cell attachment, and is the target of the neutralizing antibodies. In a phase 1 clinical study on 195 volunteers treated with BNT162b1 (10 mg, 20 mg, 30 mg, or 100 mg doses) or BNT162b2 (10 mg, 20 mg, or 30 mg doses) vaccines or placebo 21 days apart, both the binding and neutralizing antibody response was found to be age and “somewhat” dose dependent.⁹

Higher neutralization titers were measured at day 28 and 35 (7 and 14 days after the second dose, respectively) and compared with titers of persons who recovered from a COVID-19 infection.⁹ Serum neutralization was measured using a fluorescence-based high-throughput neutralization assay, while binding activity was assessed using the receptor-binding domain (RBD)–binding or S1-binding IgG direct Luminex immunoassays.

The overall reactogenicity/immunogenicity profile of BNT162b2 administered twice (30 mg each time) led to its selection for the phase 3 clinical trial.^9,10 In a large phase 3 clinical trial on 43,458 participants, the BNT162b2 vaccine given at 30 mg doses 21 days apart conferred 95% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁰ No safety concerns to stop the trial were identified, though related severe and life-threatening events were reported in 0.3% and 0.1% of the volunteers, respectively. We note that these incidence rates were the same for the treated and the placebo group.

The mRNA-1273 vaccine from Moderna also encodes the SARS-CoV-2 S-glycoprotein. In a dose escalation phase 1 trial of 45 participants aged between 18 and 55 years (25 mg, 100 mg or 250 mg, given at days 1 and 29) and 40 participants aged ≥ 57 years (25 mg and 100 mg, given at days 1 and 29), a dose-dependent effect was observed for both binding (receptor-binding domain and S-2p IgG on enzyme-linked immunosorbent assay [ELISA])and neutralizing antibodies (SARS-CoV-2 nanoluciferase high-throughput neutralization assay, focus reduction neutralization test mNeonGreen and SARS-CoV-2 plaque-reduction neutralization testing assay) development.^11,12 The geometric mean of both binding and neutralizing antibodies declined over time but persisted high as late as 119 days after the first burst of 100 mg dose.¹³ The same dose of the vaccine also elicited a strong T helper-1 response with little T helper-2 response across all ages.¹¹ The strength of the memory cellular response remains to be defined and is the subject of ongoing investigations. In a large phase 3 clinical trial with 30,420 participants, the Moderna COVID-19 mRNA-1273 vaccine, given 28 days apart at the dose of 100 mg, met 94.1% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁴

Less than 0.1% of volunteers in both groups withdrew from the trial due to adverse effects (AEs); 0.5% in the placebo group and 0.3% in the treated group had AEs after the first dose, which precluded receiving the second dose.¹⁴

The Johnson and Johnson/Jannsen JNJ-78436735 vaccine is based upon a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector, which encodes the full-length, stabilized S-glycoprotein of SARS-CoV-2. The currently reported results of the phase 1 and 2 clinical study indicated that 805 volunteers (402 participants between ages 18 and 55 years and 403 individuals aged ≥ 65 years) were randomized to receive a single or double dose of either 5 x 10¹⁰ viral particles per 0.5 mL (low dose) or 1 x 10¹¹ viral particles per 0.5 mL (high dose), each compared with a placebo group. Incidence of seroconversion to binding antibodies against the full-length stabilized S-glycoprotein, as measured by ELISA, showed ≥ 96% seroconversion by day 29 after the first dose. The incidence of seroconversion to neutralizing antibodies was ≥ 90% as early as early as 29 days after the first of either dose. In this study, neutralization activity was measured using the wild-type virus microneutralization assay based on the Victoria/1/2020/ SARS-CoV-2 strain.¹⁵ We note that the data related to this study have been partially reported and additional information will be available when each participant will have received the second dose.

In a large phase 3 clinical trial with 40,000 participants aged between 18 and 100 years, the Johnson and Johnson/Jannsen JNJ-78436735 vaccine, given as single dose of 5 x 10¹⁰ viral particles per 0.5 mL, met 65.5% clinical efficacy in the likelihood of being affected by symptomatic COVID-19 ≥ 28 days postimmunization.¹⁶ In this study, the vaccine efficacy was found to have a geographic distribution with highest efficacy in the US (74.4%), followed by Latin America (64.7%) where Brazil showed a predominance of the P2 COVID-19 lineage (64.7%), and Africa (52%) where the B.1.351 lineage was most frequent (94.5%). The vaccine also proved to be effective in reducing the likelihood of asymptomatic seroconversion, as measured by the level of a non-S protein, eg, 0.7% of positive cases in the vaccine group vs 2.8% in the placebo group. Immunological data indicated that the vaccine response was mainly driven by T-helper 1 lymphocytes. As of April 13, 2021 the FDA has recommend suspending the administration of the Johnson and Johnson/Janssen vaccine due to the occurrence of severe blood clots reported in a 6 subjects out of ~6.8 millions administered doses.¹

It is noteworthy to highlight that all vaccines reduced the likelihood of hospitalizations and deaths due to COVID-19.

As of April 17, 2021, the CDC reports that more than 130 million (40%) Americans, nearly 1/3 of the population, have received at least 1 dose of any of the 3 available vaccines, including 4.6 million at the VHA.¹⁷ Using the Vaccine Adverse Event Reporting System and v-safe, the US is conducting what has been defined the most “intense and comprehensive safety monitoring in the US history.”¹⁸ Thus far, data affirm the overall safety of the available vaccines against COVID-19. Individuals should not receive the COVID-19 vaccines if they have had a severe allergic reaction to any ingredient in the vaccine or a severe allergic reaction to a prior dose of the vaccine. Additionally, individuals who have received convalescent plasma should wait 90 days before getting the COVID-19 vaccine.

Vaccination for Persons with MS

PwMS or those on immunosuppressive medications were excluded from the clinical trial led by Pfizer-BioNTech. There is no mention of MS as comorbidity in the study from Moderna, although this condition is not listed as an exclusion criterion either. The results of the phase 3 clinical trial for the Johnson and Johnson/Janssen vaccine are not fully public yet, thus this information is not known as well. As a result, the use of this vaccine in pwMS under immunomodulatory agents is based on previous knowledge of other vaccines. Evidence is growing for the safety of the BNT162b2 COVID-19 vaccination in pwMS.¹⁹ Data regarding COVID-19 efficacy and safety are still largely based on previous knowledge on other vaccines.^20,21

Immunization of pwMS is considered safe and should proceed with confidence in those persons who have no other contraindication to receive a vaccine. A fundamental problem for pwMS treated with immunomodulatory or immunosuppressive medications is whether the vaccine will remain safe or be able to solicit an adequate immune response.^20,21 As of the time of publication 2021, there is consensus that mRNA based or inactivated vaccines are also considered safe in pwMS undergoing immunomodulatory or immunosuppressive treatments.^20-23 We advise a one-on-one conversation between each veteran with MS and their primary neurologist to understand the importance of the vaccination, the minimal risks associated with it and if any specific treatment modification should be made.

To provide guidance, the National MS Society released a position statement that is regularly updated.²² Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. In addition, on the basis of available literature and the American Academy of Neurology recommendations on the use of vaccines in general, the following recommendations are proposed.^20-23

Recommendation 1: injections, orals, and natalizumab. Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. Neither delay in start nor adjustments in dosing or timing of administration are advised for pwMS taking currently available either generic or brand formulations of β interferons, glatiramer acetate, teriflunomide, dimethyl or monomethyl fumarate, or natalizumab.²²

Recommendation 2: anti-CD20 monoclonal infusions. As an attenuated humoral response is predicted in pwMS treated with anti-CD20 monoclonal infusions, coordinating the timing of vaccination with treatment schedule may maximize efficacy of the vaccine. Whenever possible, it is advised to be vaccinated ≥ 12 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting anti-CD20 monoclonal infusions are advised to be fully vaccinated first and start these medications ≥ 2 to 4 weeks later.²²

Recommendation 3: alemtuzumab infusion. Given its effect on CD52+ cells, it is advised to be vaccinated ≥ 24 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting alemtuzumab infusions are advised to get fully vaccinated first and start this medication 4 weeks or more after completing the vaccine.²²

Recommendation 4: sphingosine 1 phosphate receptor modulators, oral cladribine, and ofatumumab. PwMS starting any of these medications are advised to be fully vaccinated first and start these medications 2 to 4 weeks after completing the vaccine. PwMS already on those medications are not advised to change the schedule of administration. When possible, though, one should resume the dose of cladribine or ofatumumab 2 to 4 weeks after the last dose of the vaccine. ²⁰

Notably, all these recommendations hold true when there is enough disease stability to allow delaying treatment. We also add that it remains unclear if persons with an overall very low number of lymphocytes will be able to elicit a strong reaction to the vaccine. Blood collection and analysis of white blood cell count and lymphocyte subset estimates should be obtained in those persons with a markedly suppressed immune system. Whenever possible, to maximize outcome, timing the vaccination with treatment should be considered in those persons with a markedly reduced number of T-helper 1 cells.

Vaccination for Veterans

Currently the VHA is offering to veterans the Pfizer and Moderna COVID-19 vaccines with FDA EUAs. In accordance with FDA regulations, the VHA has paused administration of the Johnson and Johnson/Janssen vaccine. The VHA has launched its vaccination program in December 2020 by first providing the vaccine to health care personnel, nursing home patients, spinal cord injury patients, chemotherapy patients, dialysis and transplant patients, as well as homeless veterans. Most VA health care systems have passed this phase and are now able to provide vaccines to veterans with MS.

In December 2020, the MSCoE released a position statement regarding the importance and safety of the COVID-19 vaccine for veterans with MS.²⁴ This statement will be updated on a regular basis as new information becomes available from major organizations like the National MS Society, FDA, CDC, and World Health Organization (WHO) or relevant literature.

Conclusions

Older veterans with progressive MS and associated comorbidities are at higher risk of death should they be infected by COVID-19. Fortunately, we live in a time where vaccines are recognized as a critical tool to prevent this infection and to significantly reduce its morbidity and mortality. Yet, hesitancy to vaccinate has been identified as one of the most important threats to public health by the WHO in 2019.²⁵ Understandably such hesitancy is even more profound for the COVID-19 vaccine, which is being administered under an EUA. In light of this indecision, and given the current state of the pandemic, we urge health care providers to educate every veteran about the benefits of being vaccinated against COVID-19. Within the VHA, a solid campaign of vaccination has been put in place at an unprecedented speed.

Health care providers interacting with veterans with MS are encouraged to use the MSCoE website (www.va.gov/ms) for any questions or concerns, or to reach out to MSCoE staff. It is vitally important that our community of veterans receives appropriate education on the importance of this vaccination for their own safety, for that of their household and society.

This article has been updated to reflect new US Food and Drug Administration and Centers for Disease Control and Prevention recommendations to pause administration of the Johnson and Johnson Jansen (JNJ-78436735) COVID-19 vaccine.¹

Since the outbreak of the pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2),a plethora of studies have been performed to increase our knowledge of its associated illness COVID-19.² There is no cure for COVID-19, which can be lethal. In the absence of a cure, preventive measures are of vital importance. In order to help prevent the spread of the virus, the Centers for Diseases Control and Prevention (CDC) advocates for: (1) the use of a face mask over the mouth and nose; (2) a minimum of 6-foot distance between individuals; and (3) avoidance of gatherings.As of March 2021, the US Food and Drug Administration (FDA) approved 3 vaccines for the prevention of COVID-19, under an emergency use authorization (EUA).^3-5

COVID-19 and Multiple Sclerosis

Since the beginning of the pandemic, neurologists have faced a new challenge—determining whether persons with multiple sclerosis (pwMS) were more at risk than others of becoming ill from COVID-19 or were destined for a worse outcome. The National MS Society has advised a personalized approach in relation to particularly vulnerable persons when needed and has also initiated worldwide registries to collect information regarding incidence and outcome of COVID-19 in pwMS. Accordingly, through the MS Center of Excellence (MSCoE), the Veterans Health Administration (VHA) has established a national registry assembling data regarding COVID-19 in veterans with MS.

A recent descriptive literature review summarized the outcomes of 873 persons with both MS and COVID-19 and reported that about 36% of COVID-19 cases were treated with B-cell depleting therapies (ocrelizumab or rituximab).⁶ This proportion was relatively higher when compared with other disease modifying agents. Of those who became infected with SARS-CoV-2, death from COVID-19 occurred in about 4%, and an additional 3% required assisted invasive or noninvasive ventilation. Persons reported to have passed away from COVID-19 generally were older; had progressive MS; or had associated comorbidities such as obesity, hypertension, heart or lung conditions, or cancers. Of these, 50% were not on any disease modifying agent, 25% were on B-cell depleting therapies (ocrelizumab or rituximab), and the remaining 25% were on various medications for MS. It is important to highlight that no formal statistical analyses were performed in this review. On the contrary, in the recently published Italian report on 844 pwMS who had suspected or confirmed COVID-19, the authors used univariate and multivariate models to analyze their findings and noted that the use of ocrelizumab was significantly associated with a worse clinical outcome.⁷ These authors also identified age, sex, disability score, and recent (within 1 month) use of steroids as risk factors for a severe COVID-19 outcome. The incidence of death from COVID-19 in this cohort was 1.54%.

The recently published data from the North American Registry of the National MS Society based on 1,626 patients reported a 3.3% incidence of death from COVID-19.⁸ The following factors were identified as risks for worse outcome: male sex, nonambulatory status, age, Black race, and cardiovascular disease. The use of rituximab, ocrelizumab, and steroids (the latter medication over the preceding 2 months) increased the risks of hospitalization for COVID-19.

COVID-19 Vaccines

Of the 3 available vaccines, the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine is approved for individuals aged ≥ 16 years, while the Moderna COVID-19 (mRNA-1273) and the Johnson and Johnson/Jannsen COVID-19 (JNJ-78436735) vaccines are approved for individuals aged ≥ 18 years, though the latter vaccine has been temporarily suspended.^1,3-5 The EUAs were released following the disclosure of the results of 3 phase 3 clinical trials and several phase 1 and 2 clinical trials.^9-16

The BNT162b2 vaccine from Pfizer-BioNTech encodes the SARS-CoV-2 full-length spike protein (S) in prefusion conformation locked by the mutation in 2 prolines.⁹ Differently from the BNT162b2 vaccine, the BNT162b1 vaccine encodes a secreted trimerized SARS-CoV-2 receptor–binding domain. The S-glycoprotein is required for viral entry, as implicated in host cell attachment, and is the target of the neutralizing antibodies. In a phase 1 clinical study on 195 volunteers treated with BNT162b1 (10 mg, 20 mg, 30 mg, or 100 mg doses) or BNT162b2 (10 mg, 20 mg, or 30 mg doses) vaccines or placebo 21 days apart, both the binding and neutralizing antibody response was found to be age and “somewhat” dose dependent.⁹

Higher neutralization titers were measured at day 28 and 35 (7 and 14 days after the second dose, respectively) and compared with titers of persons who recovered from a COVID-19 infection.⁹ Serum neutralization was measured using a fluorescence-based high-throughput neutralization assay, while binding activity was assessed using the receptor-binding domain (RBD)–binding or S1-binding IgG direct Luminex immunoassays.

The overall reactogenicity/immunogenicity profile of BNT162b2 administered twice (30 mg each time) led to its selection for the phase 3 clinical trial.^9,10 In a large phase 3 clinical trial on 43,458 participants, the BNT162b2 vaccine given at 30 mg doses 21 days apart conferred 95% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁰ No safety concerns to stop the trial were identified, though related severe and life-threatening events were reported in 0.3% and 0.1% of the volunteers, respectively. We note that these incidence rates were the same for the treated and the placebo group.

The mRNA-1273 vaccine from Moderna also encodes the SARS-CoV-2 S-glycoprotein. In a dose escalation phase 1 trial of 45 participants aged between 18 and 55 years (25 mg, 100 mg or 250 mg, given at days 1 and 29) and 40 participants aged ≥ 57 years (25 mg and 100 mg, given at days 1 and 29), a dose-dependent effect was observed for both binding (receptor-binding domain and S-2p IgG on enzyme-linked immunosorbent assay [ELISA])and neutralizing antibodies (SARS-CoV-2 nanoluciferase high-throughput neutralization assay, focus reduction neutralization test mNeonGreen and SARS-CoV-2 plaque-reduction neutralization testing assay) development.^11,12 The geometric mean of both binding and neutralizing antibodies declined over time but persisted high as late as 119 days after the first burst of 100 mg dose.¹³ The same dose of the vaccine also elicited a strong T helper-1 response with little T helper-2 response across all ages.¹¹ The strength of the memory cellular response remains to be defined and is the subject of ongoing investigations. In a large phase 3 clinical trial with 30,420 participants, the Moderna COVID-19 mRNA-1273 vaccine, given 28 days apart at the dose of 100 mg, met 94.1% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁴

Less than 0.1% of volunteers in both groups withdrew from the trial due to adverse effects (AEs); 0.5% in the placebo group and 0.3% in the treated group had AEs after the first dose, which precluded receiving the second dose.¹⁴

The Johnson and Johnson/Jannsen JNJ-78436735 vaccine is based upon a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector, which encodes the full-length, stabilized S-glycoprotein of SARS-CoV-2. The currently reported results of the phase 1 and 2 clinical study indicated that 805 volunteers (402 participants between ages 18 and 55 years and 403 individuals aged ≥ 65 years) were randomized to receive a single or double dose of either 5 x 10¹⁰ viral particles per 0.5 mL (low dose) or 1 x 10¹¹ viral particles per 0.5 mL (high dose), each compared with a placebo group. Incidence of seroconversion to binding antibodies against the full-length stabilized S-glycoprotein, as measured by ELISA, showed ≥ 96% seroconversion by day 29 after the first dose. The incidence of seroconversion to neutralizing antibodies was ≥ 90% as early as early as 29 days after the first of either dose. In this study, neutralization activity was measured using the wild-type virus microneutralization assay based on the Victoria/1/2020/ SARS-CoV-2 strain.¹⁵ We note that the data related to this study have been partially reported and additional information will be available when each participant will have received the second dose.

In a large phase 3 clinical trial with 40,000 participants aged between 18 and 100 years, the Johnson and Johnson/Jannsen JNJ-78436735 vaccine, given as single dose of 5 x 10¹⁰ viral particles per 0.5 mL, met 65.5% clinical efficacy in the likelihood of being affected by symptomatic COVID-19 ≥ 28 days postimmunization.¹⁶ In this study, the vaccine efficacy was found to have a geographic distribution with highest efficacy in the US (74.4%), followed by Latin America (64.7%) where Brazil showed a predominance of the P2 COVID-19 lineage (64.7%), and Africa (52%) where the B.1.351 lineage was most frequent (94.5%). The vaccine also proved to be effective in reducing the likelihood of asymptomatic seroconversion, as measured by the level of a non-S protein, eg, 0.7% of positive cases in the vaccine group vs 2.8% in the placebo group. Immunological data indicated that the vaccine response was mainly driven by T-helper 1 lymphocytes. As of April 13, 2021 the FDA has recommend suspending the administration of the Johnson and Johnson/Janssen vaccine due to the occurrence of severe blood clots reported in a 6 subjects out of ~6.8 millions administered doses.¹

It is noteworthy to highlight that all vaccines reduced the likelihood of hospitalizations and deaths due to COVID-19.

As of April 17, 2021, the CDC reports that more than 130 million (40%) Americans, nearly 1/3 of the population, have received at least 1 dose of any of the 3 available vaccines, including 4.6 million at the VHA.¹⁷ Using the Vaccine Adverse Event Reporting System and v-safe, the US is conducting what has been defined the most “intense and comprehensive safety monitoring in the US history.”¹⁸ Thus far, data affirm the overall safety of the available vaccines against COVID-19. Individuals should not receive the COVID-19 vaccines if they have had a severe allergic reaction to any ingredient in the vaccine or a severe allergic reaction to a prior dose of the vaccine. Additionally, individuals who have received convalescent plasma should wait 90 days before getting the COVID-19 vaccine.

Vaccination for Persons with MS

PwMS or those on immunosuppressive medications were excluded from the clinical trial led by Pfizer-BioNTech. There is no mention of MS as comorbidity in the study from Moderna, although this condition is not listed as an exclusion criterion either. The results of the phase 3 clinical trial for the Johnson and Johnson/Janssen vaccine are not fully public yet, thus this information is not known as well. As a result, the use of this vaccine in pwMS under immunomodulatory agents is based on previous knowledge of other vaccines. Evidence is growing for the safety of the BNT162b2 COVID-19 vaccination in pwMS.¹⁹ Data regarding COVID-19 efficacy and safety are still largely based on previous knowledge on other vaccines.^20,21

Immunization of pwMS is considered safe and should proceed with confidence in those persons who have no other contraindication to receive a vaccine. A fundamental problem for pwMS treated with immunomodulatory or immunosuppressive medications is whether the vaccine will remain safe or be able to solicit an adequate immune response.^20,21 As of the time of publication 2021, there is consensus that mRNA based or inactivated vaccines are also considered safe in pwMS undergoing immunomodulatory or immunosuppressive treatments.^20-23 We advise a one-on-one conversation between each veteran with MS and their primary neurologist to understand the importance of the vaccination, the minimal risks associated with it and if any specific treatment modification should be made.

To provide guidance, the National MS Society released a position statement that is regularly updated.²² Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. In addition, on the basis of available literature and the American Academy of Neurology recommendations on the use of vaccines in general, the following recommendations are proposed.^20-23

Recommendation 1: injections, orals, and natalizumab. Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. Neither delay in start nor adjustments in dosing or timing of administration are advised for pwMS taking currently available either generic or brand formulations of β interferons, glatiramer acetate, teriflunomide, dimethyl or monomethyl fumarate, or natalizumab.²²

Recommendation 2: anti-CD20 monoclonal infusions. As an attenuated humoral response is predicted in pwMS treated with anti-CD20 monoclonal infusions, coordinating the timing of vaccination with treatment schedule may maximize efficacy of the vaccine. Whenever possible, it is advised to be vaccinated ≥ 12 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting anti-CD20 monoclonal infusions are advised to be fully vaccinated first and start these medications ≥ 2 to 4 weeks later.²²

Recommendation 3: alemtuzumab infusion. Given its effect on CD52+ cells, it is advised to be vaccinated ≥ 24 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting alemtuzumab infusions are advised to get fully vaccinated first and start this medication 4 weeks or more after completing the vaccine.²²

Recommendation 4: sphingosine 1 phosphate receptor modulators, oral cladribine, and ofatumumab. PwMS starting any of these medications are advised to be fully vaccinated first and start these medications 2 to 4 weeks after completing the vaccine. PwMS already on those medications are not advised to change the schedule of administration. When possible, though, one should resume the dose of cladribine or ofatumumab 2 to 4 weeks after the last dose of the vaccine. ²⁰

Notably, all these recommendations hold true when there is enough disease stability to allow delaying treatment. We also add that it remains unclear if persons with an overall very low number of lymphocytes will be able to elicit a strong reaction to the vaccine. Blood collection and analysis of white blood cell count and lymphocyte subset estimates should be obtained in those persons with a markedly suppressed immune system. Whenever possible, to maximize outcome, timing the vaccination with treatment should be considered in those persons with a markedly reduced number of T-helper 1 cells.

Vaccination for Veterans

Currently the VHA is offering to veterans the Pfizer and Moderna COVID-19 vaccines with FDA EUAs. In accordance with FDA regulations, the VHA has paused administration of the Johnson and Johnson/Janssen vaccine. The VHA has launched its vaccination program in December 2020 by first providing the vaccine to health care personnel, nursing home patients, spinal cord injury patients, chemotherapy patients, dialysis and transplant patients, as well as homeless veterans. Most VA health care systems have passed this phase and are now able to provide vaccines to veterans with MS.

In December 2020, the MSCoE released a position statement regarding the importance and safety of the COVID-19 vaccine for veterans with MS.²⁴ This statement will be updated on a regular basis as new information becomes available from major organizations like the National MS Society, FDA, CDC, and World Health Organization (WHO) or relevant literature.

Conclusions

Older veterans with progressive MS and associated comorbidities are at higher risk of death should they be infected by COVID-19. Fortunately, we live in a time where vaccines are recognized as a critical tool to prevent this infection and to significantly reduce its morbidity and mortality. Yet, hesitancy to vaccinate has been identified as one of the most important threats to public health by the WHO in 2019.²⁵ Understandably such hesitancy is even more profound for the COVID-19 vaccine, which is being administered under an EUA. In light of this indecision, and given the current state of the pandemic, we urge health care providers to educate every veteran about the benefits of being vaccinated against COVID-19. Within the VHA, a solid campaign of vaccination has been put in place at an unprecedented speed.

Health care providers interacting with veterans with MS are encouraged to use the MSCoE website (www.va.gov/ms) for any questions or concerns, or to reach out to MSCoE staff. It is vitally important that our community of veterans receives appropriate education on the importance of this vaccination for their own safety, for that of their household and society.

This article has been updated to reflect new US Food and Drug Administration and Centers for Disease Control and Prevention recommendations to pause administration of the Johnson and Johnson Jansen (JNJ-78436735) COVID-19 vaccine.¹

Since the outbreak of the pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2),a plethora of studies have been performed to increase our knowledge of its associated illness COVID-19.² There is no cure for COVID-19, which can be lethal. In the absence of a cure, preventive measures are of vital importance. In order to help prevent the spread of the virus, the Centers for Diseases Control and Prevention (CDC) advocates for: (1) the use of a face mask over the mouth and nose; (2) a minimum of 6-foot distance between individuals; and (3) avoidance of gatherings.As of March 2021, the US Food and Drug Administration (FDA) approved 3 vaccines for the prevention of COVID-19, under an emergency use authorization (EUA).^3-5

COVID-19 and Multiple Sclerosis

Since the beginning of the pandemic, neurologists have faced a new challenge—determining whether persons with multiple sclerosis (pwMS) were more at risk than others of becoming ill from COVID-19 or were destined for a worse outcome. The National MS Society has advised a personalized approach in relation to particularly vulnerable persons when needed and has also initiated worldwide registries to collect information regarding incidence and outcome of COVID-19 in pwMS. Accordingly, through the MS Center of Excellence (MSCoE), the Veterans Health Administration (VHA) has established a national registry assembling data regarding COVID-19 in veterans with MS.

A recent descriptive literature review summarized the outcomes of 873 persons with both MS and COVID-19 and reported that about 36% of COVID-19 cases were treated with B-cell depleting therapies (ocrelizumab or rituximab).⁶ This proportion was relatively higher when compared with other disease modifying agents. Of those who became infected with SARS-CoV-2, death from COVID-19 occurred in about 4%, and an additional 3% required assisted invasive or noninvasive ventilation. Persons reported to have passed away from COVID-19 generally were older; had progressive MS; or had associated comorbidities such as obesity, hypertension, heart or lung conditions, or cancers. Of these, 50% were not on any disease modifying agent, 25% were on B-cell depleting therapies (ocrelizumab or rituximab), and the remaining 25% were on various medications for MS. It is important to highlight that no formal statistical analyses were performed in this review. On the contrary, in the recently published Italian report on 844 pwMS who had suspected or confirmed COVID-19, the authors used univariate and multivariate models to analyze their findings and noted that the use of ocrelizumab was significantly associated with a worse clinical outcome.⁷ These authors also identified age, sex, disability score, and recent (within 1 month) use of steroids as risk factors for a severe COVID-19 outcome. The incidence of death from COVID-19 in this cohort was 1.54%.

The recently published data from the North American Registry of the National MS Society based on 1,626 patients reported a 3.3% incidence of death from COVID-19.⁸ The following factors were identified as risks for worse outcome: male sex, nonambulatory status, age, Black race, and cardiovascular disease. The use of rituximab, ocrelizumab, and steroids (the latter medication over the preceding 2 months) increased the risks of hospitalization for COVID-19.

COVID-19 Vaccines

Of the 3 available vaccines, the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine is approved for individuals aged ≥ 16 years, while the Moderna COVID-19 (mRNA-1273) and the Johnson and Johnson/Jannsen COVID-19 (JNJ-78436735) vaccines are approved for individuals aged ≥ 18 years, though the latter vaccine has been temporarily suspended.^1,3-5 The EUAs were released following the disclosure of the results of 3 phase 3 clinical trials and several phase 1 and 2 clinical trials.^9-16

The BNT162b2 vaccine from Pfizer-BioNTech encodes the SARS-CoV-2 full-length spike protein (S) in prefusion conformation locked by the mutation in 2 prolines.⁹ Differently from the BNT162b2 vaccine, the BNT162b1 vaccine encodes a secreted trimerized SARS-CoV-2 receptor–binding domain. The S-glycoprotein is required for viral entry, as implicated in host cell attachment, and is the target of the neutralizing antibodies. In a phase 1 clinical study on 195 volunteers treated with BNT162b1 (10 mg, 20 mg, 30 mg, or 100 mg doses) or BNT162b2 (10 mg, 20 mg, or 30 mg doses) vaccines or placebo 21 days apart, both the binding and neutralizing antibody response was found to be age and “somewhat” dose dependent.⁹

Higher neutralization titers were measured at day 28 and 35 (7 and 14 days after the second dose, respectively) and compared with titers of persons who recovered from a COVID-19 infection.⁹ Serum neutralization was measured using a fluorescence-based high-throughput neutralization assay, while binding activity was assessed using the receptor-binding domain (RBD)–binding or S1-binding IgG direct Luminex immunoassays.

The overall reactogenicity/immunogenicity profile of BNT162b2 administered twice (30 mg each time) led to its selection for the phase 3 clinical trial.^9,10 In a large phase 3 clinical trial on 43,458 participants, the BNT162b2 vaccine given at 30 mg doses 21 days apart conferred 95% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁰ No safety concerns to stop the trial were identified, though related severe and life-threatening events were reported in 0.3% and 0.1% of the volunteers, respectively. We note that these incidence rates were the same for the treated and the placebo group.

The mRNA-1273 vaccine from Moderna also encodes the SARS-CoV-2 S-glycoprotein. In a dose escalation phase 1 trial of 45 participants aged between 18 and 55 years (25 mg, 100 mg or 250 mg, given at days 1 and 29) and 40 participants aged ≥ 57 years (25 mg and 100 mg, given at days 1 and 29), a dose-dependent effect was observed for both binding (receptor-binding domain and S-2p IgG on enzyme-linked immunosorbent assay [ELISA])and neutralizing antibodies (SARS-CoV-2 nanoluciferase high-throughput neutralization assay, focus reduction neutralization test mNeonGreen and SARS-CoV-2 plaque-reduction neutralization testing assay) development.^11,12 The geometric mean of both binding and neutralizing antibodies declined over time but persisted high as late as 119 days after the first burst of 100 mg dose.¹³ The same dose of the vaccine also elicited a strong T helper-1 response with little T helper-2 response across all ages.¹¹ The strength of the memory cellular response remains to be defined and is the subject of ongoing investigations. In a large phase 3 clinical trial with 30,420 participants, the Moderna COVID-19 mRNA-1273 vaccine, given 28 days apart at the dose of 100 mg, met 94.1% clinical efficacy in reducing the likelihood of being affected by symptomatic COVID-19.¹⁴

Less than 0.1% of volunteers in both groups withdrew from the trial due to adverse effects (AEs); 0.5% in the placebo group and 0.3% in the treated group had AEs after the first dose, which precluded receiving the second dose.¹⁴

The Johnson and Johnson/Jannsen JNJ-78436735 vaccine is based upon a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector, which encodes the full-length, stabilized S-glycoprotein of SARS-CoV-2. The currently reported results of the phase 1 and 2 clinical study indicated that 805 volunteers (402 participants between ages 18 and 55 years and 403 individuals aged ≥ 65 years) were randomized to receive a single or double dose of either 5 x 10¹⁰ viral particles per 0.5 mL (low dose) or 1 x 10¹¹ viral particles per 0.5 mL (high dose), each compared with a placebo group. Incidence of seroconversion to binding antibodies against the full-length stabilized S-glycoprotein, as measured by ELISA, showed ≥ 96% seroconversion by day 29 after the first dose. The incidence of seroconversion to neutralizing antibodies was ≥ 90% as early as early as 29 days after the first of either dose. In this study, neutralization activity was measured using the wild-type virus microneutralization assay based on the Victoria/1/2020/ SARS-CoV-2 strain.¹⁵ We note that the data related to this study have been partially reported and additional information will be available when each participant will have received the second dose.

In a large phase 3 clinical trial with 40,000 participants aged between 18 and 100 years, the Johnson and Johnson/Jannsen JNJ-78436735 vaccine, given as single dose of 5 x 10¹⁰ viral particles per 0.5 mL, met 65.5% clinical efficacy in the likelihood of being affected by symptomatic COVID-19 ≥ 28 days postimmunization.¹⁶ In this study, the vaccine efficacy was found to have a geographic distribution with highest efficacy in the US (74.4%), followed by Latin America (64.7%) where Brazil showed a predominance of the P2 COVID-19 lineage (64.7%), and Africa (52%) where the B.1.351 lineage was most frequent (94.5%). The vaccine also proved to be effective in reducing the likelihood of asymptomatic seroconversion, as measured by the level of a non-S protein, eg, 0.7% of positive cases in the vaccine group vs 2.8% in the placebo group. Immunological data indicated that the vaccine response was mainly driven by T-helper 1 lymphocytes. As of April 13, 2021 the FDA has recommend suspending the administration of the Johnson and Johnson/Janssen vaccine due to the occurrence of severe blood clots reported in a 6 subjects out of ~6.8 millions administered doses.¹

It is noteworthy to highlight that all vaccines reduced the likelihood of hospitalizations and deaths due to COVID-19.

As of April 17, 2021, the CDC reports that more than 130 million (40%) Americans, nearly 1/3 of the population, have received at least 1 dose of any of the 3 available vaccines, including 4.6 million at the VHA.¹⁷ Using the Vaccine Adverse Event Reporting System and v-safe, the US is conducting what has been defined the most “intense and comprehensive safety monitoring in the US history.”¹⁸ Thus far, data affirm the overall safety of the available vaccines against COVID-19. Individuals should not receive the COVID-19 vaccines if they have had a severe allergic reaction to any ingredient in the vaccine or a severe allergic reaction to a prior dose of the vaccine. Additionally, individuals who have received convalescent plasma should wait 90 days before getting the COVID-19 vaccine.

Vaccination for Persons with MS

PwMS or those on immunosuppressive medications were excluded from the clinical trial led by Pfizer-BioNTech. There is no mention of MS as comorbidity in the study from Moderna, although this condition is not listed as an exclusion criterion either. The results of the phase 3 clinical trial for the Johnson and Johnson/Janssen vaccine are not fully public yet, thus this information is not known as well. As a result, the use of this vaccine in pwMS under immunomodulatory agents is based on previous knowledge of other vaccines. Evidence is growing for the safety of the BNT162b2 COVID-19 vaccination in pwMS.¹⁹ Data regarding COVID-19 efficacy and safety are still largely based on previous knowledge on other vaccines.^20,21

Immunization of pwMS is considered safe and should proceed with confidence in those persons who have no other contraindication to receive a vaccine. A fundamental problem for pwMS treated with immunomodulatory or immunosuppressive medications is whether the vaccine will remain safe or be able to solicit an adequate immune response.^20,21 As of the time of publication 2021, there is consensus that mRNA based or inactivated vaccines are also considered safe in pwMS undergoing immunomodulatory or immunosuppressive treatments.^20-23 We advise a one-on-one conversation between each veteran with MS and their primary neurologist to understand the importance of the vaccination, the minimal risks associated with it and if any specific treatment modification should be made.

To provide guidance, the National MS Society released a position statement that is regularly updated.²² Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. In addition, on the basis of available literature and the American Academy of Neurology recommendations on the use of vaccines in general, the following recommendations are proposed.^20-23

Recommendation 1: injections, orals, and natalizumab. Given the risks associated with discontinuation of disease modifying agents, pwMS opting to receive a COVID-19 vaccine should continue taking their medications unless recommended otherwise by their primary neurologist. Neither delay in start nor adjustments in dosing or timing of administration are advised for pwMS taking currently available either generic or brand formulations of β interferons, glatiramer acetate, teriflunomide, dimethyl or monomethyl fumarate, or natalizumab.²²

Recommendation 2: anti-CD20 monoclonal infusions. As an attenuated humoral response is predicted in pwMS treated with anti-CD20 monoclonal infusions, coordinating the timing of vaccination with treatment schedule may maximize efficacy of the vaccine. Whenever possible, it is advised to be vaccinated ≥ 12 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting anti-CD20 monoclonal infusions are advised to be fully vaccinated first and start these medications ≥ 2 to 4 weeks later.²²

Recommendation 3: alemtuzumab infusion. Given its effect on CD52+ cells, it is advised to be vaccinated ≥ 24 weeks after the last infusion and to resume infusion 4 weeks after the last dose of the vaccine. PwMS starting alemtuzumab infusions are advised to get fully vaccinated first and start this medication 4 weeks or more after completing the vaccine.²²

Recommendation 4: sphingosine 1 phosphate receptor modulators, oral cladribine, and ofatumumab. PwMS starting any of these medications are advised to be fully vaccinated first and start these medications 2 to 4 weeks after completing the vaccine. PwMS already on those medications are not advised to change the schedule of administration. When possible, though, one should resume the dose of cladribine or ofatumumab 2 to 4 weeks after the last dose of the vaccine. ²⁰

Notably, all these recommendations hold true when there is enough disease stability to allow delaying treatment. We also add that it remains unclear if persons with an overall very low number of lymphocytes will be able to elicit a strong reaction to the vaccine. Blood collection and analysis of white blood cell count and lymphocyte subset estimates should be obtained in those persons with a markedly suppressed immune system. Whenever possible, to maximize outcome, timing the vaccination with treatment should be considered in those persons with a markedly reduced number of T-helper 1 cells.

Vaccination for Veterans

Currently the VHA is offering to veterans the Pfizer and Moderna COVID-19 vaccines with FDA EUAs. In accordance with FDA regulations, the VHA has paused administration of the Johnson and Johnson/Janssen vaccine. The VHA has launched its vaccination program in December 2020 by first providing the vaccine to health care personnel, nursing home patients, spinal cord injury patients, chemotherapy patients, dialysis and transplant patients, as well as homeless veterans. Most VA health care systems have passed this phase and are now able to provide vaccines to veterans with MS.

In December 2020, the MSCoE released a position statement regarding the importance and safety of the COVID-19 vaccine for veterans with MS.²⁴ This statement will be updated on a regular basis as new information becomes available from major organizations like the National MS Society, FDA, CDC, and World Health Organization (WHO) or relevant literature.

Conclusions

Older veterans with progressive MS and associated comorbidities are at higher risk of death should they be infected by COVID-19. Fortunately, we live in a time where vaccines are recognized as a critical tool to prevent this infection and to significantly reduce its morbidity and mortality. Yet, hesitancy to vaccinate has been identified as one of the most important threats to public health by the WHO in 2019.²⁵ Understandably such hesitancy is even more profound for the COVID-19 vaccine, which is being administered under an EUA. In light of this indecision, and given the current state of the pandemic, we urge health care providers to educate every veteran about the benefits of being vaccinated against COVID-19. Within the VHA, a solid campaign of vaccination has been put in place at an unprecedented speed.

Health care providers interacting with veterans with MS are encouraged to use the MSCoE website (www.va.gov/ms) for any questions or concerns, or to reach out to MSCoE staff. It is vitally important that our community of veterans receives appropriate education on the importance of this vaccination for their own safety, for that of their household and society.

It is often assumed that cognitive decline is an inevitable part of aging, but a new study of centenarians suggests otherwise.

Investigators found that despite the presence of neuropathologies associated with Alzheimer’s disease (AD), many centenarians maintained high levels of cognitive performance.

“Cognitive decline is not inevitable,” senior author Henne Holstege, PhD, assistant professor, Amsterdam Alzheimer Center and Clinical Genetics, Amsterdam University Medical Center, said in an interview.

“At 100 years or older, high levels of cognitive performance can be maintained for several years, even when individuals are exposed to risk factors associated with cognitive decline,” she said.

The study was published online Jan. 15 in JAMA Network Open.
 

Escaping cognitive decline

Dr. Holstege said her interest in researching aging and cognitive health was inspired by the “fascinating” story of Hendrikje van Andel-Schipper, who died at age 115 in 2015 “completely cognitively healthy.” Her mother, who died at age 100, also was cognitively intact at the end of her life.

“I wanted to know how it is possible that some people can completely escape all aspects of cognitive decline while reaching extreme ages,” Dr. Holstege said.

To discover the secret to cognitive health in the oldest old, Dr. Holstege initiated the 100-Plus Study, which involved a cohort of healthy centenarians.

The investigators conducted extensive neuropsychological testing and collected blood and fecal samples to examine “the myriad factors that influence physical health, including genetics, neuropathology, blood markers, and the gut microbiome, to explore the molecular and neuropsychologic constellations associated with the escape from cognitive decline.”

The goal of the research was to investigate “to what extent centenarians were able to maintain their cognitive health after study inclusion, and to what extent this was associated with genetic, physical, or neuropathological features,” she said.

The study included 330 centenarians who completed one or more neuropsychological assessments. Neuropathologic studies were available for 44 participants.

To assess baseline cognitive performance, the researchers administered a wide array of neurocognitive tests, as well as the Mini–Mental State Examination, from which mean z scores for cognitive domains were calculated.

Additional factors in the analysis included sex, age, APOE status, cognitive reserve, physical health, and whether participants lived independently.

At autopsy, amyloid-beta (A-beta) level, the level of intracellular accumulation of phosphorylated tau protein in neurofibrillary tangles (NFTs), and the neuritic plaque (NP) load were assessed.
 

Resilience and cognitive reserve

At baseline, the median age of the centenarians (n = 330, 72.4% women) was 100.5 years (interquartile range, 100.2-101.7). A little over half (56.7%) lived independently, and the majority had good vision (65%) and hearing (56.4%). Most (78.8%) were able to walk independently, and 37.9% had achieved the highest International Standard Classification of Education level of postsecondary education.

The researchers found “varying degrees of neuropathology” in the brains of the 44 donors, including A-beta, NFT, and NPs.

The duration of follow-up in analyzing cognitive trajectories ranged from 0 to 4 years (median, 1.6 years).

Assessments of all cognitive domains showed no decline, with the exception of a “slight” decrement in memory function (beta −.10 SD per year; 95% confidence interval, –.14 to –.05 SD; P < .001).

Cognitive performance was associated with factors of physical health or cognitive reserve, for example, greater independence in performing activities of daily living, as assessed by the Barthel index (beta .37 SD per year; 95% CI, .24-.49; P < .001), or higher educational level (beta .41 SD per year; 95% CI, .29-.53; P < .001).

Despite findings of neuropathologic “hallmarks” of AD post mortem in the brains of the centenarians, these were not associated with cognitive performance or rate of decline.

APOE epsilon-4 or an APOE epsilon-3 alleles also were not significantly associated with cognitive performance or decline, suggesting that the “effects of APOE alleles are exerted before the age of 100 years,” the authors noted.

“Our findings suggest that after reaching age 100 years, cognitive performance remains relatively stable during ensuing years. Therefore, these centenarians might be resilient or resistant against different risk factors of cognitive decline,” the authors wrote. They also speculate that resilience may be attributable to greater cognitive reserve.

“Our preliminary data indicate that approximately 60% of the chance to reach 100 years old is heritable. Therefore, to get a better understanding of which genetic factors associate with the prolonged maintenance of cognitive health, we are looking into which genetic variants occur more commonly in centenarians compared to younger individuals,” said Dr. Holstege.

“Of course, more research needs to be performed to get a better understanding of how such genetic elements might sustain brain health,” she added.
 

A ‘landmark study’

Commenting on the study in an interview, Thomas Perls, MD, MPH, professor of medicine, Boston University, called it a “landmark” study in research on exceptional longevity in humans.

Dr. Perls, the author of an accompanying editorial, noted that “one cannot absolutely assume a certain level or disability or risk for disease just because a person has achieved extreme age – in fact, if anything, their ability to achieve much older ages likely indicates that they have resistance or resilience to aging-related problems.”

Understanding the mechanism of the resilience could lead to treatment or prevention of AD, said Dr. Perls, who was not involved in the research.

“People have to be careful about ageist myths and attitudes and not have the ageist idea that the older you get, the sicker you get, because many individuals disprove that,” he cautioned.

The study was supported by Stichting Alzheimer Nederland and Stichting Vumc Fonds. Research from the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Dr. Holstege and Dr. Perls reported having no relevant financial relationships. The other authors’ disclosures are listed on the original article.

A version of this article first appeared on Medscape.com.

It is often assumed that cognitive decline is an inevitable part of aging, but a new study of centenarians suggests otherwise.

Investigators found that despite the presence of neuropathologies associated with Alzheimer’s disease (AD), many centenarians maintained high levels of cognitive performance.

“Cognitive decline is not inevitable,” senior author Henne Holstege, PhD, assistant professor, Amsterdam Alzheimer Center and Clinical Genetics, Amsterdam University Medical Center, said in an interview.

“At 100 years or older, high levels of cognitive performance can be maintained for several years, even when individuals are exposed to risk factors associated with cognitive decline,” she said.

The study was published online Jan. 15 in JAMA Network Open.
 

Escaping cognitive decline

Dr. Holstege said her interest in researching aging and cognitive health was inspired by the “fascinating” story of Hendrikje van Andel-Schipper, who died at age 115 in 2015 “completely cognitively healthy.” Her mother, who died at age 100, also was cognitively intact at the end of her life.

“I wanted to know how it is possible that some people can completely escape all aspects of cognitive decline while reaching extreme ages,” Dr. Holstege said.

To discover the secret to cognitive health in the oldest old, Dr. Holstege initiated the 100-Plus Study, which involved a cohort of healthy centenarians.

The investigators conducted extensive neuropsychological testing and collected blood and fecal samples to examine “the myriad factors that influence physical health, including genetics, neuropathology, blood markers, and the gut microbiome, to explore the molecular and neuropsychologic constellations associated with the escape from cognitive decline.”

The goal of the research was to investigate “to what extent centenarians were able to maintain their cognitive health after study inclusion, and to what extent this was associated with genetic, physical, or neuropathological features,” she said.

The study included 330 centenarians who completed one or more neuropsychological assessments. Neuropathologic studies were available for 44 participants.

To assess baseline cognitive performance, the researchers administered a wide array of neurocognitive tests, as well as the Mini–Mental State Examination, from which mean z scores for cognitive domains were calculated.

Additional factors in the analysis included sex, age, APOE status, cognitive reserve, physical health, and whether participants lived independently.

At autopsy, amyloid-beta (A-beta) level, the level of intracellular accumulation of phosphorylated tau protein in neurofibrillary tangles (NFTs), and the neuritic plaque (NP) load were assessed.
 

Resilience and cognitive reserve

At baseline, the median age of the centenarians (n = 330, 72.4% women) was 100.5 years (interquartile range, 100.2-101.7). A little over half (56.7%) lived independently, and the majority had good vision (65%) and hearing (56.4%). Most (78.8%) were able to walk independently, and 37.9% had achieved the highest International Standard Classification of Education level of postsecondary education.

The researchers found “varying degrees of neuropathology” in the brains of the 44 donors, including A-beta, NFT, and NPs.

The duration of follow-up in analyzing cognitive trajectories ranged from 0 to 4 years (median, 1.6 years).

Assessments of all cognitive domains showed no decline, with the exception of a “slight” decrement in memory function (beta −.10 SD per year; 95% confidence interval, –.14 to –.05 SD; P < .001).

Cognitive performance was associated with factors of physical health or cognitive reserve, for example, greater independence in performing activities of daily living, as assessed by the Barthel index (beta .37 SD per year; 95% CI, .24-.49; P < .001), or higher educational level (beta .41 SD per year; 95% CI, .29-.53; P < .001).

Despite findings of neuropathologic “hallmarks” of AD post mortem in the brains of the centenarians, these were not associated with cognitive performance or rate of decline.

APOE epsilon-4 or an APOE epsilon-3 alleles also were not significantly associated with cognitive performance or decline, suggesting that the “effects of APOE alleles are exerted before the age of 100 years,” the authors noted.

“Our findings suggest that after reaching age 100 years, cognitive performance remains relatively stable during ensuing years. Therefore, these centenarians might be resilient or resistant against different risk factors of cognitive decline,” the authors wrote. They also speculate that resilience may be attributable to greater cognitive reserve.

“Our preliminary data indicate that approximately 60% of the chance to reach 100 years old is heritable. Therefore, to get a better understanding of which genetic factors associate with the prolonged maintenance of cognitive health, we are looking into which genetic variants occur more commonly in centenarians compared to younger individuals,” said Dr. Holstege.

“Of course, more research needs to be performed to get a better understanding of how such genetic elements might sustain brain health,” she added.
 

A ‘landmark study’

Commenting on the study in an interview, Thomas Perls, MD, MPH, professor of medicine, Boston University, called it a “landmark” study in research on exceptional longevity in humans.

Dr. Perls, the author of an accompanying editorial, noted that “one cannot absolutely assume a certain level or disability or risk for disease just because a person has achieved extreme age – in fact, if anything, their ability to achieve much older ages likely indicates that they have resistance or resilience to aging-related problems.”

Understanding the mechanism of the resilience could lead to treatment or prevention of AD, said Dr. Perls, who was not involved in the research.

“People have to be careful about ageist myths and attitudes and not have the ageist idea that the older you get, the sicker you get, because many individuals disprove that,” he cautioned.

The study was supported by Stichting Alzheimer Nederland and Stichting Vumc Fonds. Research from the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Dr. Holstege and Dr. Perls reported having no relevant financial relationships. The other authors’ disclosures are listed on the original article.

A version of this article first appeared on Medscape.com.

It is often assumed that cognitive decline is an inevitable part of aging, but a new study of centenarians suggests otherwise.

Investigators found that despite the presence of neuropathologies associated with Alzheimer’s disease (AD), many centenarians maintained high levels of cognitive performance.

“Cognitive decline is not inevitable,” senior author Henne Holstege, PhD, assistant professor, Amsterdam Alzheimer Center and Clinical Genetics, Amsterdam University Medical Center, said in an interview.

“At 100 years or older, high levels of cognitive performance can be maintained for several years, even when individuals are exposed to risk factors associated with cognitive decline,” she said.

The study was published online Jan. 15 in JAMA Network Open.
 

Escaping cognitive decline

Dr. Holstege said her interest in researching aging and cognitive health was inspired by the “fascinating” story of Hendrikje van Andel-Schipper, who died at age 115 in 2015 “completely cognitively healthy.” Her mother, who died at age 100, also was cognitively intact at the end of her life.

“I wanted to know how it is possible that some people can completely escape all aspects of cognitive decline while reaching extreme ages,” Dr. Holstege said.

To discover the secret to cognitive health in the oldest old, Dr. Holstege initiated the 100-Plus Study, which involved a cohort of healthy centenarians.

The investigators conducted extensive neuropsychological testing and collected blood and fecal samples to examine “the myriad factors that influence physical health, including genetics, neuropathology, blood markers, and the gut microbiome, to explore the molecular and neuropsychologic constellations associated with the escape from cognitive decline.”

The goal of the research was to investigate “to what extent centenarians were able to maintain their cognitive health after study inclusion, and to what extent this was associated with genetic, physical, or neuropathological features,” she said.

The study included 330 centenarians who completed one or more neuropsychological assessments. Neuropathologic studies were available for 44 participants.

To assess baseline cognitive performance, the researchers administered a wide array of neurocognitive tests, as well as the Mini–Mental State Examination, from which mean z scores for cognitive domains were calculated.

Additional factors in the analysis included sex, age, APOE status, cognitive reserve, physical health, and whether participants lived independently.

At autopsy, amyloid-beta (A-beta) level, the level of intracellular accumulation of phosphorylated tau protein in neurofibrillary tangles (NFTs), and the neuritic plaque (NP) load were assessed.
 

Resilience and cognitive reserve

At baseline, the median age of the centenarians (n = 330, 72.4% women) was 100.5 years (interquartile range, 100.2-101.7). A little over half (56.7%) lived independently, and the majority had good vision (65%) and hearing (56.4%). Most (78.8%) were able to walk independently, and 37.9% had achieved the highest International Standard Classification of Education level of postsecondary education.

The researchers found “varying degrees of neuropathology” in the brains of the 44 donors, including A-beta, NFT, and NPs.

The duration of follow-up in analyzing cognitive trajectories ranged from 0 to 4 years (median, 1.6 years).

Assessments of all cognitive domains showed no decline, with the exception of a “slight” decrement in memory function (beta −.10 SD per year; 95% confidence interval, –.14 to –.05 SD; P < .001).

Cognitive performance was associated with factors of physical health or cognitive reserve, for example, greater independence in performing activities of daily living, as assessed by the Barthel index (beta .37 SD per year; 95% CI, .24-.49; P < .001), or higher educational level (beta .41 SD per year; 95% CI, .29-.53; P < .001).

Despite findings of neuropathologic “hallmarks” of AD post mortem in the brains of the centenarians, these were not associated with cognitive performance or rate of decline.

APOE epsilon-4 or an APOE epsilon-3 alleles also were not significantly associated with cognitive performance or decline, suggesting that the “effects of APOE alleles are exerted before the age of 100 years,” the authors noted.

“Our findings suggest that after reaching age 100 years, cognitive performance remains relatively stable during ensuing years. Therefore, these centenarians might be resilient or resistant against different risk factors of cognitive decline,” the authors wrote. They also speculate that resilience may be attributable to greater cognitive reserve.

“Our preliminary data indicate that approximately 60% of the chance to reach 100 years old is heritable. Therefore, to get a better understanding of which genetic factors associate with the prolonged maintenance of cognitive health, we are looking into which genetic variants occur more commonly in centenarians compared to younger individuals,” said Dr. Holstege.

“Of course, more research needs to be performed to get a better understanding of how such genetic elements might sustain brain health,” she added.
 

A ‘landmark study’

Commenting on the study in an interview, Thomas Perls, MD, MPH, professor of medicine, Boston University, called it a “landmark” study in research on exceptional longevity in humans.

Dr. Perls, the author of an accompanying editorial, noted that “one cannot absolutely assume a certain level or disability or risk for disease just because a person has achieved extreme age – in fact, if anything, their ability to achieve much older ages likely indicates that they have resistance or resilience to aging-related problems.”

Understanding the mechanism of the resilience could lead to treatment or prevention of AD, said Dr. Perls, who was not involved in the research.

“People have to be careful about ageist myths and attitudes and not have the ageist idea that the older you get, the sicker you get, because many individuals disprove that,” he cautioned.

The study was supported by Stichting Alzheimer Nederland and Stichting Vumc Fonds. Research from the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Dr. Holstege and Dr. Perls reported having no relevant financial relationships. The other authors’ disclosures are listed on the original article.

A version of this article first appeared on Medscape.com.

Patients with migraine experienced about a 60% reduction in pain intensity and number of headache days per month after exposure to green light therapy, according to results of a small study from the University of Arizona, Tucson.

“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”

“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.

The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.

The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
 

White versus green

The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.

Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.

The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.

The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.

On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).

“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.

“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
 

Better than white light

Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.

The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.

Patients with migraine experienced about a 60% reduction in pain intensity and number of headache days per month after exposure to green light therapy, according to results of a small study from the University of Arizona, Tucson.

“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”

“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.

The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.

The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
 

White versus green

The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.

Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.

The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.

The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.

On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).

“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.

“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
 

Better than white light

Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.

The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.

Patients with migraine experienced about a 60% reduction in pain intensity and number of headache days per month after exposure to green light therapy, according to results of a small study from the University of Arizona, Tucson.

“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”

“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.

The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.

The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
 

White versus green

The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.

Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.

The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.

The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.

On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).

“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.

“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
 

Better than white light

Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.

The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.