Neurology

In patients with tuberous sclerosis complex (TSC), preventive treatment with vigabatrin is safe and changes the natural history of seizures, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. This treatment strategy reduces the risk and severity of epilepsy, said the investigators.

As much as 90% of patients with TSC have epilepsy. Seizures generally start during infancy and are often resistant to medication. Clinicians are increasingly able to diagnose TSC prenatally, thus creating an opportunity for pursuing preventive strategies.

In the multicenter EPISTOP trial, Katarzyna Kotulska, MD, head of neurology and epileptology at Children’s Memorial Health Institute in Warsaw, and colleagues compared the efficacy and safety of preventive vigabatrin treatment with those of conventional vigabatrin treatment in infants with TSC. The researchers followed 94 infants with TSC and without a history of seizures with monthly video EEG. Conventional treatment was initiated after the first electrographic or clinical seizure, and preventive treatment was administered when epileptiform discharges were visible on EEG but before the first seizure.

Six sites randomly assigned patients to treatment in a equal groups in a randomized, controlled trial. At four other sites, treatment allocation was fixed in an open-label trial. All patients were followed until age 2 years. The study’s primary endpoint was the time to first clinical seizure.

A total of 53 patients participated in the randomized, controlled trial, and 41 participated in the open-label study; 79 patients completed the study. Of this group, 25 received preventive treatment, 25 received conventional treatment, and 22 patients had seizures before epileptiform activity was detected on EEG. Seven patients had neither seizures nor abnormal EEG.

The time to first clinical seizure was significantly longer in patients who received preventive treatment, compared with those who received conventional treatment. In the randomized, controlled trial, time to first seizure was 364 days in the preventive treatment group and 124 days in the conventional treatment group. In the open-label trial, time to first seizure was 426 days in the preventive treatment group and 106 days in the conventional treatment group.

A pooled analysis indicated that, at 24 months, preventive treatment significantly reduced the risk of clinical seizures (odds ratio, 0.21), drug-resistant epilepsy (OR, 0.23), and infantile spasms (OR, 0). The investigators did not record any adverse events related to preventive treatment.

The study was funded by the 7th Framework Program of the European Union. Dr. Kotulska did not report any disclosures.

egreb@mdedge.com

SOURCE: Kotulska K et al. CNS-ICNA 2020, Abstract PL13.

In patients with tuberous sclerosis complex (TSC), preventive treatment with vigabatrin is safe and changes the natural history of seizures, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. This treatment strategy reduces the risk and severity of epilepsy, said the investigators.

As much as 90% of patients with TSC have epilepsy. Seizures generally start during infancy and are often resistant to medication. Clinicians are increasingly able to diagnose TSC prenatally, thus creating an opportunity for pursuing preventive strategies.

In the multicenter EPISTOP trial, Katarzyna Kotulska, MD, head of neurology and epileptology at Children’s Memorial Health Institute in Warsaw, and colleagues compared the efficacy and safety of preventive vigabatrin treatment with those of conventional vigabatrin treatment in infants with TSC. The researchers followed 94 infants with TSC and without a history of seizures with monthly video EEG. Conventional treatment was initiated after the first electrographic or clinical seizure, and preventive treatment was administered when epileptiform discharges were visible on EEG but before the first seizure.

Six sites randomly assigned patients to treatment in a equal groups in a randomized, controlled trial. At four other sites, treatment allocation was fixed in an open-label trial. All patients were followed until age 2 years. The study’s primary endpoint was the time to first clinical seizure.

A total of 53 patients participated in the randomized, controlled trial, and 41 participated in the open-label study; 79 patients completed the study. Of this group, 25 received preventive treatment, 25 received conventional treatment, and 22 patients had seizures before epileptiform activity was detected on EEG. Seven patients had neither seizures nor abnormal EEG.

The time to first clinical seizure was significantly longer in patients who received preventive treatment, compared with those who received conventional treatment. In the randomized, controlled trial, time to first seizure was 364 days in the preventive treatment group and 124 days in the conventional treatment group. In the open-label trial, time to first seizure was 426 days in the preventive treatment group and 106 days in the conventional treatment group.

A pooled analysis indicated that, at 24 months, preventive treatment significantly reduced the risk of clinical seizures (odds ratio, 0.21), drug-resistant epilepsy (OR, 0.23), and infantile spasms (OR, 0). The investigators did not record any adverse events related to preventive treatment.

The study was funded by the 7th Framework Program of the European Union. Dr. Kotulska did not report any disclosures.

egreb@mdedge.com

SOURCE: Kotulska K et al. CNS-ICNA 2020, Abstract PL13.

In patients with tuberous sclerosis complex (TSC), preventive treatment with vigabatrin is safe and changes the natural history of seizures, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. This treatment strategy reduces the risk and severity of epilepsy, said the investigators.

As much as 90% of patients with TSC have epilepsy. Seizures generally start during infancy and are often resistant to medication. Clinicians are increasingly able to diagnose TSC prenatally, thus creating an opportunity for pursuing preventive strategies.

In the multicenter EPISTOP trial, Katarzyna Kotulska, MD, head of neurology and epileptology at Children’s Memorial Health Institute in Warsaw, and colleagues compared the efficacy and safety of preventive vigabatrin treatment with those of conventional vigabatrin treatment in infants with TSC. The researchers followed 94 infants with TSC and without a history of seizures with monthly video EEG. Conventional treatment was initiated after the first electrographic or clinical seizure, and preventive treatment was administered when epileptiform discharges were visible on EEG but before the first seizure.

Six sites randomly assigned patients to treatment in a equal groups in a randomized, controlled trial. At four other sites, treatment allocation was fixed in an open-label trial. All patients were followed until age 2 years. The study’s primary endpoint was the time to first clinical seizure.

A total of 53 patients participated in the randomized, controlled trial, and 41 participated in the open-label study; 79 patients completed the study. Of this group, 25 received preventive treatment, 25 received conventional treatment, and 22 patients had seizures before epileptiform activity was detected on EEG. Seven patients had neither seizures nor abnormal EEG.

The time to first clinical seizure was significantly longer in patients who received preventive treatment, compared with those who received conventional treatment. In the randomized, controlled trial, time to first seizure was 364 days in the preventive treatment group and 124 days in the conventional treatment group. In the open-label trial, time to first seizure was 426 days in the preventive treatment group and 106 days in the conventional treatment group.

A pooled analysis indicated that, at 24 months, preventive treatment significantly reduced the risk of clinical seizures (odds ratio, 0.21), drug-resistant epilepsy (OR, 0.23), and infantile spasms (OR, 0). The investigators did not record any adverse events related to preventive treatment.

The study was funded by the 7th Framework Program of the European Union. Dr. Kotulska did not report any disclosures.

egreb@mdedge.com

SOURCE: Kotulska K et al. CNS-ICNA 2020, Abstract PL13.

Children with stereotypies consult neurologists less often than do those with tics, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. The former also are younger at their first visit than are the latter. Compared with children with tics, children with stereotypies also have fewer comorbidities and receive fewer recommendations for interventions. This difference between groups may not merely reflect the younger age at presentation of children with stereotypies (e.g., at an age before a comorbidity is manifest). “At least in our population, it does seem to reflect an overall lower burden of comorbidities,” said Shannon Dean, MD, PhD, assistant professor of neurology at the Kennedy Krieger Institute of Johns Hopkins University in Baltimore.

Common pediatric movement disorders

Tics (i.e., short-lasting, sudden, repetitive movements) and stereotypies (i.e., rhythmic, fixed, deliberate, but purposeless movements) are common pediatric movement disorders with favorable prognoses. The disorders share several comorbidities, the most common of which are ADHD, anxiety, and obsessive-compulsive disorder (OCD). Dr. Dean and colleagues examined differences in comorbidity burden, resource use, and need for intervention between children with tics and those with stereotypies.

The investigators performed a retrospective chart review and identified 63 children diagnosed with stereotypies. They matched each of these children, by age when possible, with a child first diagnosed with a chronic or provisional tic disorder during the same year. All patients presented to the University of Rochester (N.Y.) Child Neurology Clinic between 2003 and 2016. Dr. Dean and colleagues excluded children with diagnoses for which stereotypies are considered a secondary feature (e.g., autism, intellectual disability, and blindness). They also excluded children who had tics and stereotypies.

The researchers examined the groups’ total number of visits, comorbidities, and recommended interventions. They also analyzed data from a follow-up survey that were available for 20 of the 63 patients with stereotypies. They tested continuous or discrete variables for normal distribution and used T tests or Mann–Whitney U as appropriate. To analyze categorical data, they used chi squared or Fisher’s exact test for groups smaller than five.
 

Differing rates of intervention

Children with stereotypies were younger at first visit (mean age, 5.6 years vs. 7.1 years) and at last visit (mean age, 6.5 years vs. 9.8 years) and had fewer total visits (1.8 vs. 4.5), compared with children with tics.

The three most common comorbidities in the population were more prevalent among patients with tics than among patients with stereotypies. The prevalence of ADHD was 27% among patients with stereotypies and 48% among patients with tics. The prevalence of OCD was 8% among children with stereotypies and 41% among children with tics. The prevalence of anxiety was 21% among children with stereotypies and 63% among children with tics. Children with stereotypies also had fewer neuropsychiatric comorbidities overall than did children with tics (0.7 per patient versus 1.9 per patient).

The clinicians had recommended at least one medication for tics in 22% of the children with tics. No medication is available for children with stereotypies. The clinicians recommended behavioral therapy for 13% of the children with tics, but for none of the children with stereotypies, “because none of them had functional impairment that would warrant intervention,” said Dr. Dean. The clinicians also made more recommendations for pharmaceutical and behavioral treatments for comorbidities in patients with tics than in patients with stereotypies.

When the investigators examined the follow-up survey data, they found that patients with stereotypies were older at last contact than patients with tics. Last contact was defined as the time of the survey for patients with stereotypies and the time of the last clinic visit for patients with tics. When Dr. Dean and colleagues examined the three most common comorbidities, however, they again found that the burden was greater among patients with tics (1.5 per patient) than among patients with stereotypies (0.8 per patient).

The study was funded by the T32 Experimental Therapeutics Training Grant from the University of Rochester, N.Y. Dr. Dean did not report any disclosures.

egreb@mdedge.com

SOURCE: Dean S et al. CNS-ICNA 2020. Abstract PL52.

Children with stereotypies consult neurologists less often than do those with tics, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. The former also are younger at their first visit than are the latter. Compared with children with tics, children with stereotypies also have fewer comorbidities and receive fewer recommendations for interventions. This difference between groups may not merely reflect the younger age at presentation of children with stereotypies (e.g., at an age before a comorbidity is manifest). “At least in our population, it does seem to reflect an overall lower burden of comorbidities,” said Shannon Dean, MD, PhD, assistant professor of neurology at the Kennedy Krieger Institute of Johns Hopkins University in Baltimore.

Common pediatric movement disorders

Tics (i.e., short-lasting, sudden, repetitive movements) and stereotypies (i.e., rhythmic, fixed, deliberate, but purposeless movements) are common pediatric movement disorders with favorable prognoses. The disorders share several comorbidities, the most common of which are ADHD, anxiety, and obsessive-compulsive disorder (OCD). Dr. Dean and colleagues examined differences in comorbidity burden, resource use, and need for intervention between children with tics and those with stereotypies.

The investigators performed a retrospective chart review and identified 63 children diagnosed with stereotypies. They matched each of these children, by age when possible, with a child first diagnosed with a chronic or provisional tic disorder during the same year. All patients presented to the University of Rochester (N.Y.) Child Neurology Clinic between 2003 and 2016. Dr. Dean and colleagues excluded children with diagnoses for which stereotypies are considered a secondary feature (e.g., autism, intellectual disability, and blindness). They also excluded children who had tics and stereotypies.

The researchers examined the groups’ total number of visits, comorbidities, and recommended interventions. They also analyzed data from a follow-up survey that were available for 20 of the 63 patients with stereotypies. They tested continuous or discrete variables for normal distribution and used T tests or Mann–Whitney U as appropriate. To analyze categorical data, they used chi squared or Fisher’s exact test for groups smaller than five.
 

Differing rates of intervention

Children with stereotypies were younger at first visit (mean age, 5.6 years vs. 7.1 years) and at last visit (mean age, 6.5 years vs. 9.8 years) and had fewer total visits (1.8 vs. 4.5), compared with children with tics.

The three most common comorbidities in the population were more prevalent among patients with tics than among patients with stereotypies. The prevalence of ADHD was 27% among patients with stereotypies and 48% among patients with tics. The prevalence of OCD was 8% among children with stereotypies and 41% among children with tics. The prevalence of anxiety was 21% among children with stereotypies and 63% among children with tics. Children with stereotypies also had fewer neuropsychiatric comorbidities overall than did children with tics (0.7 per patient versus 1.9 per patient).

The clinicians had recommended at least one medication for tics in 22% of the children with tics. No medication is available for children with stereotypies. The clinicians recommended behavioral therapy for 13% of the children with tics, but for none of the children with stereotypies, “because none of them had functional impairment that would warrant intervention,” said Dr. Dean. The clinicians also made more recommendations for pharmaceutical and behavioral treatments for comorbidities in patients with tics than in patients with stereotypies.

When the investigators examined the follow-up survey data, they found that patients with stereotypies were older at last contact than patients with tics. Last contact was defined as the time of the survey for patients with stereotypies and the time of the last clinic visit for patients with tics. When Dr. Dean and colleagues examined the three most common comorbidities, however, they again found that the burden was greater among patients with tics (1.5 per patient) than among patients with stereotypies (0.8 per patient).

The study was funded by the T32 Experimental Therapeutics Training Grant from the University of Rochester, N.Y. Dr. Dean did not report any disclosures.

egreb@mdedge.com

SOURCE: Dean S et al. CNS-ICNA 2020. Abstract PL52.

Children with stereotypies consult neurologists less often than do those with tics, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. The former also are younger at their first visit than are the latter. Compared with children with tics, children with stereotypies also have fewer comorbidities and receive fewer recommendations for interventions. This difference between groups may not merely reflect the younger age at presentation of children with stereotypies (e.g., at an age before a comorbidity is manifest). “At least in our population, it does seem to reflect an overall lower burden of comorbidities,” said Shannon Dean, MD, PhD, assistant professor of neurology at the Kennedy Krieger Institute of Johns Hopkins University in Baltimore.

Common pediatric movement disorders

Tics (i.e., short-lasting, sudden, repetitive movements) and stereotypies (i.e., rhythmic, fixed, deliberate, but purposeless movements) are common pediatric movement disorders with favorable prognoses. The disorders share several comorbidities, the most common of which are ADHD, anxiety, and obsessive-compulsive disorder (OCD). Dr. Dean and colleagues examined differences in comorbidity burden, resource use, and need for intervention between children with tics and those with stereotypies.

The investigators performed a retrospective chart review and identified 63 children diagnosed with stereotypies. They matched each of these children, by age when possible, with a child first diagnosed with a chronic or provisional tic disorder during the same year. All patients presented to the University of Rochester (N.Y.) Child Neurology Clinic between 2003 and 2016. Dr. Dean and colleagues excluded children with diagnoses for which stereotypies are considered a secondary feature (e.g., autism, intellectual disability, and blindness). They also excluded children who had tics and stereotypies.

The researchers examined the groups’ total number of visits, comorbidities, and recommended interventions. They also analyzed data from a follow-up survey that were available for 20 of the 63 patients with stereotypies. They tested continuous or discrete variables for normal distribution and used T tests or Mann–Whitney U as appropriate. To analyze categorical data, they used chi squared or Fisher’s exact test for groups smaller than five.
 

Differing rates of intervention

Children with stereotypies were younger at first visit (mean age, 5.6 years vs. 7.1 years) and at last visit (mean age, 6.5 years vs. 9.8 years) and had fewer total visits (1.8 vs. 4.5), compared with children with tics.

The three most common comorbidities in the population were more prevalent among patients with tics than among patients with stereotypies. The prevalence of ADHD was 27% among patients with stereotypies and 48% among patients with tics. The prevalence of OCD was 8% among children with stereotypies and 41% among children with tics. The prevalence of anxiety was 21% among children with stereotypies and 63% among children with tics. Children with stereotypies also had fewer neuropsychiatric comorbidities overall than did children with tics (0.7 per patient versus 1.9 per patient).

The clinicians had recommended at least one medication for tics in 22% of the children with tics. No medication is available for children with stereotypies. The clinicians recommended behavioral therapy for 13% of the children with tics, but for none of the children with stereotypies, “because none of them had functional impairment that would warrant intervention,” said Dr. Dean. The clinicians also made more recommendations for pharmaceutical and behavioral treatments for comorbidities in patients with tics than in patients with stereotypies.

When the investigators examined the follow-up survey data, they found that patients with stereotypies were older at last contact than patients with tics. Last contact was defined as the time of the survey for patients with stereotypies and the time of the last clinic visit for patients with tics. When Dr. Dean and colleagues examined the three most common comorbidities, however, they again found that the burden was greater among patients with tics (1.5 per patient) than among patients with stereotypies (0.8 per patient).

The study was funded by the T32 Experimental Therapeutics Training Grant from the University of Rochester, N.Y. Dr. Dean did not report any disclosures.

egreb@mdedge.com

SOURCE: Dean S et al. CNS-ICNA 2020. Abstract PL52.

New developments in treatment of neuromyelitis optica spectrum disorder (NMOSD) have opened up options for disease treatment in pediatric patients, but have led to some uncertainty and confusion as well.

At the2020 CNS-ICNA Conjoint Meeting, held virtually this year, presenters discussed some of the challenges of differential diagnosis and treatment choice in pediatric NMOSD, which is easily confused with multiple sclerosis.

NMOSD used to be considered a monophasic disease restricted to the optic nerve and spinal cord, but is now known to affect other regions of the central nervous system and to relapse in some patients.
 

Diagnosis

The disease is often mediated by antibodies to the aquaporin-4 (AQP-4) water channel, but about 30% of adult patients lack the antibody, and AQP-4 seronegativity is more common in the pediatric population. Another common antibody found in 40%–50% of children with NMOSD targets myelin oligodendrocyte glycoprotein (MOG).

It is important to be aware that false negatives can occur in serology assays, and false positives are common, particularly in ELISA assays, Silvia N. Tenembaum, MD, said during her presentation. For those reasons, serology is not enough for a diagnosis. “Patients should also have compatible symptoms and MRI findings,” said Dr. Tenembaum, director of the pediatric neuroimmunology program at National Pediatric Hospital in Buenos Aires.

According to international consensus criteria, to be diagnosed with NMOSD, AQP-4 seropositive patients should also have at least one core clinical symptom: optic neuritis, acute myelitis, area postrema syndrome, other acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome, or symptomatic cerebral syndrome. AQP-4 seronegative patients or with unknown status should have at least two core symptoms, one of which must be optic neuritis, acute myelitis, or area postrema syndrome. Both conventional MRI and advanced new techniques are important for achieving differential diagnosis.

The most common symptom in children is optic neuritis, which occurs in 50%-70% of patients. Cerebral syndromes with or without encephalopathy and large tumefactive white matter lesions are also common, according to Dr. Tenembaum.

There are many conditions that mimic the spinal cord and optic nerve symptoms of NMOSD, which must be ruled out. One example is optic myelopathy and vision loss from late-onset biotinylase deficiency. It is critical to rule that out because it is treatable with supplements. Optic neuropathy, papillitis, and papilledema can also resemble NMOSD.

It is critical to achieve an early diagnosis of NMOSD in children, because some MS drugs can worsen NMOSD, according to Thaís Armangue, MD, PhD, head of neuroimmunology at SJD Barcelona Children’s Hospital, who also presented at the session. She pointed out that the MOG antibody, while common in children, is also associated with many demyelinating diseases. Some 50%-60% of children with acute disseminated encephalomyelitis (ADEM) have high titers of MOG antibodies. Although early studies suggested that persistent anti-MOG antibodies were associated with risk of developing MS, more recent studies show it predicts a non-MS disease course, particularly at titers greater than 1:1280, according to Dr. Tenembaum. Persistent anti-MOG antibodies are also associated with relapsing disease, but it is associated with other syndromes besides NMOSD. “The probability is that [MOG antibodies are] useful, but they cannot guide chronic immunotherapy, because even monophasic patients can last maybe 12 months before they become MOG negative, and we cannot wait so many months” to determine treatment course, said Dr. Tenembaum.

For monophasic ADEM or NMOSD, there is no need for chronic treatment. But children with MS and recurrent NMOSD require early chronic immunotherapy because specific therapies have been shown to improve prognosis.
 

Acute treatment

When it comes to acute treatment of NMOSD, the goal is to suppress the inflammatory attack but also to minimize long-term damage and optimize long-term neurological function. “The potential for irreversible injury with an attack is very high, and cumulative disabilities in NMOSD can result directly from attacks,” E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children at the University of Toronto, said during her talk.

IV steroids are generally the first choice, with a preference for methylprednisolone. Pediatric patients that are MOG antibody positive usually respond better and more quickly than do adults, with rapid daily improvements in mobility, vomiting, and eyesight. Dr. Yeh recommends weaning good responders off steroids because AQP-4 positive patients are likely to relapse without a steroid wean, and antibody testing may be unavailable or results may be delayed. The wean can range from 4 weeks to 4-6 months, depending on antibody status, likelihood of AQP-4 positivity, and clinical parameters.

Inadequate responses are usually pretty evident. If there is only light perception by day 4 or 5, or paralyzed patients are nonambulatory and achieve only twitchy movements by that time, second-line therapies should be considered, including therapeutic plasma exchange (TPE) with 5-7 exchanges or intravenous immunoglobulins (IVIg).

Dr. Yeh called for quick treatment. Whatever you do, “please do it sooner rather than later if you think there’s no response [to steroids],” Dr. Yeh said.

TPE is the first choice, according to Dr. Yeh. “There seems to be a fair amount of information that suggests that if you’re having difficulty getting a response to steroids, TPE can make a difference in these patients,” she said. But in some cases TPE may not be available, and IVIg can be attempted first. If it achieves no or only marginal improvement, TPE can be attempted later, but it must be kept in mind that TPE conducted too soon could wash out IVIg. Patients who get much better on IVIg can undergo a steroid wean, and then be evaluated for prophylactic therapy, said Dr. Yeh.

The evidence for IVIg is limited, reflecting the difficulty of studying treatments in rare populations. Still, when TPE is not available and the patient is quite impaired, IVIg makes sense to try. “Absence of evidence does not mean that the therapy doesn’t work, and I don’t think we should throw out the baby with the bath water,” said Dr. Yeh.

Although IVIg treatment is generally well tolerated, there have been a few serious adverse events, such as anaphylactic shock and aseptic meningitis, according to Andrea Savransky, MD, a pediatrician at National Pediatric Hospital in Buenos Aires, who also spoke at the session. “I think it is important to weigh the benefits against the risk,” Dr. Savransky said. She noted that TPE should not be taken lightly. One study showed more complications in pediatric patients than in adult patients, and it must be performed in specialized centers.
 

Emerging treaments

Tanuja Chitnis, MD, director of the Partners Pediatric MS Center at Massachusetts General Hospital, Boston, discussed some of the emerging treatments for pediatric NMOSD. Rituximab has been associated with success in some retrospective studies, but dosing should be personalized. Dr. Chitnis reported that B cells can return before 6 months, so she monitors B cells beginning 2 months after induction, redosing after 4 or 5 months rather than 6 if B cells return.

Nevertheless, relapses can still occur after rituximab therapy. “There is room for additional therapies to address this gap,” said Dr. Chitnis. Three new antibodies have received approval for treatment of NMOSD in adults. These include the complement inhibitor eculizumab, the IL-6 receptor antibody satralizumab, and the anti-CD19 antibody inebilizumab. Phase 3 clinical trials in children have been conducted for eculizumab and are in the planning stage for inebilizumab, and pediatric patients were included in pivotal trials for satralizumab.

Eculizumab treatment resulted in a 94.2% reduction in relapse risk in AQP4-positive adults. Satralizumab showed a 79% reduction in relapse risk among AQP-4 positive subjects with NMOSD or neuromyelitis optica and a 34% reduction in those who were AQP-4 negative. The pediatric subgroup had similar levels of response to adults, though the numbers were too small for a subgroup analysis.

In AQP-4 positive patients, inebilizumab treatment yielded a 77% reduction in relapse rate. In all patients, there was a 73% reduction.

For MOG antibody-positive patients with AQP-4 negative disease, novel therapies are at earlier stages of development. Typical MS therapies such as interferon beta and glatiramer acetate don’t seem to be effective. Some that have shown signs of efficacy include azathioprine, mycophenylate mofetil, rituximab, and IVIg infusion, but the state of the field is not encouraging. “This is an observation now being studied in larger cohorts, but in general I have not found that there’s a very strong response to any of these therapies, possibly with the exception of IVIg,” said Dr. Chitnis.

Dr. Tenembaum has no relevant financial disclosures. Dr. Armangue has received speaking honoraria from Novartis and travel expenses for scientific meetings from Merck, Biogen, and Roche. Dr. Yeh is on the scientific advisory board of Juno Therapeutics and has received research support from Biogen. Dr. Chitnis advises Biogen-Idec, Novartis, and Alexion, serves on clinical trial advisory boards for Novartis and Sanofi Aventis, and has received research support from Verily, EMD Serono, and Novartis. Dr. Savransky has received honoraria from Genzyme de Argentina SA.

New developments in treatment of neuromyelitis optica spectrum disorder (NMOSD) have opened up options for disease treatment in pediatric patients, but have led to some uncertainty and confusion as well.

At the2020 CNS-ICNA Conjoint Meeting, held virtually this year, presenters discussed some of the challenges of differential diagnosis and treatment choice in pediatric NMOSD, which is easily confused with multiple sclerosis.

NMOSD used to be considered a monophasic disease restricted to the optic nerve and spinal cord, but is now known to affect other regions of the central nervous system and to relapse in some patients.
 

Diagnosis

The disease is often mediated by antibodies to the aquaporin-4 (AQP-4) water channel, but about 30% of adult patients lack the antibody, and AQP-4 seronegativity is more common in the pediatric population. Another common antibody found in 40%–50% of children with NMOSD targets myelin oligodendrocyte glycoprotein (MOG).

It is important to be aware that false negatives can occur in serology assays, and false positives are common, particularly in ELISA assays, Silvia N. Tenembaum, MD, said during her presentation. For those reasons, serology is not enough for a diagnosis. “Patients should also have compatible symptoms and MRI findings,” said Dr. Tenembaum, director of the pediatric neuroimmunology program at National Pediatric Hospital in Buenos Aires.

According to international consensus criteria, to be diagnosed with NMOSD, AQP-4 seropositive patients should also have at least one core clinical symptom: optic neuritis, acute myelitis, area postrema syndrome, other acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome, or symptomatic cerebral syndrome. AQP-4 seronegative patients or with unknown status should have at least two core symptoms, one of which must be optic neuritis, acute myelitis, or area postrema syndrome. Both conventional MRI and advanced new techniques are important for achieving differential diagnosis.

The most common symptom in children is optic neuritis, which occurs in 50%-70% of patients. Cerebral syndromes with or without encephalopathy and large tumefactive white matter lesions are also common, according to Dr. Tenembaum.

There are many conditions that mimic the spinal cord and optic nerve symptoms of NMOSD, which must be ruled out. One example is optic myelopathy and vision loss from late-onset biotinylase deficiency. It is critical to rule that out because it is treatable with supplements. Optic neuropathy, papillitis, and papilledema can also resemble NMOSD.

It is critical to achieve an early diagnosis of NMOSD in children, because some MS drugs can worsen NMOSD, according to Thaís Armangue, MD, PhD, head of neuroimmunology at SJD Barcelona Children’s Hospital, who also presented at the session. She pointed out that the MOG antibody, while common in children, is also associated with many demyelinating diseases. Some 50%-60% of children with acute disseminated encephalomyelitis (ADEM) have high titers of MOG antibodies. Although early studies suggested that persistent anti-MOG antibodies were associated with risk of developing MS, more recent studies show it predicts a non-MS disease course, particularly at titers greater than 1:1280, according to Dr. Tenembaum. Persistent anti-MOG antibodies are also associated with relapsing disease, but it is associated with other syndromes besides NMOSD. “The probability is that [MOG antibodies are] useful, but they cannot guide chronic immunotherapy, because even monophasic patients can last maybe 12 months before they become MOG negative, and we cannot wait so many months” to determine treatment course, said Dr. Tenembaum.

For monophasic ADEM or NMOSD, there is no need for chronic treatment. But children with MS and recurrent NMOSD require early chronic immunotherapy because specific therapies have been shown to improve prognosis.
 

Acute treatment

When it comes to acute treatment of NMOSD, the goal is to suppress the inflammatory attack but also to minimize long-term damage and optimize long-term neurological function. “The potential for irreversible injury with an attack is very high, and cumulative disabilities in NMOSD can result directly from attacks,” E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children at the University of Toronto, said during her talk.

IV steroids are generally the first choice, with a preference for methylprednisolone. Pediatric patients that are MOG antibody positive usually respond better and more quickly than do adults, with rapid daily improvements in mobility, vomiting, and eyesight. Dr. Yeh recommends weaning good responders off steroids because AQP-4 positive patients are likely to relapse without a steroid wean, and antibody testing may be unavailable or results may be delayed. The wean can range from 4 weeks to 4-6 months, depending on antibody status, likelihood of AQP-4 positivity, and clinical parameters.

Inadequate responses are usually pretty evident. If there is only light perception by day 4 or 5, or paralyzed patients are nonambulatory and achieve only twitchy movements by that time, second-line therapies should be considered, including therapeutic plasma exchange (TPE) with 5-7 exchanges or intravenous immunoglobulins (IVIg).

Dr. Yeh called for quick treatment. Whatever you do, “please do it sooner rather than later if you think there’s no response [to steroids],” Dr. Yeh said.

TPE is the first choice, according to Dr. Yeh. “There seems to be a fair amount of information that suggests that if you’re having difficulty getting a response to steroids, TPE can make a difference in these patients,” she said. But in some cases TPE may not be available, and IVIg can be attempted first. If it achieves no or only marginal improvement, TPE can be attempted later, but it must be kept in mind that TPE conducted too soon could wash out IVIg. Patients who get much better on IVIg can undergo a steroid wean, and then be evaluated for prophylactic therapy, said Dr. Yeh.

The evidence for IVIg is limited, reflecting the difficulty of studying treatments in rare populations. Still, when TPE is not available and the patient is quite impaired, IVIg makes sense to try. “Absence of evidence does not mean that the therapy doesn’t work, and I don’t think we should throw out the baby with the bath water,” said Dr. Yeh.

Although IVIg treatment is generally well tolerated, there have been a few serious adverse events, such as anaphylactic shock and aseptic meningitis, according to Andrea Savransky, MD, a pediatrician at National Pediatric Hospital in Buenos Aires, who also spoke at the session. “I think it is important to weigh the benefits against the risk,” Dr. Savransky said. She noted that TPE should not be taken lightly. One study showed more complications in pediatric patients than in adult patients, and it must be performed in specialized centers.
 

Emerging treaments

Tanuja Chitnis, MD, director of the Partners Pediatric MS Center at Massachusetts General Hospital, Boston, discussed some of the emerging treatments for pediatric NMOSD. Rituximab has been associated with success in some retrospective studies, but dosing should be personalized. Dr. Chitnis reported that B cells can return before 6 months, so she monitors B cells beginning 2 months after induction, redosing after 4 or 5 months rather than 6 if B cells return.

Nevertheless, relapses can still occur after rituximab therapy. “There is room for additional therapies to address this gap,” said Dr. Chitnis. Three new antibodies have received approval for treatment of NMOSD in adults. These include the complement inhibitor eculizumab, the IL-6 receptor antibody satralizumab, and the anti-CD19 antibody inebilizumab. Phase 3 clinical trials in children have been conducted for eculizumab and are in the planning stage for inebilizumab, and pediatric patients were included in pivotal trials for satralizumab.

Eculizumab treatment resulted in a 94.2% reduction in relapse risk in AQP4-positive adults. Satralizumab showed a 79% reduction in relapse risk among AQP-4 positive subjects with NMOSD or neuromyelitis optica and a 34% reduction in those who were AQP-4 negative. The pediatric subgroup had similar levels of response to adults, though the numbers were too small for a subgroup analysis.

In AQP-4 positive patients, inebilizumab treatment yielded a 77% reduction in relapse rate. In all patients, there was a 73% reduction.

For MOG antibody-positive patients with AQP-4 negative disease, novel therapies are at earlier stages of development. Typical MS therapies such as interferon beta and glatiramer acetate don’t seem to be effective. Some that have shown signs of efficacy include azathioprine, mycophenylate mofetil, rituximab, and IVIg infusion, but the state of the field is not encouraging. “This is an observation now being studied in larger cohorts, but in general I have not found that there’s a very strong response to any of these therapies, possibly with the exception of IVIg,” said Dr. Chitnis.

Dr. Tenembaum has no relevant financial disclosures. Dr. Armangue has received speaking honoraria from Novartis and travel expenses for scientific meetings from Merck, Biogen, and Roche. Dr. Yeh is on the scientific advisory board of Juno Therapeutics and has received research support from Biogen. Dr. Chitnis advises Biogen-Idec, Novartis, and Alexion, serves on clinical trial advisory boards for Novartis and Sanofi Aventis, and has received research support from Verily, EMD Serono, and Novartis. Dr. Savransky has received honoraria from Genzyme de Argentina SA.

New developments in treatment of neuromyelitis optica spectrum disorder (NMOSD) have opened up options for disease treatment in pediatric patients, but have led to some uncertainty and confusion as well.

At the2020 CNS-ICNA Conjoint Meeting, held virtually this year, presenters discussed some of the challenges of differential diagnosis and treatment choice in pediatric NMOSD, which is easily confused with multiple sclerosis.

NMOSD used to be considered a monophasic disease restricted to the optic nerve and spinal cord, but is now known to affect other regions of the central nervous system and to relapse in some patients.
 

Diagnosis

The disease is often mediated by antibodies to the aquaporin-4 (AQP-4) water channel, but about 30% of adult patients lack the antibody, and AQP-4 seronegativity is more common in the pediatric population. Another common antibody found in 40%–50% of children with NMOSD targets myelin oligodendrocyte glycoprotein (MOG).

It is important to be aware that false negatives can occur in serology assays, and false positives are common, particularly in ELISA assays, Silvia N. Tenembaum, MD, said during her presentation. For those reasons, serology is not enough for a diagnosis. “Patients should also have compatible symptoms and MRI findings,” said Dr. Tenembaum, director of the pediatric neuroimmunology program at National Pediatric Hospital in Buenos Aires.

According to international consensus criteria, to be diagnosed with NMOSD, AQP-4 seropositive patients should also have at least one core clinical symptom: optic neuritis, acute myelitis, area postrema syndrome, other acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome, or symptomatic cerebral syndrome. AQP-4 seronegative patients or with unknown status should have at least two core symptoms, one of which must be optic neuritis, acute myelitis, or area postrema syndrome. Both conventional MRI and advanced new techniques are important for achieving differential diagnosis.

The most common symptom in children is optic neuritis, which occurs in 50%-70% of patients. Cerebral syndromes with or without encephalopathy and large tumefactive white matter lesions are also common, according to Dr. Tenembaum.

There are many conditions that mimic the spinal cord and optic nerve symptoms of NMOSD, which must be ruled out. One example is optic myelopathy and vision loss from late-onset biotinylase deficiency. It is critical to rule that out because it is treatable with supplements. Optic neuropathy, papillitis, and papilledema can also resemble NMOSD.

It is critical to achieve an early diagnosis of NMOSD in children, because some MS drugs can worsen NMOSD, according to Thaís Armangue, MD, PhD, head of neuroimmunology at SJD Barcelona Children’s Hospital, who also presented at the session. She pointed out that the MOG antibody, while common in children, is also associated with many demyelinating diseases. Some 50%-60% of children with acute disseminated encephalomyelitis (ADEM) have high titers of MOG antibodies. Although early studies suggested that persistent anti-MOG antibodies were associated with risk of developing MS, more recent studies show it predicts a non-MS disease course, particularly at titers greater than 1:1280, according to Dr. Tenembaum. Persistent anti-MOG antibodies are also associated with relapsing disease, but it is associated with other syndromes besides NMOSD. “The probability is that [MOG antibodies are] useful, but they cannot guide chronic immunotherapy, because even monophasic patients can last maybe 12 months before they become MOG negative, and we cannot wait so many months” to determine treatment course, said Dr. Tenembaum.

For monophasic ADEM or NMOSD, there is no need for chronic treatment. But children with MS and recurrent NMOSD require early chronic immunotherapy because specific therapies have been shown to improve prognosis.
 

Acute treatment

When it comes to acute treatment of NMOSD, the goal is to suppress the inflammatory attack but also to minimize long-term damage and optimize long-term neurological function. “The potential for irreversible injury with an attack is very high, and cumulative disabilities in NMOSD can result directly from attacks,” E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children at the University of Toronto, said during her talk.

IV steroids are generally the first choice, with a preference for methylprednisolone. Pediatric patients that are MOG antibody positive usually respond better and more quickly than do adults, with rapid daily improvements in mobility, vomiting, and eyesight. Dr. Yeh recommends weaning good responders off steroids because AQP-4 positive patients are likely to relapse without a steroid wean, and antibody testing may be unavailable or results may be delayed. The wean can range from 4 weeks to 4-6 months, depending on antibody status, likelihood of AQP-4 positivity, and clinical parameters.

Inadequate responses are usually pretty evident. If there is only light perception by day 4 or 5, or paralyzed patients are nonambulatory and achieve only twitchy movements by that time, second-line therapies should be considered, including therapeutic plasma exchange (TPE) with 5-7 exchanges or intravenous immunoglobulins (IVIg).

Dr. Yeh called for quick treatment. Whatever you do, “please do it sooner rather than later if you think there’s no response [to steroids],” Dr. Yeh said.

TPE is the first choice, according to Dr. Yeh. “There seems to be a fair amount of information that suggests that if you’re having difficulty getting a response to steroids, TPE can make a difference in these patients,” she said. But in some cases TPE may not be available, and IVIg can be attempted first. If it achieves no or only marginal improvement, TPE can be attempted later, but it must be kept in mind that TPE conducted too soon could wash out IVIg. Patients who get much better on IVIg can undergo a steroid wean, and then be evaluated for prophylactic therapy, said Dr. Yeh.

The evidence for IVIg is limited, reflecting the difficulty of studying treatments in rare populations. Still, when TPE is not available and the patient is quite impaired, IVIg makes sense to try. “Absence of evidence does not mean that the therapy doesn’t work, and I don’t think we should throw out the baby with the bath water,” said Dr. Yeh.

Although IVIg treatment is generally well tolerated, there have been a few serious adverse events, such as anaphylactic shock and aseptic meningitis, according to Andrea Savransky, MD, a pediatrician at National Pediatric Hospital in Buenos Aires, who also spoke at the session. “I think it is important to weigh the benefits against the risk,” Dr. Savransky said. She noted that TPE should not be taken lightly. One study showed more complications in pediatric patients than in adult patients, and it must be performed in specialized centers.
 

Emerging treaments

Tanuja Chitnis, MD, director of the Partners Pediatric MS Center at Massachusetts General Hospital, Boston, discussed some of the emerging treatments for pediatric NMOSD. Rituximab has been associated with success in some retrospective studies, but dosing should be personalized. Dr. Chitnis reported that B cells can return before 6 months, so she monitors B cells beginning 2 months after induction, redosing after 4 or 5 months rather than 6 if B cells return.

Nevertheless, relapses can still occur after rituximab therapy. “There is room for additional therapies to address this gap,” said Dr. Chitnis. Three new antibodies have received approval for treatment of NMOSD in adults. These include the complement inhibitor eculizumab, the IL-6 receptor antibody satralizumab, and the anti-CD19 antibody inebilizumab. Phase 3 clinical trials in children have been conducted for eculizumab and are in the planning stage for inebilizumab, and pediatric patients were included in pivotal trials for satralizumab.

Eculizumab treatment resulted in a 94.2% reduction in relapse risk in AQP4-positive adults. Satralizumab showed a 79% reduction in relapse risk among AQP-4 positive subjects with NMOSD or neuromyelitis optica and a 34% reduction in those who were AQP-4 negative. The pediatric subgroup had similar levels of response to adults, though the numbers were too small for a subgroup analysis.

In AQP-4 positive patients, inebilizumab treatment yielded a 77% reduction in relapse rate. In all patients, there was a 73% reduction.

For MOG antibody-positive patients with AQP-4 negative disease, novel therapies are at earlier stages of development. Typical MS therapies such as interferon beta and glatiramer acetate don’t seem to be effective. Some that have shown signs of efficacy include azathioprine, mycophenylate mofetil, rituximab, and IVIg infusion, but the state of the field is not encouraging. “This is an observation now being studied in larger cohorts, but in general I have not found that there’s a very strong response to any of these therapies, possibly with the exception of IVIg,” said Dr. Chitnis.

Dr. Tenembaum has no relevant financial disclosures. Dr. Armangue has received speaking honoraria from Novartis and travel expenses for scientific meetings from Merck, Biogen, and Roche. Dr. Yeh is on the scientific advisory board of Juno Therapeutics and has received research support from Biogen. Dr. Chitnis advises Biogen-Idec, Novartis, and Alexion, serves on clinical trial advisory boards for Novartis and Sanofi Aventis, and has received research support from Verily, EMD Serono, and Novartis. Dr. Savransky has received honoraria from Genzyme de Argentina SA.

After almost 2 decades of progress, the global state of measles vaccination and measles mortality is deteriorating. Vaccine hesitancy, natural disasters, geopolitical disruptions, and most recently the COVID-19 pandemic have combined to undermine efforts, which had aimed to eradicate measles by this year.

One of the most serious concerns of measles infection is its long-term neurological complications, including the fatal subacute sclerosing panencephalitis (SSPE) and measles inclusion-body encephalitis (MIBE), which is usually seen in immune deficient children. Although some efforts are being made to determine which patients might be most vulnerable to these outcomes, and to treat them, the best approach is still prevention and vaccination, according to Banu Anlar, MD, of Hacettepe University, Ankara, Turkey, who spoke during a session at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

Worldwide vaccination strategies have slipped in recent years, leading to upticks in measles cases and vaccination rates. As a result, in 2018 the World Health Organization postponed its goal of eliminating measles by 2020. Future eradication goals will likely need to be modified, according to Anaita Udwadia Hegde MD, a pediatric neurologist in Mumbai, India, who also presented at the session.

After measles deaths dropped 74% between 2000 and 2010, coinciding with widespread increases in vaccination, the WHO felt emboldened to deal the disease a knockout blow. In 2010, it held a Global Technical Consultation to determine the feasibility of an eradication campaign, which concluded it should be possible by 2020. Several characteristics of measles made that a reasonable goal: It is passed only among humans, with no known animal reservoir; natural infection grants lifelong immunity; there is only one serotype; the virus is genetically stable; the vaccine is safe and leads to 95%-97% seroconversion after two doses, which provides long-term protection against known genotypes; the disease is easily recognized and tested for; and it had been successfully eliminated already in some regions of the world.

As of 2017, analyses showed that the vaccination program saved the lives of about 1.5 million children. That was a cause for celebration, but the goal of eradication has remained elusive. Vaccination rates have trailed targets. In 2018, UNICEF and WHO estimated that 86% of children globally received the first measles vaccine, unchanged from 2010 and below the goal of 95%. Only 69% of children received the second dose, below the goal of 80%. Four countries in Europe lost their measles elimination status in 2018.

Other attempts to eradicate diseases have met with mixed results. The only full success was smallpox, eliminated in 1977. Similar efforts with polio, malaria, guinea worm, and now measles have all come up short. Those failures could complicate future efforts because global agencies and donors may be leery of past failures because of potential harm to their reputations, according to Dr. Hegde.

Such programs require sustained financial commitment and political support as well as local trust. Nevertheless, they must continue for ethical reasons, said Dr. Hegde, but also for economic ones: Every $1 spent on vaccination programs saves $58 in future costs in low- and middle-income countries. Missed childhood vaccination also results in future vulnerable teenagers and young adults, and these populations are much harder to reach and can drive large outbreaks.

Several factors are contributing to the global regression in vaccine coverage, according to Kristen Feemster, MD, MPH, a pediatric infectious disease physician and the global director of medical affairs at Merck. Globalization has enabled the spread of the disease. Most cases in the United States are imported by travelers to countries where the disease is endemic. “Measles can happen anywhere in the world, and when it does it can travel and spread. If you have an unvaccinated traveler who is exposed to measles abroad, they can return home and spread it to anyone else who is unvaccinated or not otherwise immune. When we see cases they’ve been sporadic, but if you return to a community where immunization rates are low, you have the potential for more sustained spread,” Dr. Feemster said during her presentation.

Why are so many travelers unvaccinated? A key reason is that vaccine hesitance is growing. Most affected individuals involved in outbreaks are unvaccinated, usually by choice rather than for medical reasons. Concerns continue over the measles vaccine and autism, growing out of the debunked studies of Andrew Wakefield. In one example, a Somali community in Minnesota experienced a higher than usual number of autism cases and parents sought reasons to explain it. They discovered the supposed connection between vaccination and autism, and Wakefield himself met with a group of them. The result was a drop in vaccination and, in 2011 and 2017, sizable measles outbreaks.

2020 has of course brought a fresh challenge to measles vaccine with the COVID-19 pandemic, which has reduced access to health care and shifted scientific and health care interest away from measles and other vaccine-preventable diseases. On the positive side, social distancing, mask wearing, and restricted movement are likely reducing exposure to measles, but reduced vaccination rates are likely to result in future outbreaks. “There’s been a significant decrease in rates for routine immunizations globally, so there’s a potential for yet another resurgence of measles and other vaccine-preventable diseases,” said Dr. Feemster.

Dr. Feemster is an employee of Merck. Dr. Anlar and Dr. Hegde did not disclose any relevant financial relationships.

After almost 2 decades of progress, the global state of measles vaccination and measles mortality is deteriorating. Vaccine hesitancy, natural disasters, geopolitical disruptions, and most recently the COVID-19 pandemic have combined to undermine efforts, which had aimed to eradicate measles by this year.

One of the most serious concerns of measles infection is its long-term neurological complications, including the fatal subacute sclerosing panencephalitis (SSPE) and measles inclusion-body encephalitis (MIBE), which is usually seen in immune deficient children. Although some efforts are being made to determine which patients might be most vulnerable to these outcomes, and to treat them, the best approach is still prevention and vaccination, according to Banu Anlar, MD, of Hacettepe University, Ankara, Turkey, who spoke during a session at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

Worldwide vaccination strategies have slipped in recent years, leading to upticks in measles cases and vaccination rates. As a result, in 2018 the World Health Organization postponed its goal of eliminating measles by 2020. Future eradication goals will likely need to be modified, according to Anaita Udwadia Hegde MD, a pediatric neurologist in Mumbai, India, who also presented at the session.

After measles deaths dropped 74% between 2000 and 2010, coinciding with widespread increases in vaccination, the WHO felt emboldened to deal the disease a knockout blow. In 2010, it held a Global Technical Consultation to determine the feasibility of an eradication campaign, which concluded it should be possible by 2020. Several characteristics of measles made that a reasonable goal: It is passed only among humans, with no known animal reservoir; natural infection grants lifelong immunity; there is only one serotype; the virus is genetically stable; the vaccine is safe and leads to 95%-97% seroconversion after two doses, which provides long-term protection against known genotypes; the disease is easily recognized and tested for; and it had been successfully eliminated already in some regions of the world.

As of 2017, analyses showed that the vaccination program saved the lives of about 1.5 million children. That was a cause for celebration, but the goal of eradication has remained elusive. Vaccination rates have trailed targets. In 2018, UNICEF and WHO estimated that 86% of children globally received the first measles vaccine, unchanged from 2010 and below the goal of 95%. Only 69% of children received the second dose, below the goal of 80%. Four countries in Europe lost their measles elimination status in 2018.

Other attempts to eradicate diseases have met with mixed results. The only full success was smallpox, eliminated in 1977. Similar efforts with polio, malaria, guinea worm, and now measles have all come up short. Those failures could complicate future efforts because global agencies and donors may be leery of past failures because of potential harm to their reputations, according to Dr. Hegde.

Such programs require sustained financial commitment and political support as well as local trust. Nevertheless, they must continue for ethical reasons, said Dr. Hegde, but also for economic ones: Every $1 spent on vaccination programs saves $58 in future costs in low- and middle-income countries. Missed childhood vaccination also results in future vulnerable teenagers and young adults, and these populations are much harder to reach and can drive large outbreaks.

Several factors are contributing to the global regression in vaccine coverage, according to Kristen Feemster, MD, MPH, a pediatric infectious disease physician and the global director of medical affairs at Merck. Globalization has enabled the spread of the disease. Most cases in the United States are imported by travelers to countries where the disease is endemic. “Measles can happen anywhere in the world, and when it does it can travel and spread. If you have an unvaccinated traveler who is exposed to measles abroad, they can return home and spread it to anyone else who is unvaccinated or not otherwise immune. When we see cases they’ve been sporadic, but if you return to a community where immunization rates are low, you have the potential for more sustained spread,” Dr. Feemster said during her presentation.

Why are so many travelers unvaccinated? A key reason is that vaccine hesitance is growing. Most affected individuals involved in outbreaks are unvaccinated, usually by choice rather than for medical reasons. Concerns continue over the measles vaccine and autism, growing out of the debunked studies of Andrew Wakefield. In one example, a Somali community in Minnesota experienced a higher than usual number of autism cases and parents sought reasons to explain it. They discovered the supposed connection between vaccination and autism, and Wakefield himself met with a group of them. The result was a drop in vaccination and, in 2011 and 2017, sizable measles outbreaks.

2020 has of course brought a fresh challenge to measles vaccine with the COVID-19 pandemic, which has reduced access to health care and shifted scientific and health care interest away from measles and other vaccine-preventable diseases. On the positive side, social distancing, mask wearing, and restricted movement are likely reducing exposure to measles, but reduced vaccination rates are likely to result in future outbreaks. “There’s been a significant decrease in rates for routine immunizations globally, so there’s a potential for yet another resurgence of measles and other vaccine-preventable diseases,” said Dr. Feemster.

Dr. Feemster is an employee of Merck. Dr. Anlar and Dr. Hegde did not disclose any relevant financial relationships.

After almost 2 decades of progress, the global state of measles vaccination and measles mortality is deteriorating. Vaccine hesitancy, natural disasters, geopolitical disruptions, and most recently the COVID-19 pandemic have combined to undermine efforts, which had aimed to eradicate measles by this year.

One of the most serious concerns of measles infection is its long-term neurological complications, including the fatal subacute sclerosing panencephalitis (SSPE) and measles inclusion-body encephalitis (MIBE), which is usually seen in immune deficient children. Although some efforts are being made to determine which patients might be most vulnerable to these outcomes, and to treat them, the best approach is still prevention and vaccination, according to Banu Anlar, MD, of Hacettepe University, Ankara, Turkey, who spoke during a session at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

Worldwide vaccination strategies have slipped in recent years, leading to upticks in measles cases and vaccination rates. As a result, in 2018 the World Health Organization postponed its goal of eliminating measles by 2020. Future eradication goals will likely need to be modified, according to Anaita Udwadia Hegde MD, a pediatric neurologist in Mumbai, India, who also presented at the session.

After measles deaths dropped 74% between 2000 and 2010, coinciding with widespread increases in vaccination, the WHO felt emboldened to deal the disease a knockout blow. In 2010, it held a Global Technical Consultation to determine the feasibility of an eradication campaign, which concluded it should be possible by 2020. Several characteristics of measles made that a reasonable goal: It is passed only among humans, with no known animal reservoir; natural infection grants lifelong immunity; there is only one serotype; the virus is genetically stable; the vaccine is safe and leads to 95%-97% seroconversion after two doses, which provides long-term protection against known genotypes; the disease is easily recognized and tested for; and it had been successfully eliminated already in some regions of the world.

As of 2017, analyses showed that the vaccination program saved the lives of about 1.5 million children. That was a cause for celebration, but the goal of eradication has remained elusive. Vaccination rates have trailed targets. In 2018, UNICEF and WHO estimated that 86% of children globally received the first measles vaccine, unchanged from 2010 and below the goal of 95%. Only 69% of children received the second dose, below the goal of 80%. Four countries in Europe lost their measles elimination status in 2018.

Other attempts to eradicate diseases have met with mixed results. The only full success was smallpox, eliminated in 1977. Similar efforts with polio, malaria, guinea worm, and now measles have all come up short. Those failures could complicate future efforts because global agencies and donors may be leery of past failures because of potential harm to their reputations, according to Dr. Hegde.

Such programs require sustained financial commitment and political support as well as local trust. Nevertheless, they must continue for ethical reasons, said Dr. Hegde, but also for economic ones: Every $1 spent on vaccination programs saves $58 in future costs in low- and middle-income countries. Missed childhood vaccination also results in future vulnerable teenagers and young adults, and these populations are much harder to reach and can drive large outbreaks.

Several factors are contributing to the global regression in vaccine coverage, according to Kristen Feemster, MD, MPH, a pediatric infectious disease physician and the global director of medical affairs at Merck. Globalization has enabled the spread of the disease. Most cases in the United States are imported by travelers to countries where the disease is endemic. “Measles can happen anywhere in the world, and when it does it can travel and spread. If you have an unvaccinated traveler who is exposed to measles abroad, they can return home and spread it to anyone else who is unvaccinated or not otherwise immune. When we see cases they’ve been sporadic, but if you return to a community where immunization rates are low, you have the potential for more sustained spread,” Dr. Feemster said during her presentation.

Why are so many travelers unvaccinated? A key reason is that vaccine hesitance is growing. Most affected individuals involved in outbreaks are unvaccinated, usually by choice rather than for medical reasons. Concerns continue over the measles vaccine and autism, growing out of the debunked studies of Andrew Wakefield. In one example, a Somali community in Minnesota experienced a higher than usual number of autism cases and parents sought reasons to explain it. They discovered the supposed connection between vaccination and autism, and Wakefield himself met with a group of them. The result was a drop in vaccination and, in 2011 and 2017, sizable measles outbreaks.

2020 has of course brought a fresh challenge to measles vaccine with the COVID-19 pandemic, which has reduced access to health care and shifted scientific and health care interest away from measles and other vaccine-preventable diseases. On the positive side, social distancing, mask wearing, and restricted movement are likely reducing exposure to measles, but reduced vaccination rates are likely to result in future outbreaks. “There’s been a significant decrease in rates for routine immunizations globally, so there’s a potential for yet another resurgence of measles and other vaccine-preventable diseases,” said Dr. Feemster.

Dr. Feemster is an employee of Merck. Dr. Anlar and Dr. Hegde did not disclose any relevant financial relationships.

A more than 6-point improvement in Headache Impact Test (HIT-6) total score and a 1-2 category improvement in item-specific scores of HIT-6 appeared to be associated with meaningful change in an individual with chronic migraine, recent research suggests.

Using data from the phase 3 PROMISE-2 study, which evaluated intravenous eptinezumab in doses of 100 mg or 300 mg, or placebo every 12 weeks in 1,072 participants for the prevention of chronic migraine, Carrie R. Houts, PhD, director of psychometrics at the Vector Psychometric Group, in Chapel Hill, N.C., and colleagues determined that their finding of 6-point improvement of HIT-6 total score was consistent with other studies. However, they pointed out that little research has been done in evaluating how item-specific scores of HIT-6 impact individuals with chronic migraine. HIT-6 item scores examine whether individuals with headaches experience severe pain, limit their daily activities, have a desire to lie down, feel too tired to do daily activities, felt “fed up or irritated” because of headaches, and feel their headaches limit concentration on work or daily activities.

“The item-specific responder definitions give clinicians and researchers the ability to evaluate and track the impact of headache on specific item-level areas of patients’ lives. These responder definitions provide practical and easily interpreted results that can be used to evaluate treatment benefits over time and to improve clinician-patients communication focus on improvements in key aspects of functioning in individuals with chronic migraine,” Dr. Houts and colleagues wrote in their study, published in the October issue of Headache.

The 6-point value and the 1-2 category improvement values in item-specific scores, they suggested, could be used as a benchmark to help other clinicians and researchers detect meaningful change in individual patients with chronic migraine. Although the user guide for HIT-6 highlights a 5-point change in the total score as clinically meaningful, the authors of the guide do not provide evidence for why the 5-point value signifies clinically meaningful change, they said.
 

Determining thresholds of clinically meaningful change

In their study, Dr. Houts and colleagues used distribution-based methods to gauge responder values for the HIT-6 total score, while item-specific HIT-6 analyses were measured with Patients’ Global Impression of Change (PGIC), reduction in migraine frequency through monthly migraine days (MMDs), and EuroQol 5 dimensions 5 levels visual analog scale (EQ-5D-5L VAS). The researchers also used HIT-6 values from a literature review and from analyses in PROMISE-2 to calculate “a final chronic migraine-specific responder definition value” between baseline and 12 weeks. Participants in the PROMISE-2 study were mostly women (88.2%) and white (91.0%) with a mean age of 40.5 years.

The literature search revealed responder thresholds for the HIT-6 total score in a range between a decrease of 3 points and 8 points. Within PROMISE-2, the HIT-6 total score responder threshold was found to be between –2.6 and –2.2, which the researchers rounded down to a decrease of 3 points. When taking both sets of responder thresholds into account, the researchers calculated the median responder value as –5.5, which was rounded down to a decrease in 6 points in the HIT-6 total score. “[The estimate] appears most appropriate for discriminating between individuals with chronic migraine who have experienced meaningful change over time and those who have not,” Dr. Houts and colleagues said.

For item-specific HIT-6 scores, the mean score changes were –1 points for categories involving severe pain, limiting activities, lying down, and –2 points for categories involving feeling tired, being fed up or irritated, and limiting concentration.

“Taken together, the current chronic migraine-specific results are consistent with values derived from general headache/migraine samples and suggest that a decrease of 6 points or more on the HIT-6 total score would be considered meaningful to chronic migraine patients,” Dr. Houts and colleagues said. “This would translate to approximately a 4-category change on a single item, change on 2 items of approximately 2 and 3 categories, or a 1-category change on 3 or 4 of the 6 items, depending on the initial category.”

The researchers cautioned that the values outlined in the study “should not be used to determine clinically meaningful difference between treatment groups” and that “future work, similar to that reported here, will identify a chronic migraine-specific clinically meaningful difference between treatment groups value.”
 

A better measure of chronic migraine?

In an interview, J. D. Bartleson Jr., MD, a retired neurologist with the Mayo Clinic in Rochester, Minn., questioned why HIT-6 criteria was used in the initial PROMISE-2 study. “There is not a lot of difference between the significant and insignificant categories. Chronic migraine may be better measured with pain severity and number of headache days per month,” he said.

,“It may be appropriate to use just 1 or 2 symptoms for evaluating a given patient’s headache burden,” in terms of clinical application of the study for neurologists, Dr. Bartleson said. He emphasized that more research is needed.

This study was funded by H. Lundbeck A/S, which also provided funding of medical writing and editorial support for the manuscript. Three authors report being employees of Vector Psychometric Group at the time of the study, and the company received funding from H. Lundbeck A/S for their time conducting study-related research. Three other authors report relationships with pharmaceutical companies, medical societies, government agencies, and industry related to the study in the form of consultancies, advisory board memberships, honoraria, research support, stock or stock options, and employment. Dr. Bartleson reports no relevant conflicts of interest.

SOURCE: Houts C et al. Headache. 2020;60(9):2003-13.

A more than 6-point improvement in Headache Impact Test (HIT-6) total score and a 1-2 category improvement in item-specific scores of HIT-6 appeared to be associated with meaningful change in an individual with chronic migraine, recent research suggests.

Using data from the phase 3 PROMISE-2 study, which evaluated intravenous eptinezumab in doses of 100 mg or 300 mg, or placebo every 12 weeks in 1,072 participants for the prevention of chronic migraine, Carrie R. Houts, PhD, director of psychometrics at the Vector Psychometric Group, in Chapel Hill, N.C., and colleagues determined that their finding of 6-point improvement of HIT-6 total score was consistent with other studies. However, they pointed out that little research has been done in evaluating how item-specific scores of HIT-6 impact individuals with chronic migraine. HIT-6 item scores examine whether individuals with headaches experience severe pain, limit their daily activities, have a desire to lie down, feel too tired to do daily activities, felt “fed up or irritated” because of headaches, and feel their headaches limit concentration on work or daily activities.

“The item-specific responder definitions give clinicians and researchers the ability to evaluate and track the impact of headache on specific item-level areas of patients’ lives. These responder definitions provide practical and easily interpreted results that can be used to evaluate treatment benefits over time and to improve clinician-patients communication focus on improvements in key aspects of functioning in individuals with chronic migraine,” Dr. Houts and colleagues wrote in their study, published in the October issue of Headache.

The 6-point value and the 1-2 category improvement values in item-specific scores, they suggested, could be used as a benchmark to help other clinicians and researchers detect meaningful change in individual patients with chronic migraine. Although the user guide for HIT-6 highlights a 5-point change in the total score as clinically meaningful, the authors of the guide do not provide evidence for why the 5-point value signifies clinically meaningful change, they said.
 

Determining thresholds of clinically meaningful change

In their study, Dr. Houts and colleagues used distribution-based methods to gauge responder values for the HIT-6 total score, while item-specific HIT-6 analyses were measured with Patients’ Global Impression of Change (PGIC), reduction in migraine frequency through monthly migraine days (MMDs), and EuroQol 5 dimensions 5 levels visual analog scale (EQ-5D-5L VAS). The researchers also used HIT-6 values from a literature review and from analyses in PROMISE-2 to calculate “a final chronic migraine-specific responder definition value” between baseline and 12 weeks. Participants in the PROMISE-2 study were mostly women (88.2%) and white (91.0%) with a mean age of 40.5 years.

The literature search revealed responder thresholds for the HIT-6 total score in a range between a decrease of 3 points and 8 points. Within PROMISE-2, the HIT-6 total score responder threshold was found to be between –2.6 and –2.2, which the researchers rounded down to a decrease of 3 points. When taking both sets of responder thresholds into account, the researchers calculated the median responder value as –5.5, which was rounded down to a decrease in 6 points in the HIT-6 total score. “[The estimate] appears most appropriate for discriminating between individuals with chronic migraine who have experienced meaningful change over time and those who have not,” Dr. Houts and colleagues said.

For item-specific HIT-6 scores, the mean score changes were –1 points for categories involving severe pain, limiting activities, lying down, and –2 points for categories involving feeling tired, being fed up or irritated, and limiting concentration.

“Taken together, the current chronic migraine-specific results are consistent with values derived from general headache/migraine samples and suggest that a decrease of 6 points or more on the HIT-6 total score would be considered meaningful to chronic migraine patients,” Dr. Houts and colleagues said. “This would translate to approximately a 4-category change on a single item, change on 2 items of approximately 2 and 3 categories, or a 1-category change on 3 or 4 of the 6 items, depending on the initial category.”

The researchers cautioned that the values outlined in the study “should not be used to determine clinically meaningful difference between treatment groups” and that “future work, similar to that reported here, will identify a chronic migraine-specific clinically meaningful difference between treatment groups value.”
 

A better measure of chronic migraine?

In an interview, J. D. Bartleson Jr., MD, a retired neurologist with the Mayo Clinic in Rochester, Minn., questioned why HIT-6 criteria was used in the initial PROMISE-2 study. “There is not a lot of difference between the significant and insignificant categories. Chronic migraine may be better measured with pain severity and number of headache days per month,” he said.

,“It may be appropriate to use just 1 or 2 symptoms for evaluating a given patient’s headache burden,” in terms of clinical application of the study for neurologists, Dr. Bartleson said. He emphasized that more research is needed.

This study was funded by H. Lundbeck A/S, which also provided funding of medical writing and editorial support for the manuscript. Three authors report being employees of Vector Psychometric Group at the time of the study, and the company received funding from H. Lundbeck A/S for their time conducting study-related research. Three other authors report relationships with pharmaceutical companies, medical societies, government agencies, and industry related to the study in the form of consultancies, advisory board memberships, honoraria, research support, stock or stock options, and employment. Dr. Bartleson reports no relevant conflicts of interest.

SOURCE: Houts C et al. Headache. 2020;60(9):2003-13.

A more than 6-point improvement in Headache Impact Test (HIT-6) total score and a 1-2 category improvement in item-specific scores of HIT-6 appeared to be associated with meaningful change in an individual with chronic migraine, recent research suggests.

Using data from the phase 3 PROMISE-2 study, which evaluated intravenous eptinezumab in doses of 100 mg or 300 mg, or placebo every 12 weeks in 1,072 participants for the prevention of chronic migraine, Carrie R. Houts, PhD, director of psychometrics at the Vector Psychometric Group, in Chapel Hill, N.C., and colleagues determined that their finding of 6-point improvement of HIT-6 total score was consistent with other studies. However, they pointed out that little research has been done in evaluating how item-specific scores of HIT-6 impact individuals with chronic migraine. HIT-6 item scores examine whether individuals with headaches experience severe pain, limit their daily activities, have a desire to lie down, feel too tired to do daily activities, felt “fed up or irritated” because of headaches, and feel their headaches limit concentration on work or daily activities.

“The item-specific responder definitions give clinicians and researchers the ability to evaluate and track the impact of headache on specific item-level areas of patients’ lives. These responder definitions provide practical and easily interpreted results that can be used to evaluate treatment benefits over time and to improve clinician-patients communication focus on improvements in key aspects of functioning in individuals with chronic migraine,” Dr. Houts and colleagues wrote in their study, published in the October issue of Headache.

The 6-point value and the 1-2 category improvement values in item-specific scores, they suggested, could be used as a benchmark to help other clinicians and researchers detect meaningful change in individual patients with chronic migraine. Although the user guide for HIT-6 highlights a 5-point change in the total score as clinically meaningful, the authors of the guide do not provide evidence for why the 5-point value signifies clinically meaningful change, they said.
 

Determining thresholds of clinically meaningful change

In their study, Dr. Houts and colleagues used distribution-based methods to gauge responder values for the HIT-6 total score, while item-specific HIT-6 analyses were measured with Patients’ Global Impression of Change (PGIC), reduction in migraine frequency through monthly migraine days (MMDs), and EuroQol 5 dimensions 5 levels visual analog scale (EQ-5D-5L VAS). The researchers also used HIT-6 values from a literature review and from analyses in PROMISE-2 to calculate “a final chronic migraine-specific responder definition value” between baseline and 12 weeks. Participants in the PROMISE-2 study were mostly women (88.2%) and white (91.0%) with a mean age of 40.5 years.

The literature search revealed responder thresholds for the HIT-6 total score in a range between a decrease of 3 points and 8 points. Within PROMISE-2, the HIT-6 total score responder threshold was found to be between –2.6 and –2.2, which the researchers rounded down to a decrease of 3 points. When taking both sets of responder thresholds into account, the researchers calculated the median responder value as –5.5, which was rounded down to a decrease in 6 points in the HIT-6 total score. “[The estimate] appears most appropriate for discriminating between individuals with chronic migraine who have experienced meaningful change over time and those who have not,” Dr. Houts and colleagues said.

For item-specific HIT-6 scores, the mean score changes were –1 points for categories involving severe pain, limiting activities, lying down, and –2 points for categories involving feeling tired, being fed up or irritated, and limiting concentration.

“Taken together, the current chronic migraine-specific results are consistent with values derived from general headache/migraine samples and suggest that a decrease of 6 points or more on the HIT-6 total score would be considered meaningful to chronic migraine patients,” Dr. Houts and colleagues said. “This would translate to approximately a 4-category change on a single item, change on 2 items of approximately 2 and 3 categories, or a 1-category change on 3 or 4 of the 6 items, depending on the initial category.”

The researchers cautioned that the values outlined in the study “should not be used to determine clinically meaningful difference between treatment groups” and that “future work, similar to that reported here, will identify a chronic migraine-specific clinically meaningful difference between treatment groups value.”
 

A better measure of chronic migraine?

In an interview, J. D. Bartleson Jr., MD, a retired neurologist with the Mayo Clinic in Rochester, Minn., questioned why HIT-6 criteria was used in the initial PROMISE-2 study. “There is not a lot of difference between the significant and insignificant categories. Chronic migraine may be better measured with pain severity and number of headache days per month,” he said.

,“It may be appropriate to use just 1 or 2 symptoms for evaluating a given patient’s headache burden,” in terms of clinical application of the study for neurologists, Dr. Bartleson said. He emphasized that more research is needed.

This study was funded by H. Lundbeck A/S, which also provided funding of medical writing and editorial support for the manuscript. Three authors report being employees of Vector Psychometric Group at the time of the study, and the company received funding from H. Lundbeck A/S for their time conducting study-related research. Three other authors report relationships with pharmaceutical companies, medical societies, government agencies, and industry related to the study in the form of consultancies, advisory board memberships, honoraria, research support, stock or stock options, and employment. Dr. Bartleson reports no relevant conflicts of interest.

SOURCE: Houts C et al. Headache. 2020;60(9):2003-13.

The first dual-purpose, external trigeminal nerve stimulation device to treat and prevent acute migraine is now available over the counter to adults over age 18. The Food and Drug Administration has cleared Cefaly Dual (Cefaly Technology) which was previously available only by prescription.

Most migraines involve the trigeminal nerve, which can be accessed through the skin on the forehead. Cefaly Dual stimulates the trigeminal nerve using a reusable self-adhesive electrode placed on the forehead.

The device has two settings, ACUTE and PREVENT. In the ACUTE setting, the individual wears the device for 60 minutes at headache onset or during a migraine attack. In the PREVENT setting, the individual wears the device for 20 minutes daily to help prevent future episodes.

At the start of a session, the wearer may feel a slight tingling sensation, which gradually increases and spreads throughout the forehead and the front part of the head. After about 14 minutes, the intensity stabilizes and remains constant until the treatment session is over, according to the company. The device automatically shuts off at the end of each session. It can be used as a stand-alone option or with existing treatment, the company noted.

“For millions of people across the U.S., living with migraine pain and coping with debilitating symptoms are daily realities. It is our mission to provide consumers with increased access to an effective and safe dual modality migraine treatment that is scientifically proven to reduce the number of monthly migraine days by almost half,” Jennifer Trainor McDermott, CEO of Cefaly Technology, said in a news release.

The FDA’s over-the-counter clearance of Cefaly Dual was based on several randomized, controlled clinical trials supporting the efficacy and safety of the device, the company said.

An earlier version of the Cefaly device was approved in the United States in March 2014 to help prevent migraine headache in adults aged 18 or older. The next-generation Cefaly Dual device is “small and sleek in comparison to its older model, which uses bands along the sides to create room for batteries. The newest device is palm-sized, more portable, and uses a battery that is rechargeable via USB,” the company said.

Last spring, the company announced a buyback program where customers in the United States may return their original device and receive a discount of the purchase of the Cefaly Dual device.

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

The first dual-purpose, external trigeminal nerve stimulation device to treat and prevent acute migraine is now available over the counter to adults over age 18. The Food and Drug Administration has cleared Cefaly Dual (Cefaly Technology) which was previously available only by prescription.

Most migraines involve the trigeminal nerve, which can be accessed through the skin on the forehead. Cefaly Dual stimulates the trigeminal nerve using a reusable self-adhesive electrode placed on the forehead.

The device has two settings, ACUTE and PREVENT. In the ACUTE setting, the individual wears the device for 60 minutes at headache onset or during a migraine attack. In the PREVENT setting, the individual wears the device for 20 minutes daily to help prevent future episodes.

At the start of a session, the wearer may feel a slight tingling sensation, which gradually increases and spreads throughout the forehead and the front part of the head. After about 14 minutes, the intensity stabilizes and remains constant until the treatment session is over, according to the company. The device automatically shuts off at the end of each session. It can be used as a stand-alone option or with existing treatment, the company noted.

“For millions of people across the U.S., living with migraine pain and coping with debilitating symptoms are daily realities. It is our mission to provide consumers with increased access to an effective and safe dual modality migraine treatment that is scientifically proven to reduce the number of monthly migraine days by almost half,” Jennifer Trainor McDermott, CEO of Cefaly Technology, said in a news release.

The FDA’s over-the-counter clearance of Cefaly Dual was based on several randomized, controlled clinical trials supporting the efficacy and safety of the device, the company said.

An earlier version of the Cefaly device was approved in the United States in March 2014 to help prevent migraine headache in adults aged 18 or older. The next-generation Cefaly Dual device is “small and sleek in comparison to its older model, which uses bands along the sides to create room for batteries. The newest device is palm-sized, more portable, and uses a battery that is rechargeable via USB,” the company said.

Last spring, the company announced a buyback program where customers in the United States may return their original device and receive a discount of the purchase of the Cefaly Dual device.

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

The first dual-purpose, external trigeminal nerve stimulation device to treat and prevent acute migraine is now available over the counter to adults over age 18. The Food and Drug Administration has cleared Cefaly Dual (Cefaly Technology) which was previously available only by prescription.

Most migraines involve the trigeminal nerve, which can be accessed through the skin on the forehead. Cefaly Dual stimulates the trigeminal nerve using a reusable self-adhesive electrode placed on the forehead.

The device has two settings, ACUTE and PREVENT. In the ACUTE setting, the individual wears the device for 60 minutes at headache onset or during a migraine attack. In the PREVENT setting, the individual wears the device for 20 minutes daily to help prevent future episodes.

At the start of a session, the wearer may feel a slight tingling sensation, which gradually increases and spreads throughout the forehead and the front part of the head. After about 14 minutes, the intensity stabilizes and remains constant until the treatment session is over, according to the company. The device automatically shuts off at the end of each session. It can be used as a stand-alone option or with existing treatment, the company noted.

“For millions of people across the U.S., living with migraine pain and coping with debilitating symptoms are daily realities. It is our mission to provide consumers with increased access to an effective and safe dual modality migraine treatment that is scientifically proven to reduce the number of monthly migraine days by almost half,” Jennifer Trainor McDermott, CEO of Cefaly Technology, said in a news release.

The FDA’s over-the-counter clearance of Cefaly Dual was based on several randomized, controlled clinical trials supporting the efficacy and safety of the device, the company said.

An earlier version of the Cefaly device was approved in the United States in March 2014 to help prevent migraine headache in adults aged 18 or older. The next-generation Cefaly Dual device is “small and sleek in comparison to its older model, which uses bands along the sides to create room for batteries. The newest device is palm-sized, more portable, and uses a battery that is rechargeable via USB,” the company said.

Last spring, the company announced a buyback program where customers in the United States may return their original device and receive a discount of the purchase of the Cefaly Dual device.

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

The global burden of dementia is increasing at an alarming pace and is estimated to soon affect 81 million individuals worldwide.¹ The World Health Organization and the Institute of Medicine have recommended greater dementia awareness and education.^2,3 Despite this emphasis on dementia education, many general practitioners consider dementia care beyond their clinical domain and feel that specialists, such as geriatricians, geriatric psychiatrists, or neurologists should address dementia assessment and treatment. ⁴ Unfortunately, the geriatric health care workforce has been shrinking. The American Geriatrics Society estimates the need for 30,000 geriatricians by 2030, although there are only 7,300 board-certified geriatricians currently in the US.5 There is an urgent need for educating all medical trainees in dementia care regardless of their specialization interest. As the largest underwriter of graduate medical education in the US, the US Department of Veterans Affairs (VA) is well placed for rolling out focused dementia education. Training needs to be practical, brief, and responsive to knowledge gaps to reach the most trainees.

Despite growing emphasis on geriatric training, many medical students have limited experience with patients with dementia or their caregivers, lack exposure to interdisciplinary teams, have a poor attitude toward geriatric patients, and display specific knowledge gaps in dementia assessment and management. ^6-9 Other knowledge gaps noted in medical students included assessing behavioral problems, function, safety, and caregiver burden. Medical students also had limited exposure to interdisciplinary team dementia assessment and management.

Our goal was to develop a multicomponent, experiential, brief curriculum using team-based learning to expose senior medical students to interdisciplinary assessment of dementia. The curriculum was developed with input from the interdisciplinary team to address dementia knowledge gaps while providing an opportunity to interact with caregivers. The curriculum targeted all medical students regardless of their interest in geriatrics. Particular emphasis was placed on systems-based learning and the importance of teamwork in managing complex conditions such as dementia. Students were taught that incorporating interdisciplinary input would be more effective during dementia care planning rather than developing specialized knowledge.

Methods

Our team developed a curriculum for fourthyear medical students who rotated through the VA Memory Disorders Clinic as a part of their geriatric medicine clerkship at the University of Arkansas for Medical Sciences in Little Rock. The Memory Disorders Clinic is a consultation practice at the Central Arkansas Veterans Healthcare System (CAVHS) where patients with memory problems are evaluated by a team consisting of a geriatric psychiatrist, a geriatrician, a social worker, and a neuropsychologist. Each specialist addresses specific areas of dementia assessment and management. The curriculum included didactics, clinical experience, and team-based learning.

Didactics

An hour-long didactic session lead by the team geriatrician provided a general overview of interdisciplinary assessment of dementia to groups of 2 to 3 students at a time. The geriatrician presented an overview of dementia types, comorbidities, medications that affect memory, details of the physical examination, and laboratory, cognitive, and behavioral assessments along with treatment plan development. Students also learned about the roles of the social worker, geriatrician, neuropsychologist, and geriatric psychiatrist in the clinic. Pictographs and pie charts highlighted the role of disciplines in assessing and managing aspects of dementia.

The social work evaluation included advance care planning, functional assessment, safety assessment (driving, guns, wandering behaviors, etc), home safety evaluation, support system, and financial evaluation. Each medical student received a binder with local resources to become familiar with the depth and breadth of agencies involved in dementia care. Each medical student learned how to administer the Zarit Burden Scale to assess caregiver burden^.10 The details of the geriatrician assessment included reviewing medical comorbidities and medications contributing to dementia, a physical examination, including a focused neurologic examination, laboratory assessment, and judicious use of neuroimaging.

The neuropsychology assessment education included a battery of tests and assessments. The global screening instruments included the Modified Mini-Mental State examination (3MS), Montreal Cognitive Assessment (MoCA), and Saint Louis University Mental Status examination (SLUMS).^11-13 Executive function is evaluated using the Trails Making Test A and Trails Making Test B, Controlled Oral Word Association Test, Semantic Fluency Test, and Repeatable Battery for the Assessment of Neuropsychological Status test. Cognitive tests were compared and age- , education-, and race-adjusted norms for rating scales were listed if available. Each student was expected to show proficiency in ≥ 2 cognitive screening instruments (3MS, MoCA, or SLUMS). The geriatric psychiatry assessment included clinical history, onset, and course of memory problems from patient and caregiver perspectives, the Neuropsychiatric Inventory for assessing behavioral problems, employing the clinical dementia rating scale, integrating the team data, summarizing assessment, and formulating a treatment plan.¹⁴

Clinical

Students had a single clinical exposure. Students followed 1 patient and his or her caregiver through the team assessment and observed each provider’s assessment to learn interview techniques to adapt to the patient’s sensory or cognitive impairment and become familiar with different tools and devices used in the dementia clinic, such as hearing amplifiers. Each specialist provided hands-on experience. This encounter helped the students connect with caregivers and appreciate their role in patient care.

Systems learning was an important component integrated throughout the clinical experience. Examples include using video teleconferences to communicate findings among team members and electronic health records to seamlessly obtain and integrate data. Students learned how to create worksheets to graph laboratory data such as B12, thyroid-stimulating hormone, and rapid plasma regain levels. Student gained experience in using applications to retrieve neuroimaging data, results of sleep studies, and other data. Many patients had not received the results of their sleep study, and students had the responsibility to share these reports, including the number of apneic episodes. Students used the VA Computerized Patient Record System for reviewing patient records. One particularly useful tool was Joint Legacy Viewer, a remote access tool used to retrieve data on veterans from anywhere within the US. Students were also trained on medication and consult order menus in the system.

Team-Based

Learning The objectives of the team-based learning section were to teach students basic concepts of integrating the interdisciplinary assessment and formulating a treatment plan, to provide an opportunity to present their case in a group format, to discuss the differential diagnosis, management and treatment plan with a geriatrician in the team-based learning format, and to answer questions from other students. The instructors developed a set of prepared take-home points (Table 1). The team-based learning sessions were structured so that all take-home points were covered.

Evaluations

Evaluations were performed before and immediately after the clinical experience. In preevaluation, students reported the frequency of their participation in an interdisciplinary team assessment of any condition and specifically for dementia. In pre- and postevaluation, students rated their perception of the role of interdisciplinary team members in assessing and managing dementia, their personal abilities to assess cognition, behavioral problems, caregiver burden, and their perception of the impact of behavioral problems on dementia care. A Likert scale (poor = 1; fair = 2; good = 3; very good = 4; and excellent = 5) was employed (eApendices 1 and 2 can be found at doi:10.12788/fp.0052). The only demographic information collected was the student’s gender. Semistructured interviews were conducted to assess students’ current knowledge, experience, and needs. These interviews lasted about 20 minutes and collected information regarding the students’ knowledge about cognitive and behavioral problems in general and those occurring in dementia, their experience with screening, and any problems they encountered.

Statistical Analysis

Student baseline characteristics were assessed. Pre- and postassessments were analyzed with the McNemar test for paired data, and associations with experience were evaluated using χ² tests. Ratings were dichotomized as very good/excellent vs poor/fair/ good because our educational goal was “very good” to “excellent” experience in dementia care and to avoid expected small cell counts. Two-sided P < .05 indicated statistical significance. Data were analyzed using SAS Enterprise Guide v5.1.

Results

One hundred fourth-year medical students participated, including 54 women. Thirtysix percent reported they had not previously attended an interdisciplinary team assessment for dementia, while 18% stated that they had attended only 1 interdisciplinary team assessment for dementia.

Before the education, students rated their dementia ability as poor. Only 2% (1 of 54), of those with 0 to 1 assessment experience rated their ability for assessing dementia with an interdisciplinary team format as very good/excellent compared with 20% (9/46) of those previously attending ≥ 2 assessments (P = .03); other ratings of ability were not associated with prior experience.

There was a significant change in the students’ self-efficacy ratings pre- to postassessment (P < .05) (Table 2). Only 10% rated their ability to assess for dementia as very good/excellent in before the intervention compared with 96% in postassessment (P < .01). Students’ perception of the impact of behavioral problems on dementia care improved significantly (45% to 98%, P < .01). Similarly, student’s perception of their ability to assess behavioral problems, caregiver burden, and cognition improved significantly from 7 to 88%; 7 to 78%, and 18 to 92%, respectively (P < .01). Students perception of the role of social worker, neuropsychologist, geriatrician, and geriatric psychiatrist also improved significantly for most measures from 81 to 98% (P = .02), 87 to 98% (P = .05), 94 to 99% (P = .06), and 88 to 100% (P = .01), respectively.

The semistructured interviews revealed that awareness of behavioral problems associated with dementia varied for different behavioral problems. Although many students showed familiarity with depression, agitation, and psychosis, they were not comfortable assessing them in a patient with dementia. These students were less aware of other behavioral problems such as disinhibition, apathy, and movement disorders. Deficits were noted in the skill of administering commonly used global cognitive screens, such as the Mini-Mental State Examination (MMSE).¹⁵

In semistructured interviews, only 7% of senior medical students were comfortable assessing behavioral problems associated with dementia. Most were not aware of any validated rating scale to assess neuropsychiatric symptoms. Similarly, only 7% of students were comfortable assessing caregiver burden, and most were not aware of any validated rating scale to assess caregiver burden. Only 1 in 5 students were comfortable using 2 cognitive screens to assess cognitive deficits. Many students stated that they were not routinely expected to perform common cognitive screens, such as the MMSE during their medical training except students who had expressed an interest in psychiatry and were expected to be proficient in the MMSE. Most students were making common mistakes, such as converting the 3-command task to 3 individual single commands, helping too much with serial 7s, and giving too much positive feedback throughout the test.

Discussion

Significant knowledge gaps regarding dementia were found in our study, which is in keeping with other studies in the area. Dementia knowledge deficits among medical trainees have been identified in the United Kingdom, Australia, and the US.^6-9

In our study, a brief multicomponent experiential curriculum improved senior medical students’ perception and self-efficacy in diagnosing dementia. This is in keeping with other studies, such as the PAIRS Program.⁷ Findings from another study indicated that education for geriatric- oriented physicians should focus on experiential learning components through observation and interaction with older adults.¹⁶

A background of direct experience with older adults is associated with more positive attitudes toward older adults and increased interest in geriatric medicine.¹⁶ In our study, the exposure was brief; therefore, the results could not be compared with other long-term exposure studies. However, even with this brief intervention most students reported being comfortable with assessing caregiver burden (78%), behavioral problems of dementia (88%), and using ≥ 2 cognitive screens (92%). Comfortable in dementia assessment increased after the intervention from 10% to 96%. This finding is encouraging because brief multicomponent dementia education can be devised easily. This finding needs to be taken with caution because we did not conduct a formal skills evaluation.

A unique component of our experience was to learn medical students’ perception about the impact of neuropsychiatric symptoms on the trajectory, outcomes, and management of dementia. These symptoms included delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, motor disturbance, nighttime behaviors, and appetite and eating. Less than half the students thought that neuropsychiatric symptoms had a significant impact on dementia before the experience. Through didactics, systematic assessment of neuropsychiatric symptoms and interaction with caregivers, > 98% of students learned that these symptoms have a significant impact on dementia management.

This experience also emphasized the role of several disciplines in dementia assessment and management. Students’ experience positively influenced appreciation of the role of the memory clinic team. Our hope is that students will seek input from social workers, neuropsychologists, and other team members when working with patients with dementia or their caregivers. The common reason why primary care physicians focus on an exclusive medical model is the time commitment for communicating with an interdisciplinary team. Students experienced the feasibility of the interdisciplinary team involvement and how technology could be used for synchronous and asynchronous communication among team members. Medical students also were introduced to complex billing codes used when ≥ 3 disciplines assess/manage a geriatric patient.

Limitations

This study is limited by the lack of long-term follow-up evaluations, no metrics for practice changes clinical outcomes, and implementation in a single medical school. The postexperience evaluation in this study was performed immediately after the intervention. Long-term follow-up would inform whether the changes noted are durable. Because of the brief nature of our intervention, we do not believe that it would change practice in clinical care. It will be informative to follow this cohort of students to study whether their clinical approach to dementia care changes. The intervention needs to be replicated in other medical schools and in more heterogeneous groups to generalize the results of the study.

Conclusions

Senior medical students are not routinely exposed to interdisciplinary team assessments. Dementia knowledge gaps were prevalent in this cohort of senior medical students. Providing interdisciplinary geriatric educational experience improved their perception of their ability to assess for dementia and their recognition of the roles of interdisciplinary team members. Plans are in place to continue and expand the program to other complex geriatric syndromes.

Acknowledgments
Poster presented at the 2019 annual meeting of the American Geriatrics Society. Oral presentation at the same meeting as part of the select Geriatric Education Methods and Materials Swap workshop.

The global burden of dementia is increasing at an alarming pace and is estimated to soon affect 81 million individuals worldwide.¹ The World Health Organization and the Institute of Medicine have recommended greater dementia awareness and education.^2,3 Despite this emphasis on dementia education, many general practitioners consider dementia care beyond their clinical domain and feel that specialists, such as geriatricians, geriatric psychiatrists, or neurologists should address dementia assessment and treatment. ⁴ Unfortunately, the geriatric health care workforce has been shrinking. The American Geriatrics Society estimates the need for 30,000 geriatricians by 2030, although there are only 7,300 board-certified geriatricians currently in the US.5 There is an urgent need for educating all medical trainees in dementia care regardless of their specialization interest. As the largest underwriter of graduate medical education in the US, the US Department of Veterans Affairs (VA) is well placed for rolling out focused dementia education. Training needs to be practical, brief, and responsive to knowledge gaps to reach the most trainees.

Despite growing emphasis on geriatric training, many medical students have limited experience with patients with dementia or their caregivers, lack exposure to interdisciplinary teams, have a poor attitude toward geriatric patients, and display specific knowledge gaps in dementia assessment and management. ^6-9 Other knowledge gaps noted in medical students included assessing behavioral problems, function, safety, and caregiver burden. Medical students also had limited exposure to interdisciplinary team dementia assessment and management.

Our goal was to develop a multicomponent, experiential, brief curriculum using team-based learning to expose senior medical students to interdisciplinary assessment of dementia. The curriculum was developed with input from the interdisciplinary team to address dementia knowledge gaps while providing an opportunity to interact with caregivers. The curriculum targeted all medical students regardless of their interest in geriatrics. Particular emphasis was placed on systems-based learning and the importance of teamwork in managing complex conditions such as dementia. Students were taught that incorporating interdisciplinary input would be more effective during dementia care planning rather than developing specialized knowledge.

Methods

Our team developed a curriculum for fourthyear medical students who rotated through the VA Memory Disorders Clinic as a part of their geriatric medicine clerkship at the University of Arkansas for Medical Sciences in Little Rock. The Memory Disorders Clinic is a consultation practice at the Central Arkansas Veterans Healthcare System (CAVHS) where patients with memory problems are evaluated by a team consisting of a geriatric psychiatrist, a geriatrician, a social worker, and a neuropsychologist. Each specialist addresses specific areas of dementia assessment and management. The curriculum included didactics, clinical experience, and team-based learning.

Didactics

An hour-long didactic session lead by the team geriatrician provided a general overview of interdisciplinary assessment of dementia to groups of 2 to 3 students at a time. The geriatrician presented an overview of dementia types, comorbidities, medications that affect memory, details of the physical examination, and laboratory, cognitive, and behavioral assessments along with treatment plan development. Students also learned about the roles of the social worker, geriatrician, neuropsychologist, and geriatric psychiatrist in the clinic. Pictographs and pie charts highlighted the role of disciplines in assessing and managing aspects of dementia.

The social work evaluation included advance care planning, functional assessment, safety assessment (driving, guns, wandering behaviors, etc), home safety evaluation, support system, and financial evaluation. Each medical student received a binder with local resources to become familiar with the depth and breadth of agencies involved in dementia care. Each medical student learned how to administer the Zarit Burden Scale to assess caregiver burden^.10 The details of the geriatrician assessment included reviewing medical comorbidities and medications contributing to dementia, a physical examination, including a focused neurologic examination, laboratory assessment, and judicious use of neuroimaging.

The neuropsychology assessment education included a battery of tests and assessments. The global screening instruments included the Modified Mini-Mental State examination (3MS), Montreal Cognitive Assessment (MoCA), and Saint Louis University Mental Status examination (SLUMS).^11-13 Executive function is evaluated using the Trails Making Test A and Trails Making Test B, Controlled Oral Word Association Test, Semantic Fluency Test, and Repeatable Battery for the Assessment of Neuropsychological Status test. Cognitive tests were compared and age- , education-, and race-adjusted norms for rating scales were listed if available. Each student was expected to show proficiency in ≥ 2 cognitive screening instruments (3MS, MoCA, or SLUMS). The geriatric psychiatry assessment included clinical history, onset, and course of memory problems from patient and caregiver perspectives, the Neuropsychiatric Inventory for assessing behavioral problems, employing the clinical dementia rating scale, integrating the team data, summarizing assessment, and formulating a treatment plan.¹⁴

Clinical

Students had a single clinical exposure. Students followed 1 patient and his or her caregiver through the team assessment and observed each provider’s assessment to learn interview techniques to adapt to the patient’s sensory or cognitive impairment and become familiar with different tools and devices used in the dementia clinic, such as hearing amplifiers. Each specialist provided hands-on experience. This encounter helped the students connect with caregivers and appreciate their role in patient care.

Systems learning was an important component integrated throughout the clinical experience. Examples include using video teleconferences to communicate findings among team members and electronic health records to seamlessly obtain and integrate data. Students learned how to create worksheets to graph laboratory data such as B12, thyroid-stimulating hormone, and rapid plasma regain levels. Student gained experience in using applications to retrieve neuroimaging data, results of sleep studies, and other data. Many patients had not received the results of their sleep study, and students had the responsibility to share these reports, including the number of apneic episodes. Students used the VA Computerized Patient Record System for reviewing patient records. One particularly useful tool was Joint Legacy Viewer, a remote access tool used to retrieve data on veterans from anywhere within the US. Students were also trained on medication and consult order menus in the system.

Team-Based

Learning The objectives of the team-based learning section were to teach students basic concepts of integrating the interdisciplinary assessment and formulating a treatment plan, to provide an opportunity to present their case in a group format, to discuss the differential diagnosis, management and treatment plan with a geriatrician in the team-based learning format, and to answer questions from other students. The instructors developed a set of prepared take-home points (Table 1). The team-based learning sessions were structured so that all take-home points were covered.

Evaluations

Evaluations were performed before and immediately after the clinical experience. In preevaluation, students reported the frequency of their participation in an interdisciplinary team assessment of any condition and specifically for dementia. In pre- and postevaluation, students rated their perception of the role of interdisciplinary team members in assessing and managing dementia, their personal abilities to assess cognition, behavioral problems, caregiver burden, and their perception of the impact of behavioral problems on dementia care. A Likert scale (poor = 1; fair = 2; good = 3; very good = 4; and excellent = 5) was employed (eApendices 1 and 2 can be found at doi:10.12788/fp.0052). The only demographic information collected was the student’s gender. Semistructured interviews were conducted to assess students’ current knowledge, experience, and needs. These interviews lasted about 20 minutes and collected information regarding the students’ knowledge about cognitive and behavioral problems in general and those occurring in dementia, their experience with screening, and any problems they encountered.

Statistical Analysis

Student baseline characteristics were assessed. Pre- and postassessments were analyzed with the McNemar test for paired data, and associations with experience were evaluated using χ² tests. Ratings were dichotomized as very good/excellent vs poor/fair/ good because our educational goal was “very good” to “excellent” experience in dementia care and to avoid expected small cell counts. Two-sided P < .05 indicated statistical significance. Data were analyzed using SAS Enterprise Guide v5.1.

Results

One hundred fourth-year medical students participated, including 54 women. Thirtysix percent reported they had not previously attended an interdisciplinary team assessment for dementia, while 18% stated that they had attended only 1 interdisciplinary team assessment for dementia.

Before the education, students rated their dementia ability as poor. Only 2% (1 of 54), of those with 0 to 1 assessment experience rated their ability for assessing dementia with an interdisciplinary team format as very good/excellent compared with 20% (9/46) of those previously attending ≥ 2 assessments (P = .03); other ratings of ability were not associated with prior experience.

There was a significant change in the students’ self-efficacy ratings pre- to postassessment (P < .05) (Table 2). Only 10% rated their ability to assess for dementia as very good/excellent in before the intervention compared with 96% in postassessment (P < .01). Students’ perception of the impact of behavioral problems on dementia care improved significantly (45% to 98%, P < .01). Similarly, student’s perception of their ability to assess behavioral problems, caregiver burden, and cognition improved significantly from 7 to 88%; 7 to 78%, and 18 to 92%, respectively (P < .01). Students perception of the role of social worker, neuropsychologist, geriatrician, and geriatric psychiatrist also improved significantly for most measures from 81 to 98% (P = .02), 87 to 98% (P = .05), 94 to 99% (P = .06), and 88 to 100% (P = .01), respectively.

The semistructured interviews revealed that awareness of behavioral problems associated with dementia varied for different behavioral problems. Although many students showed familiarity with depression, agitation, and psychosis, they were not comfortable assessing them in a patient with dementia. These students were less aware of other behavioral problems such as disinhibition, apathy, and movement disorders. Deficits were noted in the skill of administering commonly used global cognitive screens, such as the Mini-Mental State Examination (MMSE).¹⁵

In semistructured interviews, only 7% of senior medical students were comfortable assessing behavioral problems associated with dementia. Most were not aware of any validated rating scale to assess neuropsychiatric symptoms. Similarly, only 7% of students were comfortable assessing caregiver burden, and most were not aware of any validated rating scale to assess caregiver burden. Only 1 in 5 students were comfortable using 2 cognitive screens to assess cognitive deficits. Many students stated that they were not routinely expected to perform common cognitive screens, such as the MMSE during their medical training except students who had expressed an interest in psychiatry and were expected to be proficient in the MMSE. Most students were making common mistakes, such as converting the 3-command task to 3 individual single commands, helping too much with serial 7s, and giving too much positive feedback throughout the test.

Discussion

Significant knowledge gaps regarding dementia were found in our study, which is in keeping with other studies in the area. Dementia knowledge deficits among medical trainees have been identified in the United Kingdom, Australia, and the US.^6-9

In our study, a brief multicomponent experiential curriculum improved senior medical students’ perception and self-efficacy in diagnosing dementia. This is in keeping with other studies, such as the PAIRS Program.⁷ Findings from another study indicated that education for geriatric- oriented physicians should focus on experiential learning components through observation and interaction with older adults.¹⁶

A background of direct experience with older adults is associated with more positive attitudes toward older adults and increased interest in geriatric medicine.¹⁶ In our study, the exposure was brief; therefore, the results could not be compared with other long-term exposure studies. However, even with this brief intervention most students reported being comfortable with assessing caregiver burden (78%), behavioral problems of dementia (88%), and using ≥ 2 cognitive screens (92%). Comfortable in dementia assessment increased after the intervention from 10% to 96%. This finding is encouraging because brief multicomponent dementia education can be devised easily. This finding needs to be taken with caution because we did not conduct a formal skills evaluation.

A unique component of our experience was to learn medical students’ perception about the impact of neuropsychiatric symptoms on the trajectory, outcomes, and management of dementia. These symptoms included delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, motor disturbance, nighttime behaviors, and appetite and eating. Less than half the students thought that neuropsychiatric symptoms had a significant impact on dementia before the experience. Through didactics, systematic assessment of neuropsychiatric symptoms and interaction with caregivers, > 98% of students learned that these symptoms have a significant impact on dementia management.

This experience also emphasized the role of several disciplines in dementia assessment and management. Students’ experience positively influenced appreciation of the role of the memory clinic team. Our hope is that students will seek input from social workers, neuropsychologists, and other team members when working with patients with dementia or their caregivers. The common reason why primary care physicians focus on an exclusive medical model is the time commitment for communicating with an interdisciplinary team. Students experienced the feasibility of the interdisciplinary team involvement and how technology could be used for synchronous and asynchronous communication among team members. Medical students also were introduced to complex billing codes used when ≥ 3 disciplines assess/manage a geriatric patient.

Limitations

This study is limited by the lack of long-term follow-up evaluations, no metrics for practice changes clinical outcomes, and implementation in a single medical school. The postexperience evaluation in this study was performed immediately after the intervention. Long-term follow-up would inform whether the changes noted are durable. Because of the brief nature of our intervention, we do not believe that it would change practice in clinical care. It will be informative to follow this cohort of students to study whether their clinical approach to dementia care changes. The intervention needs to be replicated in other medical schools and in more heterogeneous groups to generalize the results of the study.

Conclusions

Senior medical students are not routinely exposed to interdisciplinary team assessments. Dementia knowledge gaps were prevalent in this cohort of senior medical students. Providing interdisciplinary geriatric educational experience improved their perception of their ability to assess for dementia and their recognition of the roles of interdisciplinary team members. Plans are in place to continue and expand the program to other complex geriatric syndromes.

Acknowledgments
Poster presented at the 2019 annual meeting of the American Geriatrics Society. Oral presentation at the same meeting as part of the select Geriatric Education Methods and Materials Swap workshop.

The global burden of dementia is increasing at an alarming pace and is estimated to soon affect 81 million individuals worldwide.¹ The World Health Organization and the Institute of Medicine have recommended greater dementia awareness and education.^2,3 Despite this emphasis on dementia education, many general practitioners consider dementia care beyond their clinical domain and feel that specialists, such as geriatricians, geriatric psychiatrists, or neurologists should address dementia assessment and treatment. ⁴ Unfortunately, the geriatric health care workforce has been shrinking. The American Geriatrics Society estimates the need for 30,000 geriatricians by 2030, although there are only 7,300 board-certified geriatricians currently in the US.5 There is an urgent need for educating all medical trainees in dementia care regardless of their specialization interest. As the largest underwriter of graduate medical education in the US, the US Department of Veterans Affairs (VA) is well placed for rolling out focused dementia education. Training needs to be practical, brief, and responsive to knowledge gaps to reach the most trainees.

Despite growing emphasis on geriatric training, many medical students have limited experience with patients with dementia or their caregivers, lack exposure to interdisciplinary teams, have a poor attitude toward geriatric patients, and display specific knowledge gaps in dementia assessment and management. ^6-9 Other knowledge gaps noted in medical students included assessing behavioral problems, function, safety, and caregiver burden. Medical students also had limited exposure to interdisciplinary team dementia assessment and management.

Our goal was to develop a multicomponent, experiential, brief curriculum using team-based learning to expose senior medical students to interdisciplinary assessment of dementia. The curriculum was developed with input from the interdisciplinary team to address dementia knowledge gaps while providing an opportunity to interact with caregivers. The curriculum targeted all medical students regardless of their interest in geriatrics. Particular emphasis was placed on systems-based learning and the importance of teamwork in managing complex conditions such as dementia. Students were taught that incorporating interdisciplinary input would be more effective during dementia care planning rather than developing specialized knowledge.

Methods

Our team developed a curriculum for fourthyear medical students who rotated through the VA Memory Disorders Clinic as a part of their geriatric medicine clerkship at the University of Arkansas for Medical Sciences in Little Rock. The Memory Disorders Clinic is a consultation practice at the Central Arkansas Veterans Healthcare System (CAVHS) where patients with memory problems are evaluated by a team consisting of a geriatric psychiatrist, a geriatrician, a social worker, and a neuropsychologist. Each specialist addresses specific areas of dementia assessment and management. The curriculum included didactics, clinical experience, and team-based learning.

Didactics

An hour-long didactic session lead by the team geriatrician provided a general overview of interdisciplinary assessment of dementia to groups of 2 to 3 students at a time. The geriatrician presented an overview of dementia types, comorbidities, medications that affect memory, details of the physical examination, and laboratory, cognitive, and behavioral assessments along with treatment plan development. Students also learned about the roles of the social worker, geriatrician, neuropsychologist, and geriatric psychiatrist in the clinic. Pictographs and pie charts highlighted the role of disciplines in assessing and managing aspects of dementia.

The social work evaluation included advance care planning, functional assessment, safety assessment (driving, guns, wandering behaviors, etc), home safety evaluation, support system, and financial evaluation. Each medical student received a binder with local resources to become familiar with the depth and breadth of agencies involved in dementia care. Each medical student learned how to administer the Zarit Burden Scale to assess caregiver burden^.10 The details of the geriatrician assessment included reviewing medical comorbidities and medications contributing to dementia, a physical examination, including a focused neurologic examination, laboratory assessment, and judicious use of neuroimaging.

The neuropsychology assessment education included a battery of tests and assessments. The global screening instruments included the Modified Mini-Mental State examination (3MS), Montreal Cognitive Assessment (MoCA), and Saint Louis University Mental Status examination (SLUMS).^11-13 Executive function is evaluated using the Trails Making Test A and Trails Making Test B, Controlled Oral Word Association Test, Semantic Fluency Test, and Repeatable Battery for the Assessment of Neuropsychological Status test. Cognitive tests were compared and age- , education-, and race-adjusted norms for rating scales were listed if available. Each student was expected to show proficiency in ≥ 2 cognitive screening instruments (3MS, MoCA, or SLUMS). The geriatric psychiatry assessment included clinical history, onset, and course of memory problems from patient and caregiver perspectives, the Neuropsychiatric Inventory for assessing behavioral problems, employing the clinical dementia rating scale, integrating the team data, summarizing assessment, and formulating a treatment plan.¹⁴

Clinical

Students had a single clinical exposure. Students followed 1 patient and his or her caregiver through the team assessment and observed each provider’s assessment to learn interview techniques to adapt to the patient’s sensory or cognitive impairment and become familiar with different tools and devices used in the dementia clinic, such as hearing amplifiers. Each specialist provided hands-on experience. This encounter helped the students connect with caregivers and appreciate their role in patient care.

Systems learning was an important component integrated throughout the clinical experience. Examples include using video teleconferences to communicate findings among team members and electronic health records to seamlessly obtain and integrate data. Students learned how to create worksheets to graph laboratory data such as B12, thyroid-stimulating hormone, and rapid plasma regain levels. Student gained experience in using applications to retrieve neuroimaging data, results of sleep studies, and other data. Many patients had not received the results of their sleep study, and students had the responsibility to share these reports, including the number of apneic episodes. Students used the VA Computerized Patient Record System for reviewing patient records. One particularly useful tool was Joint Legacy Viewer, a remote access tool used to retrieve data on veterans from anywhere within the US. Students were also trained on medication and consult order menus in the system.

Team-Based

Learning The objectives of the team-based learning section were to teach students basic concepts of integrating the interdisciplinary assessment and formulating a treatment plan, to provide an opportunity to present their case in a group format, to discuss the differential diagnosis, management and treatment plan with a geriatrician in the team-based learning format, and to answer questions from other students. The instructors developed a set of prepared take-home points (Table 1). The team-based learning sessions were structured so that all take-home points were covered.

Evaluations

Evaluations were performed before and immediately after the clinical experience. In preevaluation, students reported the frequency of their participation in an interdisciplinary team assessment of any condition and specifically for dementia. In pre- and postevaluation, students rated their perception of the role of interdisciplinary team members in assessing and managing dementia, their personal abilities to assess cognition, behavioral problems, caregiver burden, and their perception of the impact of behavioral problems on dementia care. A Likert scale (poor = 1; fair = 2; good = 3; very good = 4; and excellent = 5) was employed (eApendices 1 and 2 can be found at doi:10.12788/fp.0052). The only demographic information collected was the student’s gender. Semistructured interviews were conducted to assess students’ current knowledge, experience, and needs. These interviews lasted about 20 minutes and collected information regarding the students’ knowledge about cognitive and behavioral problems in general and those occurring in dementia, their experience with screening, and any problems they encountered.

Statistical Analysis

Student baseline characteristics were assessed. Pre- and postassessments were analyzed with the McNemar test for paired data, and associations with experience were evaluated using χ² tests. Ratings were dichotomized as very good/excellent vs poor/fair/ good because our educational goal was “very good” to “excellent” experience in dementia care and to avoid expected small cell counts. Two-sided P < .05 indicated statistical significance. Data were analyzed using SAS Enterprise Guide v5.1.

Results

One hundred fourth-year medical students participated, including 54 women. Thirtysix percent reported they had not previously attended an interdisciplinary team assessment for dementia, while 18% stated that they had attended only 1 interdisciplinary team assessment for dementia.

Before the education, students rated their dementia ability as poor. Only 2% (1 of 54), of those with 0 to 1 assessment experience rated their ability for assessing dementia with an interdisciplinary team format as very good/excellent compared with 20% (9/46) of those previously attending ≥ 2 assessments (P = .03); other ratings of ability were not associated with prior experience.

There was a significant change in the students’ self-efficacy ratings pre- to postassessment (P < .05) (Table 2). Only 10% rated their ability to assess for dementia as very good/excellent in before the intervention compared with 96% in postassessment (P < .01). Students’ perception of the impact of behavioral problems on dementia care improved significantly (45% to 98%, P < .01). Similarly, student’s perception of their ability to assess behavioral problems, caregiver burden, and cognition improved significantly from 7 to 88%; 7 to 78%, and 18 to 92%, respectively (P < .01). Students perception of the role of social worker, neuropsychologist, geriatrician, and geriatric psychiatrist also improved significantly for most measures from 81 to 98% (P = .02), 87 to 98% (P = .05), 94 to 99% (P = .06), and 88 to 100% (P = .01), respectively.

The semistructured interviews revealed that awareness of behavioral problems associated with dementia varied for different behavioral problems. Although many students showed familiarity with depression, agitation, and psychosis, they were not comfortable assessing them in a patient with dementia. These students were less aware of other behavioral problems such as disinhibition, apathy, and movement disorders. Deficits were noted in the skill of administering commonly used global cognitive screens, such as the Mini-Mental State Examination (MMSE).¹⁵

In semistructured interviews, only 7% of senior medical students were comfortable assessing behavioral problems associated with dementia. Most were not aware of any validated rating scale to assess neuropsychiatric symptoms. Similarly, only 7% of students were comfortable assessing caregiver burden, and most were not aware of any validated rating scale to assess caregiver burden. Only 1 in 5 students were comfortable using 2 cognitive screens to assess cognitive deficits. Many students stated that they were not routinely expected to perform common cognitive screens, such as the MMSE during their medical training except students who had expressed an interest in psychiatry and were expected to be proficient in the MMSE. Most students were making common mistakes, such as converting the 3-command task to 3 individual single commands, helping too much with serial 7s, and giving too much positive feedback throughout the test.

Discussion

Significant knowledge gaps regarding dementia were found in our study, which is in keeping with other studies in the area. Dementia knowledge deficits among medical trainees have been identified in the United Kingdom, Australia, and the US.^6-9

In our study, a brief multicomponent experiential curriculum improved senior medical students’ perception and self-efficacy in diagnosing dementia. This is in keeping with other studies, such as the PAIRS Program.⁷ Findings from another study indicated that education for geriatric- oriented physicians should focus on experiential learning components through observation and interaction with older adults.¹⁶

A background of direct experience with older adults is associated with more positive attitudes toward older adults and increased interest in geriatric medicine.¹⁶ In our study, the exposure was brief; therefore, the results could not be compared with other long-term exposure studies. However, even with this brief intervention most students reported being comfortable with assessing caregiver burden (78%), behavioral problems of dementia (88%), and using ≥ 2 cognitive screens (92%). Comfortable in dementia assessment increased after the intervention from 10% to 96%. This finding is encouraging because brief multicomponent dementia education can be devised easily. This finding needs to be taken with caution because we did not conduct a formal skills evaluation.

A unique component of our experience was to learn medical students’ perception about the impact of neuropsychiatric symptoms on the trajectory, outcomes, and management of dementia. These symptoms included delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, motor disturbance, nighttime behaviors, and appetite and eating. Less than half the students thought that neuropsychiatric symptoms had a significant impact on dementia before the experience. Through didactics, systematic assessment of neuropsychiatric symptoms and interaction with caregivers, > 98% of students learned that these symptoms have a significant impact on dementia management.

This experience also emphasized the role of several disciplines in dementia assessment and management. Students’ experience positively influenced appreciation of the role of the memory clinic team. Our hope is that students will seek input from social workers, neuropsychologists, and other team members when working with patients with dementia or their caregivers. The common reason why primary care physicians focus on an exclusive medical model is the time commitment for communicating with an interdisciplinary team. Students experienced the feasibility of the interdisciplinary team involvement and how technology could be used for synchronous and asynchronous communication among team members. Medical students also were introduced to complex billing codes used when ≥ 3 disciplines assess/manage a geriatric patient.

Limitations

This study is limited by the lack of long-term follow-up evaluations, no metrics for practice changes clinical outcomes, and implementation in a single medical school. The postexperience evaluation in this study was performed immediately after the intervention. Long-term follow-up would inform whether the changes noted are durable. Because of the brief nature of our intervention, we do not believe that it would change practice in clinical care. It will be informative to follow this cohort of students to study whether their clinical approach to dementia care changes. The intervention needs to be replicated in other medical schools and in more heterogeneous groups to generalize the results of the study.

Conclusions

Senior medical students are not routinely exposed to interdisciplinary team assessments. Dementia knowledge gaps were prevalent in this cohort of senior medical students. Providing interdisciplinary geriatric educational experience improved their perception of their ability to assess for dementia and their recognition of the roles of interdisciplinary team members. Plans are in place to continue and expand the program to other complex geriatric syndromes.

Acknowledgments
Poster presented at the 2019 annual meeting of the American Geriatrics Society. Oral presentation at the same meeting as part of the select Geriatric Education Methods and Materials Swap workshop.

THE CASE

A 28-year-old woman with an extensive psychiatric history—including generalized anxiety disorder, panic disorder, and recent postpartum depression—presented with a chief complaint of right leg weakness. She stated this weakness had begun 4 days earlier. It occurred episodically and was preceded by tingling and cramping sensations. Each episode lasted a couple of minutes and spontaneously resolved. Associated with it, she experienced slurred speech and altered mentation. There was no loss of consciousness and no pain. A panic attack usually followed, consisting of feelings of impending doom, rapid breathing, palpitations, and nausea.

She had 3 prior diagnostic evaluations for this same chief complaint, twice in an emergency department (ED) and once with her primary care physician. These evaluations included lab work and extensive head imaging, which demonstrated no acute intracranial pathology. At each previous presentation, the diagnosis was an exacerbation of her anxiety disorder, and she was treated with lorazepam.

At the current presentation, her vital signs were stable. Examination revealed a notably anxious patient. She repeatedly expressed concern that she might have a brain tumor or some other deadly disease, as she had a family history of brain cancer. Her physical exam was entirely normal, including normal strength, sensation, and reflexes in all extremities.

Further head imaging (computed tomography, CT angiography, and magnetic resonance imaging of the brain) failed to reveal an etiology of her symptoms. With no clear organic cause, her medical providers again suspected an anxiety or panic episode. She was given reassurance, and an outpatient neurology consult was arranged.

THE DIAGNOSIS

One week later, at her outpatient neurology appointment, an electroencephalogram (EEG) was performed. Following photic stimulation, the EEG showed multiple right- and left-hemisphere foci of cortical hyperexcitability including a subtle sharp component (see FIGURE). Immediately following the longest of these episodes, the patient expressed a sense of anxiety and an altered sensorium similar to her prior presentations.

The EEG findings, in addition to the postictal anxiety symptoms and clinical history, were all important components that led the treating neurologist to the diagnosis of localization-related (focal) epilepsy.¹ The patient was started on oxcarbazepine, a first-line anti-epileptic medication used in the treatment of focal epilepsy.² She is being followed by a neurologist regularly and after optimizing her anti-epileptic medication, is no longer having seizures.

DISCUSSION

The difficulty of this case stems from the atypical presentation of the patient’s seizures. The key step to the correct diagnosis was a neurological consultation and an ensuing EEG. However, the patient received a vast spectrum of care, including multiple work-ups, prior to a conclusive diagnosis—which highlights an important issue health care providers must address.

Continue to: The role of bias

The role of bias. From the patient’s initial visits to the ED to her hospital admission, there was a prominent affixation, known as the anchoring bias,³ by the clinicians providing her care: All were focused heavily on her psychiatric features. Conversely, the evaluation for patients with suspected psychiatric diagnoses should focus on successfully ruling out major organic etiology with a broad differential diagnosis. It is crucial for providers to take a step back and make a conscious attempt to avoid fixation on a particular diagnosis, especially when it is psychiatric in nature. This allows the provider to actively consider alternative explanations for a patient presentation and work through a more encompassing differential.

The distinguishing symptoms. There is a common association between comorbid mood disorders (eg, depression, anxiety) and epilepsy.⁴ Another clue is ictal anxiety or nervousness, which is commonly observed in patients with partial seizures (and occurred with our patient).

These ictal episodes can be difficult to identify within the context of an isolated psychiatric diagnosis.⁵ The distinction can be clarified by the presence of associated somatic symptoms, which in this case included unilateral cramping, paresthesia, and weakness. These symptoms should clue in a practitioner to the possibility of underlying neurologic pathology, which should prompt the ordering of either an EEG or, at minimum, a neurological consultation.

THE TAKEAWAY

This case report shows how anchoring bias can lead to a delay in diagnosis and treatment. Avoidance of this type of bias requires heightened cognitive awareness by medical providers. A more system-based approach is to have structured diagnostic assessments,⁶ such as conducting a thorough neurological exam for patients with somatic symptoms and exacerbating comorbid psychiatric conditions.

It may also help to review cases like this with colleagues from diverse disciplinary backgrounds, highlighting thought processes and sharing uncertainty.³ These processes may shed light on confounding diagnoses that might be playing a role in a patient’s presentation and ultimately aid in the decision-making process.

CORRESPONDENCE
Paimon Ameli, DO, Naval Medical Center San Diego, 34800 Bob Wilson Drive, San Diego, CA 92134; paimonm@gmail.com

THE CASE

A 28-year-old woman with an extensive psychiatric history—including generalized anxiety disorder, panic disorder, and recent postpartum depression—presented with a chief complaint of right leg weakness. She stated this weakness had begun 4 days earlier. It occurred episodically and was preceded by tingling and cramping sensations. Each episode lasted a couple of minutes and spontaneously resolved. Associated with it, she experienced slurred speech and altered mentation. There was no loss of consciousness and no pain. A panic attack usually followed, consisting of feelings of impending doom, rapid breathing, palpitations, and nausea.

She had 3 prior diagnostic evaluations for this same chief complaint, twice in an emergency department (ED) and once with her primary care physician. These evaluations included lab work and extensive head imaging, which demonstrated no acute intracranial pathology. At each previous presentation, the diagnosis was an exacerbation of her anxiety disorder, and she was treated with lorazepam.

At the current presentation, her vital signs were stable. Examination revealed a notably anxious patient. She repeatedly expressed concern that she might have a brain tumor or some other deadly disease, as she had a family history of brain cancer. Her physical exam was entirely normal, including normal strength, sensation, and reflexes in all extremities.

Further head imaging (computed tomography, CT angiography, and magnetic resonance imaging of the brain) failed to reveal an etiology of her symptoms. With no clear organic cause, her medical providers again suspected an anxiety or panic episode. She was given reassurance, and an outpatient neurology consult was arranged.

THE DIAGNOSIS

One week later, at her outpatient neurology appointment, an electroencephalogram (EEG) was performed. Following photic stimulation, the EEG showed multiple right- and left-hemisphere foci of cortical hyperexcitability including a subtle sharp component (see FIGURE). Immediately following the longest of these episodes, the patient expressed a sense of anxiety and an altered sensorium similar to her prior presentations.

The EEG findings, in addition to the postictal anxiety symptoms and clinical history, were all important components that led the treating neurologist to the diagnosis of localization-related (focal) epilepsy.¹ The patient was started on oxcarbazepine, a first-line anti-epileptic medication used in the treatment of focal epilepsy.² She is being followed by a neurologist regularly and after optimizing her anti-epileptic medication, is no longer having seizures.

DISCUSSION

The difficulty of this case stems from the atypical presentation of the patient’s seizures. The key step to the correct diagnosis was a neurological consultation and an ensuing EEG. However, the patient received a vast spectrum of care, including multiple work-ups, prior to a conclusive diagnosis—which highlights an important issue health care providers must address.

Continue to: The role of bias

The role of bias. From the patient’s initial visits to the ED to her hospital admission, there was a prominent affixation, known as the anchoring bias,³ by the clinicians providing her care: All were focused heavily on her psychiatric features. Conversely, the evaluation for patients with suspected psychiatric diagnoses should focus on successfully ruling out major organic etiology with a broad differential diagnosis. It is crucial for providers to take a step back and make a conscious attempt to avoid fixation on a particular diagnosis, especially when it is psychiatric in nature. This allows the provider to actively consider alternative explanations for a patient presentation and work through a more encompassing differential.

The distinguishing symptoms. There is a common association between comorbid mood disorders (eg, depression, anxiety) and epilepsy.⁴ Another clue is ictal anxiety or nervousness, which is commonly observed in patients with partial seizures (and occurred with our patient).

These ictal episodes can be difficult to identify within the context of an isolated psychiatric diagnosis.⁵ The distinction can be clarified by the presence of associated somatic symptoms, which in this case included unilateral cramping, paresthesia, and weakness. These symptoms should clue in a practitioner to the possibility of underlying neurologic pathology, which should prompt the ordering of either an EEG or, at minimum, a neurological consultation.

THE TAKEAWAY

This case report shows how anchoring bias can lead to a delay in diagnosis and treatment. Avoidance of this type of bias requires heightened cognitive awareness by medical providers. A more system-based approach is to have structured diagnostic assessments,⁶ such as conducting a thorough neurological exam for patients with somatic symptoms and exacerbating comorbid psychiatric conditions.

It may also help to review cases like this with colleagues from diverse disciplinary backgrounds, highlighting thought processes and sharing uncertainty.³ These processes may shed light on confounding diagnoses that might be playing a role in a patient’s presentation and ultimately aid in the decision-making process.

CORRESPONDENCE
Paimon Ameli, DO, Naval Medical Center San Diego, 34800 Bob Wilson Drive, San Diego, CA 92134; paimonm@gmail.com

THE CASE

A 28-year-old woman with an extensive psychiatric history—including generalized anxiety disorder, panic disorder, and recent postpartum depression—presented with a chief complaint of right leg weakness. She stated this weakness had begun 4 days earlier. It occurred episodically and was preceded by tingling and cramping sensations. Each episode lasted a couple of minutes and spontaneously resolved. Associated with it, she experienced slurred speech and altered mentation. There was no loss of consciousness and no pain. A panic attack usually followed, consisting of feelings of impending doom, rapid breathing, palpitations, and nausea.

She had 3 prior diagnostic evaluations for this same chief complaint, twice in an emergency department (ED) and once with her primary care physician. These evaluations included lab work and extensive head imaging, which demonstrated no acute intracranial pathology. At each previous presentation, the diagnosis was an exacerbation of her anxiety disorder, and she was treated with lorazepam.

At the current presentation, her vital signs were stable. Examination revealed a notably anxious patient. She repeatedly expressed concern that she might have a brain tumor or some other deadly disease, as she had a family history of brain cancer. Her physical exam was entirely normal, including normal strength, sensation, and reflexes in all extremities.

Further head imaging (computed tomography, CT angiography, and magnetic resonance imaging of the brain) failed to reveal an etiology of her symptoms. With no clear organic cause, her medical providers again suspected an anxiety or panic episode. She was given reassurance, and an outpatient neurology consult was arranged.

THE DIAGNOSIS

One week later, at her outpatient neurology appointment, an electroencephalogram (EEG) was performed. Following photic stimulation, the EEG showed multiple right- and left-hemisphere foci of cortical hyperexcitability including a subtle sharp component (see FIGURE). Immediately following the longest of these episodes, the patient expressed a sense of anxiety and an altered sensorium similar to her prior presentations.

The EEG findings, in addition to the postictal anxiety symptoms and clinical history, were all important components that led the treating neurologist to the diagnosis of localization-related (focal) epilepsy.¹ The patient was started on oxcarbazepine, a first-line anti-epileptic medication used in the treatment of focal epilepsy.² She is being followed by a neurologist regularly and after optimizing her anti-epileptic medication, is no longer having seizures.

DISCUSSION

The difficulty of this case stems from the atypical presentation of the patient’s seizures. The key step to the correct diagnosis was a neurological consultation and an ensuing EEG. However, the patient received a vast spectrum of care, including multiple work-ups, prior to a conclusive diagnosis—which highlights an important issue health care providers must address.

Continue to: The role of bias

The role of bias. From the patient’s initial visits to the ED to her hospital admission, there was a prominent affixation, known as the anchoring bias,³ by the clinicians providing her care: All were focused heavily on her psychiatric features. Conversely, the evaluation for patients with suspected psychiatric diagnoses should focus on successfully ruling out major organic etiology with a broad differential diagnosis. It is crucial for providers to take a step back and make a conscious attempt to avoid fixation on a particular diagnosis, especially when it is psychiatric in nature. This allows the provider to actively consider alternative explanations for a patient presentation and work through a more encompassing differential.

The distinguishing symptoms. There is a common association between comorbid mood disorders (eg, depression, anxiety) and epilepsy.⁴ Another clue is ictal anxiety or nervousness, which is commonly observed in patients with partial seizures (and occurred with our patient).

These ictal episodes can be difficult to identify within the context of an isolated psychiatric diagnosis.⁵ The distinction can be clarified by the presence of associated somatic symptoms, which in this case included unilateral cramping, paresthesia, and weakness. These symptoms should clue in a practitioner to the possibility of underlying neurologic pathology, which should prompt the ordering of either an EEG or, at minimum, a neurological consultation.

THE TAKEAWAY

This case report shows how anchoring bias can lead to a delay in diagnosis and treatment. Avoidance of this type of bias requires heightened cognitive awareness by medical providers. A more system-based approach is to have structured diagnostic assessments,⁶ such as conducting a thorough neurological exam for patients with somatic symptoms and exacerbating comorbid psychiatric conditions.

It may also help to review cases like this with colleagues from diverse disciplinary backgrounds, highlighting thought processes and sharing uncertainty.³ These processes may shed light on confounding diagnoses that might be playing a role in a patient’s presentation and ultimately aid in the decision-making process.

CORRESPONDENCE
Paimon Ameli, DO, Naval Medical Center San Diego, 34800 Bob Wilson Drive, San Diego, CA 92134; paimonm@gmail.com

Remote telemedicine visits were feasible, reasonably reliable, and acceptable to individuals with Parkinson’s disease, a 1-year, phase 3 clinical trial has shown. The trial was an add-on study involving a subset of subjects from the STEADY-PD III trial of isradipine in early Parkinson’s disease.

Although the trial was conducted before SARS-CoV-2 arrived on the scene, the findings have particular relevance for being able to conduct a variety of clinical trials in the face of COVID-19 and the need to limit in-person interactions.

The 40 participants used tablets to complete three remote, video-based assessments during 1 year, with each remote visit planned to be completed within 4 weeks of an in-person visit. It was easy to enroll patients, and they completed about 95% of planned visits, said neurologist Christopher Tarolli, MD, of the University of Rochester (N.Y.).

He presented the study findings at the Movement Disorder Society’s 23rd International Congress of Parkinson’s Disease and Movement Disorders (Virtual) 2020.

“The visits were clearly feasible, and we were able to do them [84%] within that 4-week time frame around the in-person visit,” he said. “The visits were also reasonably reliable, particularly so for what we call the nonmotor outcomes and the patient-reported outcomes.”
 

In-person versus remote assessment

For the remote visits, participants completed primarily the same battery of tests as the in-person visits. Responses on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) subscales demonstrated “that there was excellent correlation between patient-reported and nonmotor outcome measures and moderate correlation between in-person and remote-performed motor assessments,” Dr. Tarolli said.  

He explained that the study used modified motor assessments (MDS-UPDRS Part III) that excluded testing of rigidity and postural instability, which require hands-on testing by a trained examiner and thus are impossible to do remotely.

Additionally, the somewhat lower correlation on this subscale was probably the result of different investigators conducting in-person versus remote assessments, with a subset of in-person investigators who tended to rate participants more severely driving down the correlation. “I think if these methods were applied in future trials, the in-person and remote investigators would optimally be the same person,” Dr. Tarolli suggested.
 

Room for error?

Indu Subramanian, MD, of the department of neurology at the University of California, Los Angeles, and director of the Parkinson’s Disease Research, Education, and Clinical Center at the West Los Angeles Veterans Affairs Hospital, commented that “the reliability of UPDRS [part] III is where I would want to have, for sure, a little bit more of a deep dive. … possibly the same patient be rated by the same person.”

She also noted that doing remote and in-person assessments within 4 weeks of each other leaves a lot of room for variability. “You could see the same patient in the morning and then do UPDRS in the afternoon, and it can be totally different depending on when you meet the person,” she said.

Only so much testing can be done remotely. Nonetheless, she questioned whether it is really a valid UPDRS if rigidity and postural stability measures are eliminated. “[Is] this now a new modified UPDRS that we’re going to use that is as good as the old UPDRS moving forward, a home version of UPDRS or whatever we’re going to call it?”

Dr. Subramanian mentioned that patients have told her that UPDRS part III does not really measure what is most important to them, such as making pastries for their grandchildren rather than rapidly tapping their fingers.

“That speaks a little bit to the fact that we should have more patient-centered outcomes and things that patients can report. … things that are not going to require necessarily an in-person exam as maybe measures that really can be used moving forward in studies,” she suggested.
 

Patient satisfaction with remote visits

Greater than 90% of the patients were satisfied or very satisfied overall with the remote visits, including the convenience, comfort, and connection (using the devices and Internet connection), with “patients describing enjoying being able to do these visits from the comfort of their own home, not having to travel,” Dr. Tarolli said. Not having to drive in an ‘off’ state “was actually something that some participants identified as a safety benefit from this as well.”

There was also a time benefit to the patients and investigators. The average length of the remote visits was 54.3 minutes each versus 74 minutes of interaction for in-person visits, mainly a result of more efficient hand-offs between the neurologist and the study coordinator during the remote visits, plus being able to pause the remote visit to give a medication dose time to take effect.

For the patient, there was a large amount of time saved when travel time was considered – a total of 190.2 minutes on average for travel and testing for the in-person visits.

About three-quarters (76%) of the study patients said that remote visits would increase their likelihood of participating in future trials. However, that result may be skewed by the fact that these were already people willing to participate in a remote trial, so the generalizability of the result may be affected. Nonetheless, Dr. Tarolli said he thinks that, as technology gets better and older people become more comfortable with it, remote visits within Parkinson’s research studies may become more common.

One caveat he mentioned is that, with remote visits, the neurologist misses a chance to observe a patient’s whole body and construct a global impression of how he or she is moving. On the other hand, remote video gives the investigator the chance to see the living environment of the patient and suggest changes for safety, such as to reduce the risk of falling for a person with unsteadiness of gait living in a crowded house.

“It really allows us to make a more holistic assessment of how our patient is functioning outside the clinic, which I think we’ve traditionally had really no way of doing,” Dr. Tarolli said.

His final suggestion for anyone contemplating conducting studies with remote visits is to develop a team that is comfortable troubleshooting the technological aspects of those visits.

UCLA’s Dr. Subramanian lauded the University of Rochester team for their efforts in moving remote visits forward. “They’re at the cutting edge of these sorts of things,” she said. “So I’m assuming that they’ll come out with more things [for visits] to become better that are going to move this forward, which is exciting.”

Dr. Tarolli has disclosed no relevant financial relationships. Dr. Subramanian has given talks for Acorda Pharmaceuticals and Acadia Pharmaceuticals in the past. The study had only university, government, foundation, and other nonprofit support.

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

Remote telemedicine visits were feasible, reasonably reliable, and acceptable to individuals with Parkinson’s disease, a 1-year, phase 3 clinical trial has shown. The trial was an add-on study involving a subset of subjects from the STEADY-PD III trial of isradipine in early Parkinson’s disease.

Although the trial was conducted before SARS-CoV-2 arrived on the scene, the findings have particular relevance for being able to conduct a variety of clinical trials in the face of COVID-19 and the need to limit in-person interactions.

The 40 participants used tablets to complete three remote, video-based assessments during 1 year, with each remote visit planned to be completed within 4 weeks of an in-person visit. It was easy to enroll patients, and they completed about 95% of planned visits, said neurologist Christopher Tarolli, MD, of the University of Rochester (N.Y.).

He presented the study findings at the Movement Disorder Society’s 23rd International Congress of Parkinson’s Disease and Movement Disorders (Virtual) 2020.

“The visits were clearly feasible, and we were able to do them [84%] within that 4-week time frame around the in-person visit,” he said. “The visits were also reasonably reliable, particularly so for what we call the nonmotor outcomes and the patient-reported outcomes.”
 

In-person versus remote assessment

For the remote visits, participants completed primarily the same battery of tests as the in-person visits. Responses on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) subscales demonstrated “that there was excellent correlation between patient-reported and nonmotor outcome measures and moderate correlation between in-person and remote-performed motor assessments,” Dr. Tarolli said.  

He explained that the study used modified motor assessments (MDS-UPDRS Part III) that excluded testing of rigidity and postural instability, which require hands-on testing by a trained examiner and thus are impossible to do remotely.

Additionally, the somewhat lower correlation on this subscale was probably the result of different investigators conducting in-person versus remote assessments, with a subset of in-person investigators who tended to rate participants more severely driving down the correlation. “I think if these methods were applied in future trials, the in-person and remote investigators would optimally be the same person,” Dr. Tarolli suggested.
 

Room for error?

Indu Subramanian, MD, of the department of neurology at the University of California, Los Angeles, and director of the Parkinson’s Disease Research, Education, and Clinical Center at the West Los Angeles Veterans Affairs Hospital, commented that “the reliability of UPDRS [part] III is where I would want to have, for sure, a little bit more of a deep dive. … possibly the same patient be rated by the same person.”

She also noted that doing remote and in-person assessments within 4 weeks of each other leaves a lot of room for variability. “You could see the same patient in the morning and then do UPDRS in the afternoon, and it can be totally different depending on when you meet the person,” she said.

Only so much testing can be done remotely. Nonetheless, she questioned whether it is really a valid UPDRS if rigidity and postural stability measures are eliminated. “[Is] this now a new modified UPDRS that we’re going to use that is as good as the old UPDRS moving forward, a home version of UPDRS or whatever we’re going to call it?”

Dr. Subramanian mentioned that patients have told her that UPDRS part III does not really measure what is most important to them, such as making pastries for their grandchildren rather than rapidly tapping their fingers.

“That speaks a little bit to the fact that we should have more patient-centered outcomes and things that patients can report. … things that are not going to require necessarily an in-person exam as maybe measures that really can be used moving forward in studies,” she suggested.
 

Patient satisfaction with remote visits

Greater than 90% of the patients were satisfied or very satisfied overall with the remote visits, including the convenience, comfort, and connection (using the devices and Internet connection), with “patients describing enjoying being able to do these visits from the comfort of their own home, not having to travel,” Dr. Tarolli said. Not having to drive in an ‘off’ state “was actually something that some participants identified as a safety benefit from this as well.”

There was also a time benefit to the patients and investigators. The average length of the remote visits was 54.3 minutes each versus 74 minutes of interaction for in-person visits, mainly a result of more efficient hand-offs between the neurologist and the study coordinator during the remote visits, plus being able to pause the remote visit to give a medication dose time to take effect.

For the patient, there was a large amount of time saved when travel time was considered – a total of 190.2 minutes on average for travel and testing for the in-person visits.

About three-quarters (76%) of the study patients said that remote visits would increase their likelihood of participating in future trials. However, that result may be skewed by the fact that these were already people willing to participate in a remote trial, so the generalizability of the result may be affected. Nonetheless, Dr. Tarolli said he thinks that, as technology gets better and older people become more comfortable with it, remote visits within Parkinson’s research studies may become more common.

One caveat he mentioned is that, with remote visits, the neurologist misses a chance to observe a patient’s whole body and construct a global impression of how he or she is moving. On the other hand, remote video gives the investigator the chance to see the living environment of the patient and suggest changes for safety, such as to reduce the risk of falling for a person with unsteadiness of gait living in a crowded house.

“It really allows us to make a more holistic assessment of how our patient is functioning outside the clinic, which I think we’ve traditionally had really no way of doing,” Dr. Tarolli said.

His final suggestion for anyone contemplating conducting studies with remote visits is to develop a team that is comfortable troubleshooting the technological aspects of those visits.

UCLA’s Dr. Subramanian lauded the University of Rochester team for their efforts in moving remote visits forward. “They’re at the cutting edge of these sorts of things,” she said. “So I’m assuming that they’ll come out with more things [for visits] to become better that are going to move this forward, which is exciting.”

Dr. Tarolli has disclosed no relevant financial relationships. Dr. Subramanian has given talks for Acorda Pharmaceuticals and Acadia Pharmaceuticals in the past. The study had only university, government, foundation, and other nonprofit support.

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

Remote telemedicine visits were feasible, reasonably reliable, and acceptable to individuals with Parkinson’s disease, a 1-year, phase 3 clinical trial has shown. The trial was an add-on study involving a subset of subjects from the STEADY-PD III trial of isradipine in early Parkinson’s disease.

Although the trial was conducted before SARS-CoV-2 arrived on the scene, the findings have particular relevance for being able to conduct a variety of clinical trials in the face of COVID-19 and the need to limit in-person interactions.

The 40 participants used tablets to complete three remote, video-based assessments during 1 year, with each remote visit planned to be completed within 4 weeks of an in-person visit. It was easy to enroll patients, and they completed about 95% of planned visits, said neurologist Christopher Tarolli, MD, of the University of Rochester (N.Y.).

He presented the study findings at the Movement Disorder Society’s 23rd International Congress of Parkinson’s Disease and Movement Disorders (Virtual) 2020.

“The visits were clearly feasible, and we were able to do them [84%] within that 4-week time frame around the in-person visit,” he said. “The visits were also reasonably reliable, particularly so for what we call the nonmotor outcomes and the patient-reported outcomes.”
 

In-person versus remote assessment

For the remote visits, participants completed primarily the same battery of tests as the in-person visits. Responses on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) subscales demonstrated “that there was excellent correlation between patient-reported and nonmotor outcome measures and moderate correlation between in-person and remote-performed motor assessments,” Dr. Tarolli said.  

He explained that the study used modified motor assessments (MDS-UPDRS Part III) that excluded testing of rigidity and postural instability, which require hands-on testing by a trained examiner and thus are impossible to do remotely.

Additionally, the somewhat lower correlation on this subscale was probably the result of different investigators conducting in-person versus remote assessments, with a subset of in-person investigators who tended to rate participants more severely driving down the correlation. “I think if these methods were applied in future trials, the in-person and remote investigators would optimally be the same person,” Dr. Tarolli suggested.
 

Room for error?

Indu Subramanian, MD, of the department of neurology at the University of California, Los Angeles, and director of the Parkinson’s Disease Research, Education, and Clinical Center at the West Los Angeles Veterans Affairs Hospital, commented that “the reliability of UPDRS [part] III is where I would want to have, for sure, a little bit more of a deep dive. … possibly the same patient be rated by the same person.”

She also noted that doing remote and in-person assessments within 4 weeks of each other leaves a lot of room for variability. “You could see the same patient in the morning and then do UPDRS in the afternoon, and it can be totally different depending on when you meet the person,” she said.

Only so much testing can be done remotely. Nonetheless, she questioned whether it is really a valid UPDRS if rigidity and postural stability measures are eliminated. “[Is] this now a new modified UPDRS that we’re going to use that is as good as the old UPDRS moving forward, a home version of UPDRS or whatever we’re going to call it?”

Dr. Subramanian mentioned that patients have told her that UPDRS part III does not really measure what is most important to them, such as making pastries for their grandchildren rather than rapidly tapping their fingers.

“That speaks a little bit to the fact that we should have more patient-centered outcomes and things that patients can report. … things that are not going to require necessarily an in-person exam as maybe measures that really can be used moving forward in studies,” she suggested.
 

Patient satisfaction with remote visits

Greater than 90% of the patients were satisfied or very satisfied overall with the remote visits, including the convenience, comfort, and connection (using the devices and Internet connection), with “patients describing enjoying being able to do these visits from the comfort of their own home, not having to travel,” Dr. Tarolli said. Not having to drive in an ‘off’ state “was actually something that some participants identified as a safety benefit from this as well.”

There was also a time benefit to the patients and investigators. The average length of the remote visits was 54.3 minutes each versus 74 minutes of interaction for in-person visits, mainly a result of more efficient hand-offs between the neurologist and the study coordinator during the remote visits, plus being able to pause the remote visit to give a medication dose time to take effect.

For the patient, there was a large amount of time saved when travel time was considered – a total of 190.2 minutes on average for travel and testing for the in-person visits.

About three-quarters (76%) of the study patients said that remote visits would increase their likelihood of participating in future trials. However, that result may be skewed by the fact that these were already people willing to participate in a remote trial, so the generalizability of the result may be affected. Nonetheless, Dr. Tarolli said he thinks that, as technology gets better and older people become more comfortable with it, remote visits within Parkinson’s research studies may become more common.

One caveat he mentioned is that, with remote visits, the neurologist misses a chance to observe a patient’s whole body and construct a global impression of how he or she is moving. On the other hand, remote video gives the investigator the chance to see the living environment of the patient and suggest changes for safety, such as to reduce the risk of falling for a person with unsteadiness of gait living in a crowded house.

“It really allows us to make a more holistic assessment of how our patient is functioning outside the clinic, which I think we’ve traditionally had really no way of doing,” Dr. Tarolli said.

His final suggestion for anyone contemplating conducting studies with remote visits is to develop a team that is comfortable troubleshooting the technological aspects of those visits.

UCLA’s Dr. Subramanian lauded the University of Rochester team for their efforts in moving remote visits forward. “They’re at the cutting edge of these sorts of things,” she said. “So I’m assuming that they’ll come out with more things [for visits] to become better that are going to move this forward, which is exciting.”

Dr. Tarolli has disclosed no relevant financial relationships. Dr. Subramanian has given talks for Acorda Pharmaceuticals and Acadia Pharmaceuticals in the past. The study had only university, government, foundation, and other nonprofit support.

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

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

egreb@mdedge.com

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

egreb@mdedge.com

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

egreb@mdedge.com

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.