Neurology

Myopathies can present with a wide variety of symptoms, so patients with muscle weakness are often seen initially by a general practitioner. Nonrheumatologists should be able to evaluate a patient presenting with muscle weakness or myalgia and be aware of red flags indicating potentially dangerous syndromes that require a prompt, thorough investigation.

This article reviews selected causes of muscle weakness, such as statin-induced and autoimmune disorders, and systemic features of inflammatory myopathies beyond myositis, such as dermatologic and pulmonary manifestations.

FOCUSING THE EVALUATION

The evaluation of a patient presenting with muscle weakness should include several assessments: 

Temporal progression. Was the onset of symptoms rapid or insidious? Patterns of onset may give clues to etiology, including the possibility of an associated autoimmune condition.

Location of muscle weakness. Are symptoms global or localized? And if localized, are they proximal or distal? Proximal weakness can be manifested by difficulty rising from a chair (hip muscles) or combing one’s hair (shoulder muscles), whereas distal weakness can involve difficulty standing on toes (gastrocnemius and soleus muscles) or performing fine motor activities (intrinsic hand muscles).

Symmetry. A focal or asymmetric pattern often has a neurologic etiology, but this could also be consistent with inclusion body myositis.

Other symptoms. Arthritis, rash, and swallowing problems point to a possible underlying rheumatologic disease. Weight gain or loss may indicate a thyroid disorder.

Family history. Some patients report that others in their family have this pattern of weakness, indicating a likely genetic myopathy. If the patient reports a relative with multiple sclerosis, lupus erythematosus, rheumatoid arthritis, or another autoimmune disease, then an immune-mediated myopathy should be considered.

Medications should be reviewed, particularly statins.

CASE 1: SLOWLY PROGRESSIVE WEAKNESS

A 65-year-old man presented with the insidious onset of muscle weakness and episodes of falling. On review of his medical record, his serum creatine kinase (CK) levels were elevated at various periods at 2 to 4 times the upper limit of normal. Electromyography (EMG) previously showed a myopathic pattern, and a muscle biopsy was abnormal, consistent with endomysial inflammation (term is consistent with “polymyositis”). He was treated for polymyositis for several years with prednisone alone, with steroids plus methotrexate, and with combined immunosuppression including methotrexate and azathioprine, but with no improvement. Eventually, another muscle biopsy revealed inclusion bodies with rimmed vacuoles, consistent with inclusion body myositis.

Inclusion body myositis

Inclusion body myositis is the most common myopathy in middle-aged to elderly people, especially men. These patients are often told “You are just getting old,” but they have a defined condition. It should also be considered in patients failing to respond to treatment or with those with “refractory” polymyositis.

The onset of muscle weakness is insidious and painless, and the weakness progresses slowly. The pattern is distal and asymmetric (eg, foot drop), and muscle atrophy typically affects the forearm flexors, quadriceps, and intrinsic muscles of the hands.¹

Magnetic resonance imaging may show marked muscle atrophy. Unfortunately, no treatment has shown efficacy, and most neuromuscular and rheumatology experts do not treat inclusion body myositis with immunosuppressive drugs. 

CASE 2: MILD MYALGIA WITHOUT WEAKNESS

A black 52-year-old man was referred because of myalgia and a CK level of 862 U/L (reference range < 200). His physician wanted to start him on a statin but was hesitant to do so without first consulting a rheumatologist.

The patient had a long history of mild arthralgias and myalgias without muscle weakness. He had dyslipidemia and hypertension. He reported no family history of myopathy and no illicit drug use. He was formerly an athlete. Medications included a thiazide diuretic and a beta-blocker. On examination, his muscles were strong (rated 5 on a scale of 5) in the upper and lower extremities, without atrophy.

His records showed that his CK levels had risen and fallen repeatedly over the past few years, ranging from 600 to 1,100 U/L. On further questioning, he reported that when he had joined the army 30 years previously, a physician had recommended he undergo a liver biopsy in view of elevated liver function tests, but that he had refused because he felt fine.

Currently, his gamma-glutamyl transpeptidase levels were normal.

Idiopathic ‘hyperCKemia’

So-called idiopathic hyperCKemia is not a form of myositis but merely a laboratory result outside the “normal” range. Reference ranges are based predominantly on measurements in white people and on an assumption that the distribution is Gaussian (bell-shaped). A normal CK level is usually defined as less than 200 U/L. Using this standard, up to 20% of men and 5% of women have hyperCKemia.²

However, CK levels vary by sex and ethnicity, with mean levels highest in black men, followed by black women, white men, and white women. The mean level in black men is higher than the standard cutoff point for normal, and especially in this population, there is wide fluctuation around the mean, leading to hyperCKemia quite frequently in black men. Exercise and manual labor also drive up CK levels.^3–5 

Idiopathic hyperCKemia is benign. D’Adda et al⁶ followed 55 patients for a mean of 7.5 years. CK levels normalized in 12 patients or at least decreased in 24. Most remained symptom-free or had minimal symptoms. 

Idiopathic hyperCKemia: Bottom line

Before prescribing a statin, determine the baseline CK level. If slightly elevated (ie, up to 3 to 5 times the upper limit of normal, or even higher) in the setting of normal muscle strength, there is no need for electromyography or muscle biopsy, and the patient can certainly receive a statin. Most of these patients do not need to see a rheumatologist but can simply have their CK and muscle strength monitored.

 

 

CLASSIFYING MYOSITIS

Myositis (idiopathic inflammatory myopathy) is a heterogeneous group of autoimmune syndromes of unknown cause characterized by chronic muscle weakness and inflammation of striated muscle. These syndromes likely arise as a result of genetic predisposition and an environmental or infectious “hit.”

Myositis is rare, with an incidence of 5 to 10 cases per million per year and an estimated prevalence of 50 to 90 cases per million. It has 2 incidence peaks: 1 in childhood (age 5–15) and another in adult midlife (age 30–50). Women are affected 2 to 3 times more often than men, with black women most commonly affected.

Myositis is traditionally classified as follows:

• Adult polymyositis
• Adult dermatomyositis
• Juvenile myositis (dermatomyositis much more frequent than polymyositis)
• Malignancy-associated myositis (usually dermatomyositis)
• Myositis overlapping with another autoimmune disease
• Inclusion body myositis.

However, polymyositis is less common than we originally thought, and the term necrotizing myopathy is now used in many patients, as noted in the case studies below. Further, myositis overlap syndromes are being increasingly diagnosed, likely related to the emergence of autoantibodies and clinical “syndromes” associated with these autoantibody subsets (discussed in cases below).

Dermatomyositis

Dermatomyositis is characterized by muscle weakness and a rash that can be obvious or subtle. Classic skin lesions are Gottron papules, which are raised, flat-topped red or purplish lesions over the knuckles, elbows, or knees.

Lesions may be confused with those of psoriasis. There can also be a V-neck rash over the anterior chest or upper back (“shawl sign”) or a rash over the lateral thigh (“holster sign”). A facial rash may occur, but unlike lupus, dermatomyositis does not spare the nasolabial area. However, the V-neck rash can be similar to that seen in lupus.

Dermatomyositis may cause muscle pain, perhaps related to muscle ischemia, whereas polymyositis and necrotizing myopathy are often painless. However, pain is also associated with fibromyalgia, which may be seen in many autoimmune conditions. It is important not to overtreat rheumatologic diseases with immunosuppression to try to control pain if the pain is actually caused by fibromyalgia.

Polymyositis mimics

Hypothyroid myopathy can present as classic polymyositis. The serum CK may be elevated, and there may be myalgias, muscle hypertrophy with stiffness, weakness, cramps, and even features of a proximal myopathy, and rhabdomyolysis. The electromyogram can be normal or myopathic. Results of muscle biopsy are often normal but may show focal necrosis and mild inflammatory infiltrates, thus mimicking that seen with inflammatory myopathy.⁷

Drug-induced or toxic myopathies can also mimic polymyositis. Statins are among the most commonly prescribed drugs in the United States, with more than 35 million people taking them. Statins are generally well tolerated but have a broad spectrum of toxicity, ranging from myalgias to life-threatening rhabdomyolysis. Myalgias lead to about 5% to 10% of patients refusing to take a statin or stopping it on their own.

Myalgias affect up to 20% of statin users in clinical practice.^8,9 A small cross-sectional study¹⁰ of 1,000 patients in a primary care setting found that the risk of muscle complaints in statin users was 1.5 times higher than in nonstatin users, similar to findings in other studies.

My strategy for managing a patient with possible statin-induced myopathy is illustrated in Figure 1.

CASE 3: WEAKNESS, VERY HIGH CK ON A STATIN

In March 2010, a 67-year-old woman presented with muscle weakness. She had a history of hypertension, hyperlipidemia, and, more than 10 years previously, uterine cancer. In 2004, she was given atorvastatin for dyslipidemia. Four years later, she developed lower-extremity weakness, which her doctor attributed to normal aging. A year after that, she found it difficult to walk up steps and lift her arms overhead. In June 2009, she stopped taking the atorvastatin on her own, but the weakness did not improve.

In September 2009, she returned to her doctor, who found her CK level was 6,473 U/L but believed it to be an error, so the test was repeated, with a result of 9,375 U/L. She had no rash or joint involvement.

She was admitted to the hospital and underwent muscle biopsy, which showed myonecrosis with no inflammation or vasculitis.  She was treated with prednisone 60 mg/day, and her elevated CK level and weakness improved.

Immune-mediated necrotizing myopathy associated with statins

The hallmark of necrotizing myopathy is myonecrosis without significant inflammation.¹² This pattern contrasts with that of polymyositis, which is characterized by lymphocytic inflammation.

Although statins became available in the United States in 1987, immune-mediated necrotizing myopathy associated with statins was first described only in 2010. In that report, Grable-Esposito et al¹³ described 25 patients from 2 neuromuscular centers seen between 2000 and 2008 who had elevated CK and proximal weakness during or after statin use, both of which persisted despite stopping the statin. Patients improved with immunosuppressive agents but had a relapse when steroids were stopped or tapered, a pattern typical in autoimmune disease.

 

 

Autoantibody defines subgroup of necrotizing myopathy

Also in 2010, Christopher-Stine et al¹⁴ reported an antibody associated with necrotizing myopathy. Of 38 patients with the condition, 16 were found to have an abnormal “doublet” autoantibody recognizing 200- and 100-kDa proteins. All patients had weakness and a high CK level, and 63% had statin exposure before the weakness (this percentage increased to 83% in patients older than 50). All responded to immunosuppressive therapy, and many had a relapse when it was withdrawn.

Statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-Co A reductase (HMGCR), and paradoxically, they also upregulate it. HMGCR has a molecular weight of 97 kDa. Mammen et al¹⁵ identified HMGCR as the 100-kDa target of the identified antibody and developed an enzyme-linked immunosorbent assay for it. Of 750 patients presenting to one center, only 45 (6%) had anti-HMGCR autoantibodies, but all 16 patients who had the abnormal doublet antibody tested positive for anti-HMGCR. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response after statins are discontinued.

Case 3 continued: Intravenous immunoglobulin brings improvement

In March 2010, when the 67-year-old patient presented to our myositis center, her CK level was 5,800 U/L, which increased as prednisone was tapered. She still felt weak. On examination, her muscle strength findings were deltoids 4+/5, neck flexors 4/5, and iliopsoas 3+/5. She was treated with methotrexate and azathioprine without benefit. She was next treated with intravenous immunoglobulin, and after 3 months, her strength normalized for the first time in years. Her CK level decreased but did not normalize. Testing showed that she was positive for anti-HMGCR auto­antibody, as this test had become commercially available.

In 2015, Mammen and Tiniakou¹⁶ suggested using intravenous immunoglobulin as first-line therapy for statin-associated autoimmune necrotizing myopathy, based on experience at a single center with 3 patients who declined glucocorticoid treatment.

Necrotizing myopathy: Bottom line

Myositis overlap syndromes

Heterogeneity is the rule in myositis, and it can present with a wide variety of signs and symptoms as outlined in Table 2.

CASE 4: FEVER, NEW ‘RHEUMATOID ARTHRITIS,’ AND LUNG DISEASE

A 52-year-old woman with knee osteoarthritis saw her primary care physician in November 2013 for dyspnea and low-grade fever. The next month, she presented with polyarthritis, muscle weakness, and Raynaud phenomenon.

In January 2014, she developed acrocyanosis of her fingers. Examination revealed hyperkeratotic, cracked areas of her fingers. Her oxygen saturation by pulse oximetry was low. She was admitted to the hospital. Her doctor suspected new onset of rheumatoid arthritis, but blood tests revealed a negative antinuclear antibody, so an autoimmune condition was deemed unlikely. Her CK was mildly elevated at 350 U/L.

Because of her dyspnea, an open-lung biopsy was performed. High-resolution computed tomography (CT) revealed infiltrates and ground-glass opacities, leading to the diagnosis of nonspecific interstitial pneumonia. A rheumatologist was consulted and recommended pulse methylprednisolone, followed by prednisone 60 mg/day and mycophenolate mofetil. Testing for Jo-1 antibodies was positive.

Antisynthetase syndrome

The antisynthetase syndrome is a clinically heterogeneous condition that can occur with any or all of the following:

• Fever
• Myositis
• Arthritis (often misdiagnosed as rheumatoid arthritis)
• Raynaud phenomenon
• Mechanic’s hands (hyperkeratotic  roughness with fissures on the lateral aspects of the fingers and finger pads)
• Interstitial lung disease.

The skin rashes and myositis may be subtle, making the presentation “lung-dominant,” and nonrheumatologists should be aware of this syndrome. Although in our patient the condition developed in a classic manner, with all of the aforementioned features of the antisynthetase syndrome, some patients will manifest one or a few of the features.

Clinically, patients with the Jo-1 antisynthetase syndrome often present differently than those with non-Jo-1 antisynthetase autoantibodies. When we compared 122 patients with Jo-1 vs 80 patients with a non-Jo-1 antisynthetase autoantibody, patients with Jo-1 antibodies were more likely to have initially received a diagnosis of myositis (83%), while  myositis was the original diagnosis in only 17% of those possessing non-Jo-1 antisynthetase autoantibodies. In fact, many patients (approximately 50%) were diagnosed as having undifferentiated connective tissue disease or an overlap syndrome, and 13% had scleroderma as their first diagnosis.¹⁷

We also found that the survival rate was higher in patients with Jo-1 syndrome compared with patients with non-Jo-1 antisynthetase syndromes. We attributed the difference in survival rates to a delayed diagnosis in the non-Jo-1 group, perhaps due to their “nonclassic” presentations of the antisynthetase syndrome, delaying appropriate treatment. Patients received a diagnosis of Jo-1 antibody syndrome after a mean of 0.4 year (range 0.2–0.8), while those with a non-Jo-1 antisynthetase autoantibody had a delay in diagnosis of 1.0 year (range 0.4–5.1) (P < .01).¹⁷

In nearly half the cases in this cohort, pulmonary fibrosis was the cause of death, with primary pulmonary hypertension being the second leading cause (11%).

Antisynthetase syndrome: Bottom line

Antisynthetase syndrome is an often fatal disease that does not always present in a typical fashion with symptoms of myositis, as lung disease may be the predominant feature. A negative antinuclear antibody test result does not imply antibody negativity, as the autoantigen in these diseases is not located in the nucleus. Prompt diagnosis and appropriate immunosuppressive therapy are critical to improving outcomes.

CASE 5: FEVER, UNDIAGNOSED LUNG DISEASE, NO MYOSITIS

In January 2001, a 39-year-old woman was admitted to the hospital after 5 weeks of fever (temperatures 103°–104°F) and myalgias. An extensive workup was negative except for low-titer antinuclear antibody and for mild basilar fibrosis noted on chest radiography. She left the hospital against medical advice because of frustration with a lack of a specific diagnosis (“fever of unknown origin”).

Two months later, at a follow-up rheumatology consult, she reported more myalgias and arthralgias, as well as fever. Chest radiography now showed pleural effusions. Her fingers had color changes consistent with Raynaud phenomenon. At that time, I diagnosed an undifferentiated connective tissue disease and told her that I suspected an autoimmune condition that would need time to reveal itself. In the meantime, I treated her empirically with prednisone.

In April, she returned, much more short of breath and with more prominent diffuse pulmonary infiltrates. Physical examination revealed subtle Gottron changes. Testing revealed poor pulmonary function: forced vital capacity (FVC) 56%, forced expiratory volume in 1 second (FEV₁) 52%, and diffusing capacity for carbon monoxide (Dlco) 40%. Blood testing was positive for anti-PL-12 antibody, one of the non-Jo-1 antisynthetase antibodies. At this time, we treated her with glucocorticoids and tacrolimus.

More than 15 years later, this patient is doing well. Her skin rash, joint symptoms, and fever have not returned, and interestingly, she never developed myositis. Her Raynaud symptoms are mild. Her most recent pulmonary function test results (January 2018) were FVC  75%, FEV₁ 87%, and Dlco 78%. Although these results are not normal, they are much improved and allow her to be completely functional without supplemental oxygen. Echocardiography showed  normal pulmonary artery systolic pressure (25 mm Hg). She was still taking tacrolimus and prednisone. When we tried to stop tacrolimus after she had done well for many years, her condition flared.

Non-Jo-1 antisynthetase syndrome: Bottom line

Patients with a non-Jo-1 antisynthetase syndrome often present without myositis symptoms and may never manifest myositis symptoms. Likely because of this presentation, diagnosis of a specific connective tissue disorder is delayed, perhaps leading to increased mortality risk from pulmonary disease. Chronic immunosuppression is often required for these autoimmune conditions.

CASE 6: DERMATOMYOSITIS, RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE

A 58-year-old woman presented in the summer of 2012 with a photosensitive rash. The following January, she returned with polyarthritis, mild muscle weakness, and a dermatomyositis-pattern rash. Her CK level was normal, and her antinuclear antibody and Sjögren syndrome antibody test results were negative. She improved on low-dose prednisone and methotrexate.

She was originally referred to me in May of that year for worsening rash and mild weakness. She denied pulmonary symptoms, but examination revealed faint basilar crackles. I increased her prednisone dosage to 20 mg/day and started mycophenolate mofetil mainly for the mild cutaneous and myositis features. I also recommended high-resolution CT of the lungs and pulmonary function tests, which she underwent in early June. High-resolution CT showed nonspecific mild infiltrates with minimal ground-glass opacities.

On July 1, she presented to her local emergency department with severe shortness of breath, requiring oxygen 12 L/min. She had a palmar rash. Repeat high-resolution CT showed dramatic worsening compared with the scan the previous month. Because of continued inadequate oxygenation, she was transferred to our center. A blood test later was positive for antimelanoma differentiation-associated gene 5 (MDA-5) autoantibody, previously known as anticlinically amyopathic dermatomyositis (anti-CADM)-140 antibody (based on immunoprecipitation results).

She died on the third day after transfer, just 2 months after I had originally seen her, at which time she had had no pulmonary symptoms.

Clinically amyopathic dermatomyositis

Anti-CADM-140, first reported from Asia,^18–20 is an autoantibody-associated disease but not an antisynthetase. It is associated with dermatomyositis; patients often have a “vasculopathy” with cutaneous ulcerations and palmar papules.

MDA-5 is a cytoplasmic protein that “senses” viral RNA and induces production of type 1 interferon. It is involved in the innate immune defense against viruses.

Anti-MDA-5 positivity is associated with a poor pulmonary outcome.²¹ In our cohort from the University of Pittsburgh, many patients died within 3 years, compared with about a 40% survival rate in patients with dermatomyositis who tested negative for this antibody. That being said, many patients with anti-MDA-5 do not develop rapidly progressive interstitial lung disease.

Autoimmune interstitial lung disease: Bottom line

Autoimmune interstitial lung disease is easy to miss, especially in the case of a non-Jo-1 syndrome, for 3 important reasons:

• The autoimmune features may initially be subtle (eg, Raynaud phenomena, mild dermatomyositis rash, undifferentiated connective tissue disease)
• Autoantibody testing is not often ordered, is not standardized, or may be unavailable 
• Providers are mistakenly reassured that a patient who tests negative for antinuclear antibody does not have an autoimmune condition.

To emphasize the last point, in a cohort of 202 patients who tested positive for an antisynthetase antibody, only half were antinuclear antibody-positive, but nearly three-quarters demonstrated anticytoplasmic staining on indirect immunofluorescence (due to the location of the autoantigen in the cytoplasm), making the latter a better screening test for an antisynthetase antibody. For scleroderma, 99% were antinculear antibody-positive, but for myositis, this test is much less sensitive.²²

Myopathies can present with a wide variety of symptoms, so patients with muscle weakness are often seen initially by a general practitioner. Nonrheumatologists should be able to evaluate a patient presenting with muscle weakness or myalgia and be aware of red flags indicating potentially dangerous syndromes that require a prompt, thorough investigation.

This article reviews selected causes of muscle weakness, such as statin-induced and autoimmune disorders, and systemic features of inflammatory myopathies beyond myositis, such as dermatologic and pulmonary manifestations.

FOCUSING THE EVALUATION

The evaluation of a patient presenting with muscle weakness should include several assessments: 

Temporal progression. Was the onset of symptoms rapid or insidious? Patterns of onset may give clues to etiology, including the possibility of an associated autoimmune condition.

Location of muscle weakness. Are symptoms global or localized? And if localized, are they proximal or distal? Proximal weakness can be manifested by difficulty rising from a chair (hip muscles) or combing one’s hair (shoulder muscles), whereas distal weakness can involve difficulty standing on toes (gastrocnemius and soleus muscles) or performing fine motor activities (intrinsic hand muscles).

Symmetry. A focal or asymmetric pattern often has a neurologic etiology, but this could also be consistent with inclusion body myositis.

Other symptoms. Arthritis, rash, and swallowing problems point to a possible underlying rheumatologic disease. Weight gain or loss may indicate a thyroid disorder.

Family history. Some patients report that others in their family have this pattern of weakness, indicating a likely genetic myopathy. If the patient reports a relative with multiple sclerosis, lupus erythematosus, rheumatoid arthritis, or another autoimmune disease, then an immune-mediated myopathy should be considered.

Medications should be reviewed, particularly statins.

CASE 1: SLOWLY PROGRESSIVE WEAKNESS

A 65-year-old man presented with the insidious onset of muscle weakness and episodes of falling. On review of his medical record, his serum creatine kinase (CK) levels were elevated at various periods at 2 to 4 times the upper limit of normal. Electromyography (EMG) previously showed a myopathic pattern, and a muscle biopsy was abnormal, consistent with endomysial inflammation (term is consistent with “polymyositis”). He was treated for polymyositis for several years with prednisone alone, with steroids plus methotrexate, and with combined immunosuppression including methotrexate and azathioprine, but with no improvement. Eventually, another muscle biopsy revealed inclusion bodies with rimmed vacuoles, consistent with inclusion body myositis.

Inclusion body myositis

Inclusion body myositis is the most common myopathy in middle-aged to elderly people, especially men. These patients are often told “You are just getting old,” but they have a defined condition. It should also be considered in patients failing to respond to treatment or with those with “refractory” polymyositis.

The onset of muscle weakness is insidious and painless, and the weakness progresses slowly. The pattern is distal and asymmetric (eg, foot drop), and muscle atrophy typically affects the forearm flexors, quadriceps, and intrinsic muscles of the hands.¹

Magnetic resonance imaging may show marked muscle atrophy. Unfortunately, no treatment has shown efficacy, and most neuromuscular and rheumatology experts do not treat inclusion body myositis with immunosuppressive drugs. 

CASE 2: MILD MYALGIA WITHOUT WEAKNESS

A black 52-year-old man was referred because of myalgia and a CK level of 862 U/L (reference range < 200). His physician wanted to start him on a statin but was hesitant to do so without first consulting a rheumatologist.

The patient had a long history of mild arthralgias and myalgias without muscle weakness. He had dyslipidemia and hypertension. He reported no family history of myopathy and no illicit drug use. He was formerly an athlete. Medications included a thiazide diuretic and a beta-blocker. On examination, his muscles were strong (rated 5 on a scale of 5) in the upper and lower extremities, without atrophy.

His records showed that his CK levels had risen and fallen repeatedly over the past few years, ranging from 600 to 1,100 U/L. On further questioning, he reported that when he had joined the army 30 years previously, a physician had recommended he undergo a liver biopsy in view of elevated liver function tests, but that he had refused because he felt fine.

Currently, his gamma-glutamyl transpeptidase levels were normal.

Idiopathic ‘hyperCKemia’

So-called idiopathic hyperCKemia is not a form of myositis but merely a laboratory result outside the “normal” range. Reference ranges are based predominantly on measurements in white people and on an assumption that the distribution is Gaussian (bell-shaped). A normal CK level is usually defined as less than 200 U/L. Using this standard, up to 20% of men and 5% of women have hyperCKemia.²

However, CK levels vary by sex and ethnicity, with mean levels highest in black men, followed by black women, white men, and white women. The mean level in black men is higher than the standard cutoff point for normal, and especially in this population, there is wide fluctuation around the mean, leading to hyperCKemia quite frequently in black men. Exercise and manual labor also drive up CK levels.^3–5 

Idiopathic hyperCKemia is benign. D’Adda et al⁶ followed 55 patients for a mean of 7.5 years. CK levels normalized in 12 patients or at least decreased in 24. Most remained symptom-free or had minimal symptoms. 

Idiopathic hyperCKemia: Bottom line

Before prescribing a statin, determine the baseline CK level. If slightly elevated (ie, up to 3 to 5 times the upper limit of normal, or even higher) in the setting of normal muscle strength, there is no need for electromyography or muscle biopsy, and the patient can certainly receive a statin. Most of these patients do not need to see a rheumatologist but can simply have their CK and muscle strength monitored.

 

 

CLASSIFYING MYOSITIS

Myositis (idiopathic inflammatory myopathy) is a heterogeneous group of autoimmune syndromes of unknown cause characterized by chronic muscle weakness and inflammation of striated muscle. These syndromes likely arise as a result of genetic predisposition and an environmental or infectious “hit.”

Myositis is rare, with an incidence of 5 to 10 cases per million per year and an estimated prevalence of 50 to 90 cases per million. It has 2 incidence peaks: 1 in childhood (age 5–15) and another in adult midlife (age 30–50). Women are affected 2 to 3 times more often than men, with black women most commonly affected.

Myositis is traditionally classified as follows:

• Adult polymyositis
• Adult dermatomyositis
• Juvenile myositis (dermatomyositis much more frequent than polymyositis)
• Malignancy-associated myositis (usually dermatomyositis)
• Myositis overlapping with another autoimmune disease
• Inclusion body myositis.

However, polymyositis is less common than we originally thought, and the term necrotizing myopathy is now used in many patients, as noted in the case studies below. Further, myositis overlap syndromes are being increasingly diagnosed, likely related to the emergence of autoantibodies and clinical “syndromes” associated with these autoantibody subsets (discussed in cases below).

Dermatomyositis

Dermatomyositis is characterized by muscle weakness and a rash that can be obvious or subtle. Classic skin lesions are Gottron papules, which are raised, flat-topped red or purplish lesions over the knuckles, elbows, or knees.

Lesions may be confused with those of psoriasis. There can also be a V-neck rash over the anterior chest or upper back (“shawl sign”) or a rash over the lateral thigh (“holster sign”). A facial rash may occur, but unlike lupus, dermatomyositis does not spare the nasolabial area. However, the V-neck rash can be similar to that seen in lupus.

Dermatomyositis may cause muscle pain, perhaps related to muscle ischemia, whereas polymyositis and necrotizing myopathy are often painless. However, pain is also associated with fibromyalgia, which may be seen in many autoimmune conditions. It is important not to overtreat rheumatologic diseases with immunosuppression to try to control pain if the pain is actually caused by fibromyalgia.

Polymyositis mimics

Hypothyroid myopathy can present as classic polymyositis. The serum CK may be elevated, and there may be myalgias, muscle hypertrophy with stiffness, weakness, cramps, and even features of a proximal myopathy, and rhabdomyolysis. The electromyogram can be normal or myopathic. Results of muscle biopsy are often normal but may show focal necrosis and mild inflammatory infiltrates, thus mimicking that seen with inflammatory myopathy.⁷

Drug-induced or toxic myopathies can also mimic polymyositis. Statins are among the most commonly prescribed drugs in the United States, with more than 35 million people taking them. Statins are generally well tolerated but have a broad spectrum of toxicity, ranging from myalgias to life-threatening rhabdomyolysis. Myalgias lead to about 5% to 10% of patients refusing to take a statin or stopping it on their own.

Myalgias affect up to 20% of statin users in clinical practice.^8,9 A small cross-sectional study¹⁰ of 1,000 patients in a primary care setting found that the risk of muscle complaints in statin users was 1.5 times higher than in nonstatin users, similar to findings in other studies.

My strategy for managing a patient with possible statin-induced myopathy is illustrated in Figure 1.

CASE 3: WEAKNESS, VERY HIGH CK ON A STATIN

In March 2010, a 67-year-old woman presented with muscle weakness. She had a history of hypertension, hyperlipidemia, and, more than 10 years previously, uterine cancer. In 2004, she was given atorvastatin for dyslipidemia. Four years later, she developed lower-extremity weakness, which her doctor attributed to normal aging. A year after that, she found it difficult to walk up steps and lift her arms overhead. In June 2009, she stopped taking the atorvastatin on her own, but the weakness did not improve.

In September 2009, she returned to her doctor, who found her CK level was 6,473 U/L but believed it to be an error, so the test was repeated, with a result of 9,375 U/L. She had no rash or joint involvement.

She was admitted to the hospital and underwent muscle biopsy, which showed myonecrosis with no inflammation or vasculitis.  She was treated with prednisone 60 mg/day, and her elevated CK level and weakness improved.

Immune-mediated necrotizing myopathy associated with statins

The hallmark of necrotizing myopathy is myonecrosis without significant inflammation.¹² This pattern contrasts with that of polymyositis, which is characterized by lymphocytic inflammation.

Although statins became available in the United States in 1987, immune-mediated necrotizing myopathy associated with statins was first described only in 2010. In that report, Grable-Esposito et al¹³ described 25 patients from 2 neuromuscular centers seen between 2000 and 2008 who had elevated CK and proximal weakness during or after statin use, both of which persisted despite stopping the statin. Patients improved with immunosuppressive agents but had a relapse when steroids were stopped or tapered, a pattern typical in autoimmune disease.

 

 

Autoantibody defines subgroup of necrotizing myopathy

Also in 2010, Christopher-Stine et al¹⁴ reported an antibody associated with necrotizing myopathy. Of 38 patients with the condition, 16 were found to have an abnormal “doublet” autoantibody recognizing 200- and 100-kDa proteins. All patients had weakness and a high CK level, and 63% had statin exposure before the weakness (this percentage increased to 83% in patients older than 50). All responded to immunosuppressive therapy, and many had a relapse when it was withdrawn.

Statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-Co A reductase (HMGCR), and paradoxically, they also upregulate it. HMGCR has a molecular weight of 97 kDa. Mammen et al¹⁵ identified HMGCR as the 100-kDa target of the identified antibody and developed an enzyme-linked immunosorbent assay for it. Of 750 patients presenting to one center, only 45 (6%) had anti-HMGCR autoantibodies, but all 16 patients who had the abnormal doublet antibody tested positive for anti-HMGCR. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response after statins are discontinued.

Case 3 continued: Intravenous immunoglobulin brings improvement

In March 2010, when the 67-year-old patient presented to our myositis center, her CK level was 5,800 U/L, which increased as prednisone was tapered. She still felt weak. On examination, her muscle strength findings were deltoids 4+/5, neck flexors 4/5, and iliopsoas 3+/5. She was treated with methotrexate and azathioprine without benefit. She was next treated with intravenous immunoglobulin, and after 3 months, her strength normalized for the first time in years. Her CK level decreased but did not normalize. Testing showed that she was positive for anti-HMGCR auto­antibody, as this test had become commercially available.

In 2015, Mammen and Tiniakou¹⁶ suggested using intravenous immunoglobulin as first-line therapy for statin-associated autoimmune necrotizing myopathy, based on experience at a single center with 3 patients who declined glucocorticoid treatment.

Necrotizing myopathy: Bottom line

Myositis overlap syndromes

Heterogeneity is the rule in myositis, and it can present with a wide variety of signs and symptoms as outlined in Table 2.

CASE 4: FEVER, NEW ‘RHEUMATOID ARTHRITIS,’ AND LUNG DISEASE

A 52-year-old woman with knee osteoarthritis saw her primary care physician in November 2013 for dyspnea and low-grade fever. The next month, she presented with polyarthritis, muscle weakness, and Raynaud phenomenon.

In January 2014, she developed acrocyanosis of her fingers. Examination revealed hyperkeratotic, cracked areas of her fingers. Her oxygen saturation by pulse oximetry was low. She was admitted to the hospital. Her doctor suspected new onset of rheumatoid arthritis, but blood tests revealed a negative antinuclear antibody, so an autoimmune condition was deemed unlikely. Her CK was mildly elevated at 350 U/L.

Because of her dyspnea, an open-lung biopsy was performed. High-resolution computed tomography (CT) revealed infiltrates and ground-glass opacities, leading to the diagnosis of nonspecific interstitial pneumonia. A rheumatologist was consulted and recommended pulse methylprednisolone, followed by prednisone 60 mg/day and mycophenolate mofetil. Testing for Jo-1 antibodies was positive.

Antisynthetase syndrome

The antisynthetase syndrome is a clinically heterogeneous condition that can occur with any or all of the following:

• Fever
• Myositis
• Arthritis (often misdiagnosed as rheumatoid arthritis)
• Raynaud phenomenon
• Mechanic’s hands (hyperkeratotic  roughness with fissures on the lateral aspects of the fingers and finger pads)
• Interstitial lung disease.

The skin rashes and myositis may be subtle, making the presentation “lung-dominant,” and nonrheumatologists should be aware of this syndrome. Although in our patient the condition developed in a classic manner, with all of the aforementioned features of the antisynthetase syndrome, some patients will manifest one or a few of the features.

Clinically, patients with the Jo-1 antisynthetase syndrome often present differently than those with non-Jo-1 antisynthetase autoantibodies. When we compared 122 patients with Jo-1 vs 80 patients with a non-Jo-1 antisynthetase autoantibody, patients with Jo-1 antibodies were more likely to have initially received a diagnosis of myositis (83%), while  myositis was the original diagnosis in only 17% of those possessing non-Jo-1 antisynthetase autoantibodies. In fact, many patients (approximately 50%) were diagnosed as having undifferentiated connective tissue disease or an overlap syndrome, and 13% had scleroderma as their first diagnosis.¹⁷

We also found that the survival rate was higher in patients with Jo-1 syndrome compared with patients with non-Jo-1 antisynthetase syndromes. We attributed the difference in survival rates to a delayed diagnosis in the non-Jo-1 group, perhaps due to their “nonclassic” presentations of the antisynthetase syndrome, delaying appropriate treatment. Patients received a diagnosis of Jo-1 antibody syndrome after a mean of 0.4 year (range 0.2–0.8), while those with a non-Jo-1 antisynthetase autoantibody had a delay in diagnosis of 1.0 year (range 0.4–5.1) (P < .01).¹⁷

In nearly half the cases in this cohort, pulmonary fibrosis was the cause of death, with primary pulmonary hypertension being the second leading cause (11%).

Antisynthetase syndrome: Bottom line

Antisynthetase syndrome is an often fatal disease that does not always present in a typical fashion with symptoms of myositis, as lung disease may be the predominant feature. A negative antinuclear antibody test result does not imply antibody negativity, as the autoantigen in these diseases is not located in the nucleus. Prompt diagnosis and appropriate immunosuppressive therapy are critical to improving outcomes.

CASE 5: FEVER, UNDIAGNOSED LUNG DISEASE, NO MYOSITIS

In January 2001, a 39-year-old woman was admitted to the hospital after 5 weeks of fever (temperatures 103°–104°F) and myalgias. An extensive workup was negative except for low-titer antinuclear antibody and for mild basilar fibrosis noted on chest radiography. She left the hospital against medical advice because of frustration with a lack of a specific diagnosis (“fever of unknown origin”).

Two months later, at a follow-up rheumatology consult, she reported more myalgias and arthralgias, as well as fever. Chest radiography now showed pleural effusions. Her fingers had color changes consistent with Raynaud phenomenon. At that time, I diagnosed an undifferentiated connective tissue disease and told her that I suspected an autoimmune condition that would need time to reveal itself. In the meantime, I treated her empirically with prednisone.

In April, she returned, much more short of breath and with more prominent diffuse pulmonary infiltrates. Physical examination revealed subtle Gottron changes. Testing revealed poor pulmonary function: forced vital capacity (FVC) 56%, forced expiratory volume in 1 second (FEV₁) 52%, and diffusing capacity for carbon monoxide (Dlco) 40%. Blood testing was positive for anti-PL-12 antibody, one of the non-Jo-1 antisynthetase antibodies. At this time, we treated her with glucocorticoids and tacrolimus.

More than 15 years later, this patient is doing well. Her skin rash, joint symptoms, and fever have not returned, and interestingly, she never developed myositis. Her Raynaud symptoms are mild. Her most recent pulmonary function test results (January 2018) were FVC  75%, FEV₁ 87%, and Dlco 78%. Although these results are not normal, they are much improved and allow her to be completely functional without supplemental oxygen. Echocardiography showed  normal pulmonary artery systolic pressure (25 mm Hg). She was still taking tacrolimus and prednisone. When we tried to stop tacrolimus after she had done well for many years, her condition flared.

Non-Jo-1 antisynthetase syndrome: Bottom line

Patients with a non-Jo-1 antisynthetase syndrome often present without myositis symptoms and may never manifest myositis symptoms. Likely because of this presentation, diagnosis of a specific connective tissue disorder is delayed, perhaps leading to increased mortality risk from pulmonary disease. Chronic immunosuppression is often required for these autoimmune conditions.

CASE 6: DERMATOMYOSITIS, RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE

A 58-year-old woman presented in the summer of 2012 with a photosensitive rash. The following January, she returned with polyarthritis, mild muscle weakness, and a dermatomyositis-pattern rash. Her CK level was normal, and her antinuclear antibody and Sjögren syndrome antibody test results were negative. She improved on low-dose prednisone and methotrexate.

She was originally referred to me in May of that year for worsening rash and mild weakness. She denied pulmonary symptoms, but examination revealed faint basilar crackles. I increased her prednisone dosage to 20 mg/day and started mycophenolate mofetil mainly for the mild cutaneous and myositis features. I also recommended high-resolution CT of the lungs and pulmonary function tests, which she underwent in early June. High-resolution CT showed nonspecific mild infiltrates with minimal ground-glass opacities.

On July 1, she presented to her local emergency department with severe shortness of breath, requiring oxygen 12 L/min. She had a palmar rash. Repeat high-resolution CT showed dramatic worsening compared with the scan the previous month. Because of continued inadequate oxygenation, she was transferred to our center. A blood test later was positive for antimelanoma differentiation-associated gene 5 (MDA-5) autoantibody, previously known as anticlinically amyopathic dermatomyositis (anti-CADM)-140 antibody (based on immunoprecipitation results).

She died on the third day after transfer, just 2 months after I had originally seen her, at which time she had had no pulmonary symptoms.

Clinically amyopathic dermatomyositis

Anti-CADM-140, first reported from Asia,^18–20 is an autoantibody-associated disease but not an antisynthetase. It is associated with dermatomyositis; patients often have a “vasculopathy” with cutaneous ulcerations and palmar papules.

MDA-5 is a cytoplasmic protein that “senses” viral RNA and induces production of type 1 interferon. It is involved in the innate immune defense against viruses.

Anti-MDA-5 positivity is associated with a poor pulmonary outcome.²¹ In our cohort from the University of Pittsburgh, many patients died within 3 years, compared with about a 40% survival rate in patients with dermatomyositis who tested negative for this antibody. That being said, many patients with anti-MDA-5 do not develop rapidly progressive interstitial lung disease.

Autoimmune interstitial lung disease: Bottom line

Autoimmune interstitial lung disease is easy to miss, especially in the case of a non-Jo-1 syndrome, for 3 important reasons:

• The autoimmune features may initially be subtle (eg, Raynaud phenomena, mild dermatomyositis rash, undifferentiated connective tissue disease)
• Autoantibody testing is not often ordered, is not standardized, or may be unavailable 
• Providers are mistakenly reassured that a patient who tests negative for antinuclear antibody does not have an autoimmune condition.

To emphasize the last point, in a cohort of 202 patients who tested positive for an antisynthetase antibody, only half were antinuclear antibody-positive, but nearly three-quarters demonstrated anticytoplasmic staining on indirect immunofluorescence (due to the location of the autoantigen in the cytoplasm), making the latter a better screening test for an antisynthetase antibody. For scleroderma, 99% were antinculear antibody-positive, but for myositis, this test is much less sensitive.²²

Myopathies can present with a wide variety of symptoms, so patients with muscle weakness are often seen initially by a general practitioner. Nonrheumatologists should be able to evaluate a patient presenting with muscle weakness or myalgia and be aware of red flags indicating potentially dangerous syndromes that require a prompt, thorough investigation.

This article reviews selected causes of muscle weakness, such as statin-induced and autoimmune disorders, and systemic features of inflammatory myopathies beyond myositis, such as dermatologic and pulmonary manifestations.

FOCUSING THE EVALUATION

The evaluation of a patient presenting with muscle weakness should include several assessments: 

Temporal progression. Was the onset of symptoms rapid or insidious? Patterns of onset may give clues to etiology, including the possibility of an associated autoimmune condition.

Location of muscle weakness. Are symptoms global or localized? And if localized, are they proximal or distal? Proximal weakness can be manifested by difficulty rising from a chair (hip muscles) or combing one’s hair (shoulder muscles), whereas distal weakness can involve difficulty standing on toes (gastrocnemius and soleus muscles) or performing fine motor activities (intrinsic hand muscles).

Symmetry. A focal or asymmetric pattern often has a neurologic etiology, but this could also be consistent with inclusion body myositis.

Other symptoms. Arthritis, rash, and swallowing problems point to a possible underlying rheumatologic disease. Weight gain or loss may indicate a thyroid disorder.

Family history. Some patients report that others in their family have this pattern of weakness, indicating a likely genetic myopathy. If the patient reports a relative with multiple sclerosis, lupus erythematosus, rheumatoid arthritis, or another autoimmune disease, then an immune-mediated myopathy should be considered.

Medications should be reviewed, particularly statins.

CASE 1: SLOWLY PROGRESSIVE WEAKNESS

A 65-year-old man presented with the insidious onset of muscle weakness and episodes of falling. On review of his medical record, his serum creatine kinase (CK) levels were elevated at various periods at 2 to 4 times the upper limit of normal. Electromyography (EMG) previously showed a myopathic pattern, and a muscle biopsy was abnormal, consistent with endomysial inflammation (term is consistent with “polymyositis”). He was treated for polymyositis for several years with prednisone alone, with steroids plus methotrexate, and with combined immunosuppression including methotrexate and azathioprine, but with no improvement. Eventually, another muscle biopsy revealed inclusion bodies with rimmed vacuoles, consistent with inclusion body myositis.

Inclusion body myositis

Inclusion body myositis is the most common myopathy in middle-aged to elderly people, especially men. These patients are often told “You are just getting old,” but they have a defined condition. It should also be considered in patients failing to respond to treatment or with those with “refractory” polymyositis.

The onset of muscle weakness is insidious and painless, and the weakness progresses slowly. The pattern is distal and asymmetric (eg, foot drop), and muscle atrophy typically affects the forearm flexors, quadriceps, and intrinsic muscles of the hands.¹

Magnetic resonance imaging may show marked muscle atrophy. Unfortunately, no treatment has shown efficacy, and most neuromuscular and rheumatology experts do not treat inclusion body myositis with immunosuppressive drugs. 

CASE 2: MILD MYALGIA WITHOUT WEAKNESS

A black 52-year-old man was referred because of myalgia and a CK level of 862 U/L (reference range < 200). His physician wanted to start him on a statin but was hesitant to do so without first consulting a rheumatologist.

The patient had a long history of mild arthralgias and myalgias without muscle weakness. He had dyslipidemia and hypertension. He reported no family history of myopathy and no illicit drug use. He was formerly an athlete. Medications included a thiazide diuretic and a beta-blocker. On examination, his muscles were strong (rated 5 on a scale of 5) in the upper and lower extremities, without atrophy.

His records showed that his CK levels had risen and fallen repeatedly over the past few years, ranging from 600 to 1,100 U/L. On further questioning, he reported that when he had joined the army 30 years previously, a physician had recommended he undergo a liver biopsy in view of elevated liver function tests, but that he had refused because he felt fine.

Currently, his gamma-glutamyl transpeptidase levels were normal.

Idiopathic ‘hyperCKemia’

So-called idiopathic hyperCKemia is not a form of myositis but merely a laboratory result outside the “normal” range. Reference ranges are based predominantly on measurements in white people and on an assumption that the distribution is Gaussian (bell-shaped). A normal CK level is usually defined as less than 200 U/L. Using this standard, up to 20% of men and 5% of women have hyperCKemia.²

However, CK levels vary by sex and ethnicity, with mean levels highest in black men, followed by black women, white men, and white women. The mean level in black men is higher than the standard cutoff point for normal, and especially in this population, there is wide fluctuation around the mean, leading to hyperCKemia quite frequently in black men. Exercise and manual labor also drive up CK levels.^3–5 

Idiopathic hyperCKemia is benign. D’Adda et al⁶ followed 55 patients for a mean of 7.5 years. CK levels normalized in 12 patients or at least decreased in 24. Most remained symptom-free or had minimal symptoms. 

Idiopathic hyperCKemia: Bottom line

Before prescribing a statin, determine the baseline CK level. If slightly elevated (ie, up to 3 to 5 times the upper limit of normal, or even higher) in the setting of normal muscle strength, there is no need for electromyography or muscle biopsy, and the patient can certainly receive a statin. Most of these patients do not need to see a rheumatologist but can simply have their CK and muscle strength monitored.

 

 

CLASSIFYING MYOSITIS

Myositis (idiopathic inflammatory myopathy) is a heterogeneous group of autoimmune syndromes of unknown cause characterized by chronic muscle weakness and inflammation of striated muscle. These syndromes likely arise as a result of genetic predisposition and an environmental or infectious “hit.”

Myositis is rare, with an incidence of 5 to 10 cases per million per year and an estimated prevalence of 50 to 90 cases per million. It has 2 incidence peaks: 1 in childhood (age 5–15) and another in adult midlife (age 30–50). Women are affected 2 to 3 times more often than men, with black women most commonly affected.

Myositis is traditionally classified as follows:

• Adult polymyositis
• Adult dermatomyositis
• Juvenile myositis (dermatomyositis much more frequent than polymyositis)
• Malignancy-associated myositis (usually dermatomyositis)
• Myositis overlapping with another autoimmune disease
• Inclusion body myositis.

However, polymyositis is less common than we originally thought, and the term necrotizing myopathy is now used in many patients, as noted in the case studies below. Further, myositis overlap syndromes are being increasingly diagnosed, likely related to the emergence of autoantibodies and clinical “syndromes” associated with these autoantibody subsets (discussed in cases below).

Dermatomyositis

Dermatomyositis is characterized by muscle weakness and a rash that can be obvious or subtle. Classic skin lesions are Gottron papules, which are raised, flat-topped red or purplish lesions over the knuckles, elbows, or knees.

Lesions may be confused with those of psoriasis. There can also be a V-neck rash over the anterior chest or upper back (“shawl sign”) or a rash over the lateral thigh (“holster sign”). A facial rash may occur, but unlike lupus, dermatomyositis does not spare the nasolabial area. However, the V-neck rash can be similar to that seen in lupus.

Dermatomyositis may cause muscle pain, perhaps related to muscle ischemia, whereas polymyositis and necrotizing myopathy are often painless. However, pain is also associated with fibromyalgia, which may be seen in many autoimmune conditions. It is important not to overtreat rheumatologic diseases with immunosuppression to try to control pain if the pain is actually caused by fibromyalgia.

Polymyositis mimics

Hypothyroid myopathy can present as classic polymyositis. The serum CK may be elevated, and there may be myalgias, muscle hypertrophy with stiffness, weakness, cramps, and even features of a proximal myopathy, and rhabdomyolysis. The electromyogram can be normal or myopathic. Results of muscle biopsy are often normal but may show focal necrosis and mild inflammatory infiltrates, thus mimicking that seen with inflammatory myopathy.⁷

Drug-induced or toxic myopathies can also mimic polymyositis. Statins are among the most commonly prescribed drugs in the United States, with more than 35 million people taking them. Statins are generally well tolerated but have a broad spectrum of toxicity, ranging from myalgias to life-threatening rhabdomyolysis. Myalgias lead to about 5% to 10% of patients refusing to take a statin or stopping it on their own.

Myalgias affect up to 20% of statin users in clinical practice.^8,9 A small cross-sectional study¹⁰ of 1,000 patients in a primary care setting found that the risk of muscle complaints in statin users was 1.5 times higher than in nonstatin users, similar to findings in other studies.

My strategy for managing a patient with possible statin-induced myopathy is illustrated in Figure 1.

CASE 3: WEAKNESS, VERY HIGH CK ON A STATIN

In March 2010, a 67-year-old woman presented with muscle weakness. She had a history of hypertension, hyperlipidemia, and, more than 10 years previously, uterine cancer. In 2004, she was given atorvastatin for dyslipidemia. Four years later, she developed lower-extremity weakness, which her doctor attributed to normal aging. A year after that, she found it difficult to walk up steps and lift her arms overhead. In June 2009, she stopped taking the atorvastatin on her own, but the weakness did not improve.

In September 2009, she returned to her doctor, who found her CK level was 6,473 U/L but believed it to be an error, so the test was repeated, with a result of 9,375 U/L. She had no rash or joint involvement.

She was admitted to the hospital and underwent muscle biopsy, which showed myonecrosis with no inflammation or vasculitis.  She was treated with prednisone 60 mg/day, and her elevated CK level and weakness improved.

Immune-mediated necrotizing myopathy associated with statins

The hallmark of necrotizing myopathy is myonecrosis without significant inflammation.¹² This pattern contrasts with that of polymyositis, which is characterized by lymphocytic inflammation.

Although statins became available in the United States in 1987, immune-mediated necrotizing myopathy associated with statins was first described only in 2010. In that report, Grable-Esposito et al¹³ described 25 patients from 2 neuromuscular centers seen between 2000 and 2008 who had elevated CK and proximal weakness during or after statin use, both of which persisted despite stopping the statin. Patients improved with immunosuppressive agents but had a relapse when steroids were stopped or tapered, a pattern typical in autoimmune disease.

 

 

Autoantibody defines subgroup of necrotizing myopathy

Also in 2010, Christopher-Stine et al¹⁴ reported an antibody associated with necrotizing myopathy. Of 38 patients with the condition, 16 were found to have an abnormal “doublet” autoantibody recognizing 200- and 100-kDa proteins. All patients had weakness and a high CK level, and 63% had statin exposure before the weakness (this percentage increased to 83% in patients older than 50). All responded to immunosuppressive therapy, and many had a relapse when it was withdrawn.

Statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-Co A reductase (HMGCR), and paradoxically, they also upregulate it. HMGCR has a molecular weight of 97 kDa. Mammen et al¹⁵ identified HMGCR as the 100-kDa target of the identified antibody and developed an enzyme-linked immunosorbent assay for it. Of 750 patients presenting to one center, only 45 (6%) had anti-HMGCR autoantibodies, but all 16 patients who had the abnormal doublet antibody tested positive for anti-HMGCR. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response after statins are discontinued.

Case 3 continued: Intravenous immunoglobulin brings improvement

In March 2010, when the 67-year-old patient presented to our myositis center, her CK level was 5,800 U/L, which increased as prednisone was tapered. She still felt weak. On examination, her muscle strength findings were deltoids 4+/5, neck flexors 4/5, and iliopsoas 3+/5. She was treated with methotrexate and azathioprine without benefit. She was next treated with intravenous immunoglobulin, and after 3 months, her strength normalized for the first time in years. Her CK level decreased but did not normalize. Testing showed that she was positive for anti-HMGCR auto­antibody, as this test had become commercially available.

In 2015, Mammen and Tiniakou¹⁶ suggested using intravenous immunoglobulin as first-line therapy for statin-associated autoimmune necrotizing myopathy, based on experience at a single center with 3 patients who declined glucocorticoid treatment.

Necrotizing myopathy: Bottom line

Myositis overlap syndromes

Heterogeneity is the rule in myositis, and it can present with a wide variety of signs and symptoms as outlined in Table 2.

CASE 4: FEVER, NEW ‘RHEUMATOID ARTHRITIS,’ AND LUNG DISEASE

A 52-year-old woman with knee osteoarthritis saw her primary care physician in November 2013 for dyspnea and low-grade fever. The next month, she presented with polyarthritis, muscle weakness, and Raynaud phenomenon.

In January 2014, she developed acrocyanosis of her fingers. Examination revealed hyperkeratotic, cracked areas of her fingers. Her oxygen saturation by pulse oximetry was low. She was admitted to the hospital. Her doctor suspected new onset of rheumatoid arthritis, but blood tests revealed a negative antinuclear antibody, so an autoimmune condition was deemed unlikely. Her CK was mildly elevated at 350 U/L.

Because of her dyspnea, an open-lung biopsy was performed. High-resolution computed tomography (CT) revealed infiltrates and ground-glass opacities, leading to the diagnosis of nonspecific interstitial pneumonia. A rheumatologist was consulted and recommended pulse methylprednisolone, followed by prednisone 60 mg/day and mycophenolate mofetil. Testing for Jo-1 antibodies was positive.

Antisynthetase syndrome

The antisynthetase syndrome is a clinically heterogeneous condition that can occur with any or all of the following:

• Fever
• Myositis
• Arthritis (often misdiagnosed as rheumatoid arthritis)
• Raynaud phenomenon
• Mechanic’s hands (hyperkeratotic  roughness with fissures on the lateral aspects of the fingers and finger pads)
• Interstitial lung disease.

The skin rashes and myositis may be subtle, making the presentation “lung-dominant,” and nonrheumatologists should be aware of this syndrome. Although in our patient the condition developed in a classic manner, with all of the aforementioned features of the antisynthetase syndrome, some patients will manifest one or a few of the features.

Clinically, patients with the Jo-1 antisynthetase syndrome often present differently than those with non-Jo-1 antisynthetase autoantibodies. When we compared 122 patients with Jo-1 vs 80 patients with a non-Jo-1 antisynthetase autoantibody, patients with Jo-1 antibodies were more likely to have initially received a diagnosis of myositis (83%), while  myositis was the original diagnosis in only 17% of those possessing non-Jo-1 antisynthetase autoantibodies. In fact, many patients (approximately 50%) were diagnosed as having undifferentiated connective tissue disease or an overlap syndrome, and 13% had scleroderma as their first diagnosis.¹⁷

We also found that the survival rate was higher in patients with Jo-1 syndrome compared with patients with non-Jo-1 antisynthetase syndromes. We attributed the difference in survival rates to a delayed diagnosis in the non-Jo-1 group, perhaps due to their “nonclassic” presentations of the antisynthetase syndrome, delaying appropriate treatment. Patients received a diagnosis of Jo-1 antibody syndrome after a mean of 0.4 year (range 0.2–0.8), while those with a non-Jo-1 antisynthetase autoantibody had a delay in diagnosis of 1.0 year (range 0.4–5.1) (P < .01).¹⁷

In nearly half the cases in this cohort, pulmonary fibrosis was the cause of death, with primary pulmonary hypertension being the second leading cause (11%).

Antisynthetase syndrome: Bottom line

Antisynthetase syndrome is an often fatal disease that does not always present in a typical fashion with symptoms of myositis, as lung disease may be the predominant feature. A negative antinuclear antibody test result does not imply antibody negativity, as the autoantigen in these diseases is not located in the nucleus. Prompt diagnosis and appropriate immunosuppressive therapy are critical to improving outcomes.

CASE 5: FEVER, UNDIAGNOSED LUNG DISEASE, NO MYOSITIS

In January 2001, a 39-year-old woman was admitted to the hospital after 5 weeks of fever (temperatures 103°–104°F) and myalgias. An extensive workup was negative except for low-titer antinuclear antibody and for mild basilar fibrosis noted on chest radiography. She left the hospital against medical advice because of frustration with a lack of a specific diagnosis (“fever of unknown origin”).

Two months later, at a follow-up rheumatology consult, she reported more myalgias and arthralgias, as well as fever. Chest radiography now showed pleural effusions. Her fingers had color changes consistent with Raynaud phenomenon. At that time, I diagnosed an undifferentiated connective tissue disease and told her that I suspected an autoimmune condition that would need time to reveal itself. In the meantime, I treated her empirically with prednisone.

In April, she returned, much more short of breath and with more prominent diffuse pulmonary infiltrates. Physical examination revealed subtle Gottron changes. Testing revealed poor pulmonary function: forced vital capacity (FVC) 56%, forced expiratory volume in 1 second (FEV₁) 52%, and diffusing capacity for carbon monoxide (Dlco) 40%. Blood testing was positive for anti-PL-12 antibody, one of the non-Jo-1 antisynthetase antibodies. At this time, we treated her with glucocorticoids and tacrolimus.

More than 15 years later, this patient is doing well. Her skin rash, joint symptoms, and fever have not returned, and interestingly, she never developed myositis. Her Raynaud symptoms are mild. Her most recent pulmonary function test results (January 2018) were FVC  75%, FEV₁ 87%, and Dlco 78%. Although these results are not normal, they are much improved and allow her to be completely functional without supplemental oxygen. Echocardiography showed  normal pulmonary artery systolic pressure (25 mm Hg). She was still taking tacrolimus and prednisone. When we tried to stop tacrolimus after she had done well for many years, her condition flared.

Non-Jo-1 antisynthetase syndrome: Bottom line

Patients with a non-Jo-1 antisynthetase syndrome often present without myositis symptoms and may never manifest myositis symptoms. Likely because of this presentation, diagnosis of a specific connective tissue disorder is delayed, perhaps leading to increased mortality risk from pulmonary disease. Chronic immunosuppression is often required for these autoimmune conditions.

CASE 6: DERMATOMYOSITIS, RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE

A 58-year-old woman presented in the summer of 2012 with a photosensitive rash. The following January, she returned with polyarthritis, mild muscle weakness, and a dermatomyositis-pattern rash. Her CK level was normal, and her antinuclear antibody and Sjögren syndrome antibody test results were negative. She improved on low-dose prednisone and methotrexate.

She was originally referred to me in May of that year for worsening rash and mild weakness. She denied pulmonary symptoms, but examination revealed faint basilar crackles. I increased her prednisone dosage to 20 mg/day and started mycophenolate mofetil mainly for the mild cutaneous and myositis features. I also recommended high-resolution CT of the lungs and pulmonary function tests, which she underwent in early June. High-resolution CT showed nonspecific mild infiltrates with minimal ground-glass opacities.

On July 1, she presented to her local emergency department with severe shortness of breath, requiring oxygen 12 L/min. She had a palmar rash. Repeat high-resolution CT showed dramatic worsening compared with the scan the previous month. Because of continued inadequate oxygenation, she was transferred to our center. A blood test later was positive for antimelanoma differentiation-associated gene 5 (MDA-5) autoantibody, previously known as anticlinically amyopathic dermatomyositis (anti-CADM)-140 antibody (based on immunoprecipitation results).

She died on the third day after transfer, just 2 months after I had originally seen her, at which time she had had no pulmonary symptoms.

Clinically amyopathic dermatomyositis

Anti-CADM-140, first reported from Asia,^18–20 is an autoantibody-associated disease but not an antisynthetase. It is associated with dermatomyositis; patients often have a “vasculopathy” with cutaneous ulcerations and palmar papules.

MDA-5 is a cytoplasmic protein that “senses” viral RNA and induces production of type 1 interferon. It is involved in the innate immune defense against viruses.

Anti-MDA-5 positivity is associated with a poor pulmonary outcome.²¹ In our cohort from the University of Pittsburgh, many patients died within 3 years, compared with about a 40% survival rate in patients with dermatomyositis who tested negative for this antibody. That being said, many patients with anti-MDA-5 do not develop rapidly progressive interstitial lung disease.

Autoimmune interstitial lung disease: Bottom line

Autoimmune interstitial lung disease is easy to miss, especially in the case of a non-Jo-1 syndrome, for 3 important reasons:

• The autoimmune features may initially be subtle (eg, Raynaud phenomena, mild dermatomyositis rash, undifferentiated connective tissue disease)
• Autoantibody testing is not often ordered, is not standardized, or may be unavailable 
• Providers are mistakenly reassured that a patient who tests negative for antinuclear antibody does not have an autoimmune condition.

To emphasize the last point, in a cohort of 202 patients who tested positive for an antisynthetase antibody, only half were antinuclear antibody-positive, but nearly three-quarters demonstrated anticytoplasmic staining on indirect immunofluorescence (due to the location of the autoantigen in the cytoplasm), making the latter a better screening test for an antisynthetase antibody. For scleroderma, 99% were antinculear antibody-positive, but for myositis, this test is much less sensitive.²²

STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.

But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.

It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment. This Canadian study asked a previously unaddressed question: Does coming off cannabis make a difference cognitively in the MS population?

The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.

All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.

By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.

The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).

She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.

bjancin@mdedge.com

SOURCE: Meza C. ECTRIMS 2019, Abstract P542.

STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.

But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.

It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment. This Canadian study asked a previously unaddressed question: Does coming off cannabis make a difference cognitively in the MS population?

The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.

All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.

By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.

The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).

She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.

bjancin@mdedge.com

SOURCE: Meza C. ECTRIMS 2019, Abstract P542.

STOCKHOLM – The good news about cognitive impairment in patients with multiple sclerosis who’ve been using cannabis heavily for symptom relief – even for many years – is that their memory, executive function, and information processing speed will improve significantly once they’ve been off the drug for just 28 days, according to the results of a randomized trial presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“It’s good for neurologists to know that, if they prescribe cannabis or their patient is self-medicating and chooses to stop, their cognition will improve considerably,” observed Cecilia Meza, a coinvestigator in the study led by Anthony Feinstein, MD, professor of psychiatry at the University of Toronto.

But there’s a surprise twist to this study, she explained in an interview: “We showed patients their results, and they also felt that their cognition was doing a lot better, but despite that, they would rather be using cannabis to feel better than to have their memory intact. The pain was that bad,” said Ms. Meza, a research coordinator at the university’s Sunnybrook Research Institute.

It’s known that cognitive impairment in healthy long-term cannabis users, provided they started as adults, is fully reversed after 28 days of abstinence. But disease-related cognitive dysfunction affects 40%-80% of patients with MS, and cannabis use may compound this impairment. This Canadian study asked a previously unaddressed question: Does coming off cannabis make a difference cognitively in the MS population?

The study included 40 MS patients with global impairment of cognition, none of whom were cannabis users prior to their diagnosis. They typically started using it for MS symptom relief 2-3 years after receiving their diagnosis. By the time they were approached for study participation, they had been using cannabis four to five times per day or more for an average of 7 years for relief of symptoms, including incontinence, spasticity, poor sleep, headaches, and difficulties in eating.

All participants were willing to try 28 days of abstinence; half were randomized to do so, while the others stayed the course. Study endpoints included change from baseline to day 28 in the Brief Repeatable Neuropsychological Battery, functional MRI done while taking the Symbol Digit Modalities Test, and urine testing to assure compliance with abstinence.

By day 28, the abstinence group – and with one exception, urine testing confirmed they were bona fide cannabis quitters for the study duration – performed significantly better on the neuropsychological test battery than at baseline, with an associated significant increase in brain activation in the bilateral inferior frontal gyri, as well as the caudate and declive cerebellum while executing the Symbol Digit Modalities Test. The control group who kept on using cannabis showed no such improvements.

The full study details were published in conjunction with Ms. Meza’s presentation (Brain. 2019 Sep 1;142[9]:2800-12).

She reported having no financial conflicts regarding the study, funded by the Multiple Sclerosis Society of Canada.

bjancin@mdedge.com

SOURCE: Meza C. ECTRIMS 2019, Abstract P542.

Mild cognitive impairment (MCI) may influence the relationship between alcohol consumption and dementia risk, a study of more than 3,000 adults suggests. In addition, alcohol dose and the frequency of alcohol intake correlate with cognitive decline and the risk of dementia, according to the study, which was published in JAMA Network Open.

Thinkstockphotos.com

“The associations of self-reported alcohol consumption with dementia risk and cognitive decline were more consistently adverse among individuals with MCI than those with normal cognition,” reported Manja Koch, PhD, a researcher in the department of nutrition at Harvard T.H. Chan School of Public Health in Boston and colleagues. “This was particularly true for the subset of individuals [with MCI] who drank more than 14.0 servings per week, whose rate of cognitive decline and risk of dementia were the highest of any subgroup.”

Among older adults with normal cognition, the results generally were consistent with those of a recent meta-analysis that found a U-shaped relationship between drinking and dementia, the researchers said (Eur J Epidemiol. 2017 Jan;32[1]:31-42.).

“Our results did not show significant associations and clearly do not suffice to suggest a clinical benefit from even limited alcohol use,” said Dr. Koch and colleagues. “Nonetheless, our findings provide some reassurance that alcohol consumed within recommended limits was not associated with an increased risk of dementia among older adults with normal baseline cognition.”

GEMS data

To study whether alcohol consumption is associated with the risk of dementia and cognitive decline in older adults with and without MCI, the investigators analyzed data from the Ginkgo Evaluation of Memory Study (GEMS). GEMS was a randomized controlled trial conducted between 2000 and 2008 that found no overall association between ginkgo biloba and dementia prevention. During the trial, participants completed the Modified Mini-Mental State Examination, the Clinical Dementia Rating scale, and the cognitive portion of the Alzheimer’s Disease Assessment Scale.

In the present study, the investigators analyzed data from 3,021 participants aged 72 years and older who were free of dementia at baseline and had provided information about their alcohol intake. Their median age was 78 years, and 46.2% were female. Fifty-eight percent consumed alcohol, including 45% of the participants with MCI at baseline.

During follow-up, 512 cases of dementia occurred. Among the 473 participants with MCI at baseline, the adjusted hazard ratio (HR) for dementia was 1.72 for those who consumed more than 14 drinks per week, compared with light drinkers who consumed less than 1 drink per week. For participants who consumed between 7 and 14 drinks per week, the adjusted HR for dementia was 0.63 among those without MCI and 0.93 among those with MCI, relative to light drinkers who consumed less than 1 drink per week.

Among adults with normal cognition at baseline, daily low-quantity drinking was associated with lower dementia risk, compared with infrequent higher-quantity drinking (HR, 0.45).
 

Trial excluded adults with excessive alcohol use

Limitations of the study include a lack of data about any changes in alcohol consumption over time. In addition, the original trial excluded people with a known history of excessive alcohol use. Furthermore, it is possible that the “long preclinical phase of dementia” and other health issues affect drinking behavior, the authors said. “At present, our findings cannot be directly translated into clinical recommendations,” the authors said. Nevertheless, the results “suggest that, while caring for older adults, physicians should carefully assess the full dimensions of drinking behavior and cognition when providing guidance to patients about alcohol consumption,” they said.

The study was supported by grants from the National Center for Complementary and Alternative Medicine; the National Institute of Neurological Disorders and Stroke; the Office of Dietary Supplements of the National Institute on Aging; the National Heart, Lung, and Blood Institute; the University of Pittsburgh Alzheimer’s Disease Research Center; the Roena Kulynych Center for Memory and Cognition Research; and Wake Forest University School of Medicine. In addition, the researchers used plasma samples from the National Cell Repository for Alzheimer’s Disease, which receives support from the National Institute on Aging. Dr. Koch had no conflicts of interest. Coauthors disclosed university and government grants and personal fees from pharmaceutical companies outside the study. One author was an employee of Genentech at the time of publication, but Genentech did not contribute to the study.

jremaly@mdedge.com

SOURCE: Koch M et al. JAMA Network Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.10319.

Mild cognitive impairment (MCI) may influence the relationship between alcohol consumption and dementia risk, a study of more than 3,000 adults suggests. In addition, alcohol dose and the frequency of alcohol intake correlate with cognitive decline and the risk of dementia, according to the study, which was published in JAMA Network Open.

Thinkstockphotos.com

“The associations of self-reported alcohol consumption with dementia risk and cognitive decline were more consistently adverse among individuals with MCI than those with normal cognition,” reported Manja Koch, PhD, a researcher in the department of nutrition at Harvard T.H. Chan School of Public Health in Boston and colleagues. “This was particularly true for the subset of individuals [with MCI] who drank more than 14.0 servings per week, whose rate of cognitive decline and risk of dementia were the highest of any subgroup.”

Among older adults with normal cognition, the results generally were consistent with those of a recent meta-analysis that found a U-shaped relationship between drinking and dementia, the researchers said (Eur J Epidemiol. 2017 Jan;32[1]:31-42.).

“Our results did not show significant associations and clearly do not suffice to suggest a clinical benefit from even limited alcohol use,” said Dr. Koch and colleagues. “Nonetheless, our findings provide some reassurance that alcohol consumed within recommended limits was not associated with an increased risk of dementia among older adults with normal baseline cognition.”

GEMS data

To study whether alcohol consumption is associated with the risk of dementia and cognitive decline in older adults with and without MCI, the investigators analyzed data from the Ginkgo Evaluation of Memory Study (GEMS). GEMS was a randomized controlled trial conducted between 2000 and 2008 that found no overall association between ginkgo biloba and dementia prevention. During the trial, participants completed the Modified Mini-Mental State Examination, the Clinical Dementia Rating scale, and the cognitive portion of the Alzheimer’s Disease Assessment Scale.

In the present study, the investigators analyzed data from 3,021 participants aged 72 years and older who were free of dementia at baseline and had provided information about their alcohol intake. Their median age was 78 years, and 46.2% were female. Fifty-eight percent consumed alcohol, including 45% of the participants with MCI at baseline.

During follow-up, 512 cases of dementia occurred. Among the 473 participants with MCI at baseline, the adjusted hazard ratio (HR) for dementia was 1.72 for those who consumed more than 14 drinks per week, compared with light drinkers who consumed less than 1 drink per week. For participants who consumed between 7 and 14 drinks per week, the adjusted HR for dementia was 0.63 among those without MCI and 0.93 among those with MCI, relative to light drinkers who consumed less than 1 drink per week.

Among adults with normal cognition at baseline, daily low-quantity drinking was associated with lower dementia risk, compared with infrequent higher-quantity drinking (HR, 0.45).
 

Trial excluded adults with excessive alcohol use

Limitations of the study include a lack of data about any changes in alcohol consumption over time. In addition, the original trial excluded people with a known history of excessive alcohol use. Furthermore, it is possible that the “long preclinical phase of dementia” and other health issues affect drinking behavior, the authors said. “At present, our findings cannot be directly translated into clinical recommendations,” the authors said. Nevertheless, the results “suggest that, while caring for older adults, physicians should carefully assess the full dimensions of drinking behavior and cognition when providing guidance to patients about alcohol consumption,” they said.

The study was supported by grants from the National Center for Complementary and Alternative Medicine; the National Institute of Neurological Disorders and Stroke; the Office of Dietary Supplements of the National Institute on Aging; the National Heart, Lung, and Blood Institute; the University of Pittsburgh Alzheimer’s Disease Research Center; the Roena Kulynych Center for Memory and Cognition Research; and Wake Forest University School of Medicine. In addition, the researchers used plasma samples from the National Cell Repository for Alzheimer’s Disease, which receives support from the National Institute on Aging. Dr. Koch had no conflicts of interest. Coauthors disclosed university and government grants and personal fees from pharmaceutical companies outside the study. One author was an employee of Genentech at the time of publication, but Genentech did not contribute to the study.

jremaly@mdedge.com

SOURCE: Koch M et al. JAMA Network Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.10319.

Mild cognitive impairment (MCI) may influence the relationship between alcohol consumption and dementia risk, a study of more than 3,000 adults suggests. In addition, alcohol dose and the frequency of alcohol intake correlate with cognitive decline and the risk of dementia, according to the study, which was published in JAMA Network Open.

Thinkstockphotos.com

“The associations of self-reported alcohol consumption with dementia risk and cognitive decline were more consistently adverse among individuals with MCI than those with normal cognition,” reported Manja Koch, PhD, a researcher in the department of nutrition at Harvard T.H. Chan School of Public Health in Boston and colleagues. “This was particularly true for the subset of individuals [with MCI] who drank more than 14.0 servings per week, whose rate of cognitive decline and risk of dementia were the highest of any subgroup.”

Among older adults with normal cognition, the results generally were consistent with those of a recent meta-analysis that found a U-shaped relationship between drinking and dementia, the researchers said (Eur J Epidemiol. 2017 Jan;32[1]:31-42.).

“Our results did not show significant associations and clearly do not suffice to suggest a clinical benefit from even limited alcohol use,” said Dr. Koch and colleagues. “Nonetheless, our findings provide some reassurance that alcohol consumed within recommended limits was not associated with an increased risk of dementia among older adults with normal baseline cognition.”

GEMS data

To study whether alcohol consumption is associated with the risk of dementia and cognitive decline in older adults with and without MCI, the investigators analyzed data from the Ginkgo Evaluation of Memory Study (GEMS). GEMS was a randomized controlled trial conducted between 2000 and 2008 that found no overall association between ginkgo biloba and dementia prevention. During the trial, participants completed the Modified Mini-Mental State Examination, the Clinical Dementia Rating scale, and the cognitive portion of the Alzheimer’s Disease Assessment Scale.

In the present study, the investigators analyzed data from 3,021 participants aged 72 years and older who were free of dementia at baseline and had provided information about their alcohol intake. Their median age was 78 years, and 46.2% were female. Fifty-eight percent consumed alcohol, including 45% of the participants with MCI at baseline.

During follow-up, 512 cases of dementia occurred. Among the 473 participants with MCI at baseline, the adjusted hazard ratio (HR) for dementia was 1.72 for those who consumed more than 14 drinks per week, compared with light drinkers who consumed less than 1 drink per week. For participants who consumed between 7 and 14 drinks per week, the adjusted HR for dementia was 0.63 among those without MCI and 0.93 among those with MCI, relative to light drinkers who consumed less than 1 drink per week.

Among adults with normal cognition at baseline, daily low-quantity drinking was associated with lower dementia risk, compared with infrequent higher-quantity drinking (HR, 0.45).
 

Trial excluded adults with excessive alcohol use

Limitations of the study include a lack of data about any changes in alcohol consumption over time. In addition, the original trial excluded people with a known history of excessive alcohol use. Furthermore, it is possible that the “long preclinical phase of dementia” and other health issues affect drinking behavior, the authors said. “At present, our findings cannot be directly translated into clinical recommendations,” the authors said. Nevertheless, the results “suggest that, while caring for older adults, physicians should carefully assess the full dimensions of drinking behavior and cognition when providing guidance to patients about alcohol consumption,” they said.

The study was supported by grants from the National Center for Complementary and Alternative Medicine; the National Institute of Neurological Disorders and Stroke; the Office of Dietary Supplements of the National Institute on Aging; the National Heart, Lung, and Blood Institute; the University of Pittsburgh Alzheimer’s Disease Research Center; the Roena Kulynych Center for Memory and Cognition Research; and Wake Forest University School of Medicine. In addition, the researchers used plasma samples from the National Cell Repository for Alzheimer’s Disease, which receives support from the National Institute on Aging. Dr. Koch had no conflicts of interest. Coauthors disclosed university and government grants and personal fees from pharmaceutical companies outside the study. One author was an employee of Genentech at the time of publication, but Genentech did not contribute to the study.

jremaly@mdedge.com

SOURCE: Koch M et al. JAMA Network Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.10319.

The Food and Drug Administration has expanded the indication of abobotulinumtoxinA (Dysport) for upper-limb spasticity to include patients aged 2 years and older, according to a release from Ipsen. This botulinum toxin product received approval for this indication in adults in 2015 and approval for lower-limb spasticity in patients aged 2 years and older in 2016. Notably, Orphan Drug Exclusivity prevents it from being indicated for patients with cerebral palsy because another botulinum toxin product, onabotulinumtoxinA (Botox), already was approved for the indication in June 2019.

Olivier Le Moal/Getty Images

Spasticity affects the muscles and joints of extremities, especially in growing children, and is usually caused by nerve damage, such as head trauma or spinal cord injury. The degree of spasticity can vary from mild muscle stiffness to severe, painful, and uncontrollable muscle spasms.

AbobotulinumtoxinA was evaluated for upper-limb spasticity in a phase 3, randomized, double-blind, low-dose controlled, multicenter study; the study enrolled 210 children aged 2-17 years with the condition and a Modified Ashworth Scale grade 2 or greater for elbow and wrist flexors. The children were randomized 1:1:1 to injections of either 8 units/kg, 16 units/kg, or 2 units/kg into the elbow flexors and wrist flexors. At 6 weeks, there were statistically significant improvements in Modified Ashworth Scale grade, the primary endpoint, with least-square mean changes from baseline of –2.0, –2.3, and –1.6, respectively.

AbobotulinumtoxinA and all other botulinum toxin products carry a boxed warning, the most serious warning the FDA issues. This warning refers to risk of botulism-like symptoms caused by the botulinum toxin spreading away from the injection area; these symptoms can included sometimes life-threatening difficulty swallowing or breathing. AbobotulinumtoxinA is contraindicated in patients with known hypersensitivity to any botulinum toxin or any of the components, those with presence of infection at proposed injection site(s), and those with known allergy to cow’s milk protein. It is also important to note that botulinum toxin preparations are not interchangeable; the potency units of one are not the same as those of another. Full prescribing information can be found on the Ipsen website.
 

cpalmer@mdedge.com

The Food and Drug Administration has expanded the indication of abobotulinumtoxinA (Dysport) for upper-limb spasticity to include patients aged 2 years and older, according to a release from Ipsen. This botulinum toxin product received approval for this indication in adults in 2015 and approval for lower-limb spasticity in patients aged 2 years and older in 2016. Notably, Orphan Drug Exclusivity prevents it from being indicated for patients with cerebral palsy because another botulinum toxin product, onabotulinumtoxinA (Botox), already was approved for the indication in June 2019.

Olivier Le Moal/Getty Images

Spasticity affects the muscles and joints of extremities, especially in growing children, and is usually caused by nerve damage, such as head trauma or spinal cord injury. The degree of spasticity can vary from mild muscle stiffness to severe, painful, and uncontrollable muscle spasms.

AbobotulinumtoxinA was evaluated for upper-limb spasticity in a phase 3, randomized, double-blind, low-dose controlled, multicenter study; the study enrolled 210 children aged 2-17 years with the condition and a Modified Ashworth Scale grade 2 or greater for elbow and wrist flexors. The children were randomized 1:1:1 to injections of either 8 units/kg, 16 units/kg, or 2 units/kg into the elbow flexors and wrist flexors. At 6 weeks, there were statistically significant improvements in Modified Ashworth Scale grade, the primary endpoint, with least-square mean changes from baseline of –2.0, –2.3, and –1.6, respectively.

AbobotulinumtoxinA and all other botulinum toxin products carry a boxed warning, the most serious warning the FDA issues. This warning refers to risk of botulism-like symptoms caused by the botulinum toxin spreading away from the injection area; these symptoms can included sometimes life-threatening difficulty swallowing or breathing. AbobotulinumtoxinA is contraindicated in patients with known hypersensitivity to any botulinum toxin or any of the components, those with presence of infection at proposed injection site(s), and those with known allergy to cow’s milk protein. It is also important to note that botulinum toxin preparations are not interchangeable; the potency units of one are not the same as those of another. Full prescribing information can be found on the Ipsen website.
 

cpalmer@mdedge.com

The Food and Drug Administration has expanded the indication of abobotulinumtoxinA (Dysport) for upper-limb spasticity to include patients aged 2 years and older, according to a release from Ipsen. This botulinum toxin product received approval for this indication in adults in 2015 and approval for lower-limb spasticity in patients aged 2 years and older in 2016. Notably, Orphan Drug Exclusivity prevents it from being indicated for patients with cerebral palsy because another botulinum toxin product, onabotulinumtoxinA (Botox), already was approved for the indication in June 2019.

Olivier Le Moal/Getty Images

Spasticity affects the muscles and joints of extremities, especially in growing children, and is usually caused by nerve damage, such as head trauma or spinal cord injury. The degree of spasticity can vary from mild muscle stiffness to severe, painful, and uncontrollable muscle spasms.

AbobotulinumtoxinA was evaluated for upper-limb spasticity in a phase 3, randomized, double-blind, low-dose controlled, multicenter study; the study enrolled 210 children aged 2-17 years with the condition and a Modified Ashworth Scale grade 2 or greater for elbow and wrist flexors. The children were randomized 1:1:1 to injections of either 8 units/kg, 16 units/kg, or 2 units/kg into the elbow flexors and wrist flexors. At 6 weeks, there were statistically significant improvements in Modified Ashworth Scale grade, the primary endpoint, with least-square mean changes from baseline of –2.0, –2.3, and –1.6, respectively.

AbobotulinumtoxinA and all other botulinum toxin products carry a boxed warning, the most serious warning the FDA issues. This warning refers to risk of botulism-like symptoms caused by the botulinum toxin spreading away from the injection area; these symptoms can included sometimes life-threatening difficulty swallowing or breathing. AbobotulinumtoxinA is contraindicated in patients with known hypersensitivity to any botulinum toxin or any of the components, those with presence of infection at proposed injection site(s), and those with known allergy to cow’s milk protein. It is also important to note that botulinum toxin preparations are not interchangeable; the potency units of one are not the same as those of another. Full prescribing information can be found on the Ipsen website.
 

cpalmer@mdedge.com

In the early morning hours of June 10, 2009, a 77-year-old man who had been undergoing chemotherapy for multiple myeloma took sleep medication. He then fell down a flight of stairs in his split-level home.

The patient sustained a laceration to his scalp but returned to bed and waited until later that morning to call his internist for an appointment. Later that day, the physician placed 11 sutures for the scalp laceration and performed a neurologic examination; he did not note any abnormalities. The patient complained of back pain, so the physician ordered a back x-ray, which revealed a TI2 fracture that had occurred from the fall. No further treatment was provided for the scalp injury, except removal of the stitches about a week later.

Six days after the fall and doctor visit, the patient’s condition began to deteriorate rapidly, with noted slurred speech and loss of consciousness. He was transported to an emergency department, where CT revealed a massive subdural hematoma. An immediate craniotomy was performed. However, on June 27, 2009, the patient died as a result of the brain bleed.

His estate filed suit against the physician and his practice, alleging medical malpractice and violations in the standard of care. The estate alleged that the standard of care required the physician to obtain a CT scan and that, had one been performed, it would have revealed a small subdural hematoma in time for it to have been successfully treated (ie, before the massive second related bleed). The estate’s theory of the case did not rest on the presentation of clinical symptoms. A medical expert who testified for the estate stated that the subdural hematoma began at the time of the fall.

The defense denied any violations in the standard of care. The physician contended that the patient had presented with no symptoms other than a head laceration, and there were no criteria for ordering CT. Further, the defense asserted that the patient was symptom free for 6 days post-fall. According to the defense, the patient experienced a sudden arterial bleed that was not caused by the fall and would not have been revealed on CT ordered at the time of initial presentation, because it did not occur until 6 days later.

VERDICT

After a 10-day trial and 25 minutes’ deliberation, the jury returned a defense verdict.

COMMENTARY

The 25-minute deliberation suggests that terms such as “bridging veins” and “shearing injury” were unlikely bandied about in the jury room. The jury was likely dismissive of the plaintiff’s claim owing to his cancer diagnosis, and perhaps rightly so. But if we eliminate the multiple myeloma diagnosis, the jury might have decided differently.

Continue to: The defendant physician...

The defendant physician did a good job of documenting a negative neurologic exam, which helped him convince the jury that the patient did not have any signs or symptoms when first evaluated. But in this patient, was imaging to rule out intracranial bleeding indicated?

As an oversimplification, we tend to think of intracranial hemorrhage in 2 varieties: the insidious and the bold. Subdural hematomas are stealthy, they are sneaky, and they prey on the old. They step out of the shadows to cause symptoms. They are the ninjas of intracranial hemorrhage. Beware.

Epidural hematomas and subarachnoid hemorrhage (SAH) are the opposite. They classically present with a sudden and severe symptom complex: with epidural hematoma, the loss of consciousness, lucid interval, and final loss of consciousness; with SAH, the “worst in your life” thunder-clap headache, which may be heralded by a sentinel headache.¹ When manifesting this way, they are brash, direct, and unsubtle to the point of being obnoxious—the Steven Stifler of intracranial bleeding.

This generalization is made to highlight the potentially sneaky nature of subdural hemorrhage. There are circumstances in which the clinical presentation of epidural hematoma and SAH will be more challenging. The question here is whether a negative initial neurologic exam can adequately screen for a potentially stealthy subdural hematoma.

Subdural hemorrhage is caused by rapidly changing velocity that may stretch and tear small bridging veins.^2,3 Subdural hematoma is more common in the elderly, those who abuse alcohol, and those with a prior history of head trauma.⁴ As the brain shrinks with age or atrophy, the subdural space enlarges and traversing veins are stretched to cover a wider distance—rendering them vulnerable to rupture.⁵ These structures may also weaken as a result of low cerebrospinal fluid (intracranial hypotension); as pressure decreases (eg, from a leak), the brain’s buoyancy is reduced, causing traction on anchoring and supporting structures (eg, bridging veins).⁵ Injury to bridging veins can even occur as a result of a coup-contrecoup mechanism in the absence of direct physical impact.^6,7 Bottom line: the injury itself may be subtle, requiring an index of suspicion to make the diagnosis.

Continue to: The case patient was...

The case patient was elderly. He had a chronic malignancy and sustained a fall down the stairs. He was taking sleeping pills, which may have slowed reflexive protective mechanisms after he started to fall (resulting in greater force imparted to his head). Multiple myeloma can predispose a patient to coagulopathy, and we don’t know in this case if this patient’s multiple myeloma made him more susceptible to bleeding—but it certainly didn’t help.⁸ The patient’s age, the mechanism of injury, and the history of malignancy made this a setup for hemorrhage.

Interestingly, we are not given details about how the patient looked during his suture removal. We are told the time between the initial fall and deterioration was 6 days. Scalp sutures were removed “about a week later,” which was after the deterioration—so this can’t be correct. Removing scalp sutures after 5 days seems premature, but that is the only possibility if 6 days elapsed between the fall and the deterioration.

In short, these are difficult cases. If intracranial bleeding can be subtle and delayed, how can we be sure a patient is not experiencing a bleed? We can only apply the relevant standard of care using all the clinical information we have. The Canadian CT Head Rule and New Orleans Criteria are clinical tools designed to help providers determine when to image (see Table for details).⁹

Applying the Canadian CT Head Rule to the facts of this case, we would image the patient because he fell down a “flight” of stairs (which is > 5 stairs) and he is 77 years old (older than 65). The New Orleans Criteria require head CT for minor injury with any positive findings.⁹ Because the patient is older than 60, he would be scanned according this rule.

In this case, the tools indicate scanning would have been appropriate. The patient’s multiple myeloma might have further impelled a decision to image. However, the jury was persuaded that the defendant’s negative neurologic exam was reasonable under the circumstances. This was likely made possible by the physician’s good recordkeeping and demonstrated genuine concern for the patient’s well-being—as well as a differing viewpoint of the patient’s age and health status.

Continue to: Finally, a word about...

Finally, a word about falls and the elderly: We’ve all heard the 80s advertising catchphrase (which lives on as a present-day meme) “I’ve fallen, and I can’t get up!” The problem is, many don’t. It would be more clinically accurate to say, “I’ve fallen, and I’ll be hospitalized for an extended period of time, then transferred to a skilled nursing facility, but I won’t survive to discharge.” The reality is that falls kill, and the severity is underestimated.¹⁰ If it were a “brain-eating amoeba,” the media would be all over it. With falls, not so much. We tend to pay less attention.

Risk factors for a fall include postural hypotension; use of benzodiazepines or other sedative-hypnotic drugs; use of ≥ 4 medications; environmental hazards for tripping; impairment in balance and transfer skills; and gait impairment.¹¹ Home setup also contributes—loose throw rugs, uneven carpet edges, cracked sidewalks, clutter and furniture, cables and wires and cords, oh my.

Do your older patients a favor by reinforcing fall risk. Instruct them to rise slowly from seated or recumbent positions; always consider central nervous system sedation and/or the coordination-hampering properties of medications, particularly in combination. Raise the issue of home safety. A brief 10-second comment from you may plant a seed in a family member’s head to do what you cannot: scan and make safe the patient’s living environment.

In the early morning hours of June 10, 2009, a 77-year-old man who had been undergoing chemotherapy for multiple myeloma took sleep medication. He then fell down a flight of stairs in his split-level home.

The patient sustained a laceration to his scalp but returned to bed and waited until later that morning to call his internist for an appointment. Later that day, the physician placed 11 sutures for the scalp laceration and performed a neurologic examination; he did not note any abnormalities. The patient complained of back pain, so the physician ordered a back x-ray, which revealed a TI2 fracture that had occurred from the fall. No further treatment was provided for the scalp injury, except removal of the stitches about a week later.

Six days after the fall and doctor visit, the patient’s condition began to deteriorate rapidly, with noted slurred speech and loss of consciousness. He was transported to an emergency department, where CT revealed a massive subdural hematoma. An immediate craniotomy was performed. However, on June 27, 2009, the patient died as a result of the brain bleed.

His estate filed suit against the physician and his practice, alleging medical malpractice and violations in the standard of care. The estate alleged that the standard of care required the physician to obtain a CT scan and that, had one been performed, it would have revealed a small subdural hematoma in time for it to have been successfully treated (ie, before the massive second related bleed). The estate’s theory of the case did not rest on the presentation of clinical symptoms. A medical expert who testified for the estate stated that the subdural hematoma began at the time of the fall.

The defense denied any violations in the standard of care. The physician contended that the patient had presented with no symptoms other than a head laceration, and there were no criteria for ordering CT. Further, the defense asserted that the patient was symptom free for 6 days post-fall. According to the defense, the patient experienced a sudden arterial bleed that was not caused by the fall and would not have been revealed on CT ordered at the time of initial presentation, because it did not occur until 6 days later.

VERDICT

After a 10-day trial and 25 minutes’ deliberation, the jury returned a defense verdict.

COMMENTARY

The 25-minute deliberation suggests that terms such as “bridging veins” and “shearing injury” were unlikely bandied about in the jury room. The jury was likely dismissive of the plaintiff’s claim owing to his cancer diagnosis, and perhaps rightly so. But if we eliminate the multiple myeloma diagnosis, the jury might have decided differently.

Continue to: The defendant physician...

The defendant physician did a good job of documenting a negative neurologic exam, which helped him convince the jury that the patient did not have any signs or symptoms when first evaluated. But in this patient, was imaging to rule out intracranial bleeding indicated?

As an oversimplification, we tend to think of intracranial hemorrhage in 2 varieties: the insidious and the bold. Subdural hematomas are stealthy, they are sneaky, and they prey on the old. They step out of the shadows to cause symptoms. They are the ninjas of intracranial hemorrhage. Beware.

Epidural hematomas and subarachnoid hemorrhage (SAH) are the opposite. They classically present with a sudden and severe symptom complex: with epidural hematoma, the loss of consciousness, lucid interval, and final loss of consciousness; with SAH, the “worst in your life” thunder-clap headache, which may be heralded by a sentinel headache.¹ When manifesting this way, they are brash, direct, and unsubtle to the point of being obnoxious—the Steven Stifler of intracranial bleeding.

This generalization is made to highlight the potentially sneaky nature of subdural hemorrhage. There are circumstances in which the clinical presentation of epidural hematoma and SAH will be more challenging. The question here is whether a negative initial neurologic exam can adequately screen for a potentially stealthy subdural hematoma.

Subdural hemorrhage is caused by rapidly changing velocity that may stretch and tear small bridging veins.^2,3 Subdural hematoma is more common in the elderly, those who abuse alcohol, and those with a prior history of head trauma.⁴ As the brain shrinks with age or atrophy, the subdural space enlarges and traversing veins are stretched to cover a wider distance—rendering them vulnerable to rupture.⁵ These structures may also weaken as a result of low cerebrospinal fluid (intracranial hypotension); as pressure decreases (eg, from a leak), the brain’s buoyancy is reduced, causing traction on anchoring and supporting structures (eg, bridging veins).⁵ Injury to bridging veins can even occur as a result of a coup-contrecoup mechanism in the absence of direct physical impact.^6,7 Bottom line: the injury itself may be subtle, requiring an index of suspicion to make the diagnosis.

Continue to: The case patient was...

The case patient was elderly. He had a chronic malignancy and sustained a fall down the stairs. He was taking sleeping pills, which may have slowed reflexive protective mechanisms after he started to fall (resulting in greater force imparted to his head). Multiple myeloma can predispose a patient to coagulopathy, and we don’t know in this case if this patient’s multiple myeloma made him more susceptible to bleeding—but it certainly didn’t help.⁸ The patient’s age, the mechanism of injury, and the history of malignancy made this a setup for hemorrhage.

Interestingly, we are not given details about how the patient looked during his suture removal. We are told the time between the initial fall and deterioration was 6 days. Scalp sutures were removed “about a week later,” which was after the deterioration—so this can’t be correct. Removing scalp sutures after 5 days seems premature, but that is the only possibility if 6 days elapsed between the fall and the deterioration.

In short, these are difficult cases. If intracranial bleeding can be subtle and delayed, how can we be sure a patient is not experiencing a bleed? We can only apply the relevant standard of care using all the clinical information we have. The Canadian CT Head Rule and New Orleans Criteria are clinical tools designed to help providers determine when to image (see Table for details).⁹

Applying the Canadian CT Head Rule to the facts of this case, we would image the patient because he fell down a “flight” of stairs (which is > 5 stairs) and he is 77 years old (older than 65). The New Orleans Criteria require head CT for minor injury with any positive findings.⁹ Because the patient is older than 60, he would be scanned according this rule.

In this case, the tools indicate scanning would have been appropriate. The patient’s multiple myeloma might have further impelled a decision to image. However, the jury was persuaded that the defendant’s negative neurologic exam was reasonable under the circumstances. This was likely made possible by the physician’s good recordkeeping and demonstrated genuine concern for the patient’s well-being—as well as a differing viewpoint of the patient’s age and health status.

Continue to: Finally, a word about...

Finally, a word about falls and the elderly: We’ve all heard the 80s advertising catchphrase (which lives on as a present-day meme) “I’ve fallen, and I can’t get up!” The problem is, many don’t. It would be more clinically accurate to say, “I’ve fallen, and I’ll be hospitalized for an extended period of time, then transferred to a skilled nursing facility, but I won’t survive to discharge.” The reality is that falls kill, and the severity is underestimated.¹⁰ If it were a “brain-eating amoeba,” the media would be all over it. With falls, not so much. We tend to pay less attention.

Risk factors for a fall include postural hypotension; use of benzodiazepines or other sedative-hypnotic drugs; use of ≥ 4 medications; environmental hazards for tripping; impairment in balance and transfer skills; and gait impairment.¹¹ Home setup also contributes—loose throw rugs, uneven carpet edges, cracked sidewalks, clutter and furniture, cables and wires and cords, oh my.

Do your older patients a favor by reinforcing fall risk. Instruct them to rise slowly from seated or recumbent positions; always consider central nervous system sedation and/or the coordination-hampering properties of medications, particularly in combination. Raise the issue of home safety. A brief 10-second comment from you may plant a seed in a family member’s head to do what you cannot: scan and make safe the patient’s living environment.

In the early morning hours of June 10, 2009, a 77-year-old man who had been undergoing chemotherapy for multiple myeloma took sleep medication. He then fell down a flight of stairs in his split-level home.

The patient sustained a laceration to his scalp but returned to bed and waited until later that morning to call his internist for an appointment. Later that day, the physician placed 11 sutures for the scalp laceration and performed a neurologic examination; he did not note any abnormalities. The patient complained of back pain, so the physician ordered a back x-ray, which revealed a TI2 fracture that had occurred from the fall. No further treatment was provided for the scalp injury, except removal of the stitches about a week later.

Six days after the fall and doctor visit, the patient’s condition began to deteriorate rapidly, with noted slurred speech and loss of consciousness. He was transported to an emergency department, where CT revealed a massive subdural hematoma. An immediate craniotomy was performed. However, on June 27, 2009, the patient died as a result of the brain bleed.

His estate filed suit against the physician and his practice, alleging medical malpractice and violations in the standard of care. The estate alleged that the standard of care required the physician to obtain a CT scan and that, had one been performed, it would have revealed a small subdural hematoma in time for it to have been successfully treated (ie, before the massive second related bleed). The estate’s theory of the case did not rest on the presentation of clinical symptoms. A medical expert who testified for the estate stated that the subdural hematoma began at the time of the fall.

The defense denied any violations in the standard of care. The physician contended that the patient had presented with no symptoms other than a head laceration, and there were no criteria for ordering CT. Further, the defense asserted that the patient was symptom free for 6 days post-fall. According to the defense, the patient experienced a sudden arterial bleed that was not caused by the fall and would not have been revealed on CT ordered at the time of initial presentation, because it did not occur until 6 days later.

VERDICT

After a 10-day trial and 25 minutes’ deliberation, the jury returned a defense verdict.

COMMENTARY

The 25-minute deliberation suggests that terms such as “bridging veins” and “shearing injury” were unlikely bandied about in the jury room. The jury was likely dismissive of the plaintiff’s claim owing to his cancer diagnosis, and perhaps rightly so. But if we eliminate the multiple myeloma diagnosis, the jury might have decided differently.

Continue to: The defendant physician...

The defendant physician did a good job of documenting a negative neurologic exam, which helped him convince the jury that the patient did not have any signs or symptoms when first evaluated. But in this patient, was imaging to rule out intracranial bleeding indicated?

As an oversimplification, we tend to think of intracranial hemorrhage in 2 varieties: the insidious and the bold. Subdural hematomas are stealthy, they are sneaky, and they prey on the old. They step out of the shadows to cause symptoms. They are the ninjas of intracranial hemorrhage. Beware.

Epidural hematomas and subarachnoid hemorrhage (SAH) are the opposite. They classically present with a sudden and severe symptom complex: with epidural hematoma, the loss of consciousness, lucid interval, and final loss of consciousness; with SAH, the “worst in your life” thunder-clap headache, which may be heralded by a sentinel headache.¹ When manifesting this way, they are brash, direct, and unsubtle to the point of being obnoxious—the Steven Stifler of intracranial bleeding.

This generalization is made to highlight the potentially sneaky nature of subdural hemorrhage. There are circumstances in which the clinical presentation of epidural hematoma and SAH will be more challenging. The question here is whether a negative initial neurologic exam can adequately screen for a potentially stealthy subdural hematoma.

Subdural hemorrhage is caused by rapidly changing velocity that may stretch and tear small bridging veins.^2,3 Subdural hematoma is more common in the elderly, those who abuse alcohol, and those with a prior history of head trauma.⁴ As the brain shrinks with age or atrophy, the subdural space enlarges and traversing veins are stretched to cover a wider distance—rendering them vulnerable to rupture.⁵ These structures may also weaken as a result of low cerebrospinal fluid (intracranial hypotension); as pressure decreases (eg, from a leak), the brain’s buoyancy is reduced, causing traction on anchoring and supporting structures (eg, bridging veins).⁵ Injury to bridging veins can even occur as a result of a coup-contrecoup mechanism in the absence of direct physical impact.^6,7 Bottom line: the injury itself may be subtle, requiring an index of suspicion to make the diagnosis.

Continue to: The case patient was...

The case patient was elderly. He had a chronic malignancy and sustained a fall down the stairs. He was taking sleeping pills, which may have slowed reflexive protective mechanisms after he started to fall (resulting in greater force imparted to his head). Multiple myeloma can predispose a patient to coagulopathy, and we don’t know in this case if this patient’s multiple myeloma made him more susceptible to bleeding—but it certainly didn’t help.⁸ The patient’s age, the mechanism of injury, and the history of malignancy made this a setup for hemorrhage.

Interestingly, we are not given details about how the patient looked during his suture removal. We are told the time between the initial fall and deterioration was 6 days. Scalp sutures were removed “about a week later,” which was after the deterioration—so this can’t be correct. Removing scalp sutures after 5 days seems premature, but that is the only possibility if 6 days elapsed between the fall and the deterioration.

In short, these are difficult cases. If intracranial bleeding can be subtle and delayed, how can we be sure a patient is not experiencing a bleed? We can only apply the relevant standard of care using all the clinical information we have. The Canadian CT Head Rule and New Orleans Criteria are clinical tools designed to help providers determine when to image (see Table for details).⁹

Applying the Canadian CT Head Rule to the facts of this case, we would image the patient because he fell down a “flight” of stairs (which is > 5 stairs) and he is 77 years old (older than 65). The New Orleans Criteria require head CT for minor injury with any positive findings.⁹ Because the patient is older than 60, he would be scanned according this rule.

In this case, the tools indicate scanning would have been appropriate. The patient’s multiple myeloma might have further impelled a decision to image. However, the jury was persuaded that the defendant’s negative neurologic exam was reasonable under the circumstances. This was likely made possible by the physician’s good recordkeeping and demonstrated genuine concern for the patient’s well-being—as well as a differing viewpoint of the patient’s age and health status.

Continue to: Finally, a word about...

Finally, a word about falls and the elderly: We’ve all heard the 80s advertising catchphrase (which lives on as a present-day meme) “I’ve fallen, and I can’t get up!” The problem is, many don’t. It would be more clinically accurate to say, “I’ve fallen, and I’ll be hospitalized for an extended period of time, then transferred to a skilled nursing facility, but I won’t survive to discharge.” The reality is that falls kill, and the severity is underestimated.¹⁰ If it were a “brain-eating amoeba,” the media would be all over it. With falls, not so much. We tend to pay less attention.

Risk factors for a fall include postural hypotension; use of benzodiazepines or other sedative-hypnotic drugs; use of ≥ 4 medications; environmental hazards for tripping; impairment in balance and transfer skills; and gait impairment.¹¹ Home setup also contributes—loose throw rugs, uneven carpet edges, cracked sidewalks, clutter and furniture, cables and wires and cords, oh my.

Do your older patients a favor by reinforcing fall risk. Instruct them to rise slowly from seated or recumbent positions; always consider central nervous system sedation and/or the coordination-hampering properties of medications, particularly in combination. Raise the issue of home safety. A brief 10-second comment from you may plant a seed in a family member’s head to do what you cannot: scan and make safe the patient’s living environment.

NEW ORLEANS – Limiting EEG during tilt-table testing to suspected pseudosyncope cases – instead of the common approaches, no EEG or EEG in everyone – greatly increases the chance of detecting the condition, according to an investigation from Vanderbilt University, Nashville.

Pseudosyncope, also known as nonsyncopal fainting (NSF), is a conversion disorder where people appear to faint, but don’t lose consciousness. It’s generally thought to be a physical manifestation of traumatic stress. Patients “aren’t faking it; they believe they are fainting,” said senior investigator Italo Biaggioni, MD, a professor of medicine and pharmacology at the university and director of the Vanderbilt Autonomic Dysfunction Center.

It’s “not benign. These patients stop working, stop driving, and need to depend on other people. They can have very dramatic episodes and hurt themselves” when they fall. “They are very disabled,” he said.

NSF is often misdiagnosed and mistreated, and sometimes unrecognized for years. Almost a third of the 39 NSF cases in Dr. Biaggioni’s series, for instance, were on anticonvulsants, and several had undergone cardiac catheterization. Often, NSF is treated as vasovagal syncope, but patients don’t respond to medications. A better way to identify it is needed. “By the time we get them, they’ve been through a lot.” Dr. Biaggioni said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

He and his team had a hunch that judicious use of EEG would help, so they limited EEG to suspected NSF cases in a series of 107 refractory syncope patients referred to Vanderbilt for head-up tilt-table testing; 39 (36%) had normal EEGs during an apparent loss of consciousness, as opposed to the slow-wave pattern of true loss of consciousness, and were diagnosed with NSF.

The 36% identified was a marked increase in incidence over more common approaches. Among 64 patients who had tilt-table testing without EEG at Vanderbilt, for instance, three (5%) were diagnosed with NSF. Historically, tilt table plus EEG in all comers has a diagnostic yield of around 18% for the condition. In short, “elective EEG monitoring during tilt-table testing” better “distinguishes between syncope” and NSF, the team concluded.

NSF is suggested by a history of more than 20 episodes of apparent fainting; episodes once a week or more; or losing consciousness for more than 5 minutes. Fainting with eyes closed, or while supine, is also suggestive.

The elective approach prevents inappropriate treatment but is also therapeutic in itself. “When we document with EEG that patients are not really fainting, and explain that to them, it automatically reduces the number of episodes,” Dr. Biaggioni said.

It also saves NSF patients from a nitroglycerin challenge and repeat tilt testing, which is the default in many places when the first round of testing doesn’t trigger an episode. Challenge testing provokes vasovagal syncope in around 10% of even healthy people, so it puts NSF patients at risk for a false positive. As a rule, “we don’t use provocative agents when we [suspect NSF],” he said.

In addition to the 39 NSF cases, 11 patients in the series were diagnosed with vasovagal syncope, and testing didn’t provoke an event in 57 (53%), which isn’t uncommon.

Baseline blood pressure and heart rates were similar across the three groups, and there were more women than men in each. Subjects were in their early 40s, on average.

NSF patients were more likely to be taking anxiety and depression medications. One NSF patient had posttraumatic stress disorder, and two had sexual abuse histories, compared with none in the nondiagnostic and vasovagal groups. The NSF group had a shorter time to an event: 9 minutes versus 19 minutes among vasovagal patients.

Tilt-table testing was done after 6 hours of fasting, and the team used standard 22-channel EEG. Cognitive-behavioral therapy is the go-to treatment for NSF, Dr. Biaggioni said.

There was no industry funding, and the authors didn’t have any disclosures.

aotto@mdedge.com

SOURCE: Muldowney JA et al. Joint Hypertension 2019, Abstract P3061.

NEW ORLEANS – Limiting EEG during tilt-table testing to suspected pseudosyncope cases – instead of the common approaches, no EEG or EEG in everyone – greatly increases the chance of detecting the condition, according to an investigation from Vanderbilt University, Nashville.

Pseudosyncope, also known as nonsyncopal fainting (NSF), is a conversion disorder where people appear to faint, but don’t lose consciousness. It’s generally thought to be a physical manifestation of traumatic stress. Patients “aren’t faking it; they believe they are fainting,” said senior investigator Italo Biaggioni, MD, a professor of medicine and pharmacology at the university and director of the Vanderbilt Autonomic Dysfunction Center.

It’s “not benign. These patients stop working, stop driving, and need to depend on other people. They can have very dramatic episodes and hurt themselves” when they fall. “They are very disabled,” he said.

NSF is often misdiagnosed and mistreated, and sometimes unrecognized for years. Almost a third of the 39 NSF cases in Dr. Biaggioni’s series, for instance, were on anticonvulsants, and several had undergone cardiac catheterization. Often, NSF is treated as vasovagal syncope, but patients don’t respond to medications. A better way to identify it is needed. “By the time we get them, they’ve been through a lot.” Dr. Biaggioni said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

He and his team had a hunch that judicious use of EEG would help, so they limited EEG to suspected NSF cases in a series of 107 refractory syncope patients referred to Vanderbilt for head-up tilt-table testing; 39 (36%) had normal EEGs during an apparent loss of consciousness, as opposed to the slow-wave pattern of true loss of consciousness, and were diagnosed with NSF.

The 36% identified was a marked increase in incidence over more common approaches. Among 64 patients who had tilt-table testing without EEG at Vanderbilt, for instance, three (5%) were diagnosed with NSF. Historically, tilt table plus EEG in all comers has a diagnostic yield of around 18% for the condition. In short, “elective EEG monitoring during tilt-table testing” better “distinguishes between syncope” and NSF, the team concluded.

NSF is suggested by a history of more than 20 episodes of apparent fainting; episodes once a week or more; or losing consciousness for more than 5 minutes. Fainting with eyes closed, or while supine, is also suggestive.

The elective approach prevents inappropriate treatment but is also therapeutic in itself. “When we document with EEG that patients are not really fainting, and explain that to them, it automatically reduces the number of episodes,” Dr. Biaggioni said.

It also saves NSF patients from a nitroglycerin challenge and repeat tilt testing, which is the default in many places when the first round of testing doesn’t trigger an episode. Challenge testing provokes vasovagal syncope in around 10% of even healthy people, so it puts NSF patients at risk for a false positive. As a rule, “we don’t use provocative agents when we [suspect NSF],” he said.

In addition to the 39 NSF cases, 11 patients in the series were diagnosed with vasovagal syncope, and testing didn’t provoke an event in 57 (53%), which isn’t uncommon.

Baseline blood pressure and heart rates were similar across the three groups, and there were more women than men in each. Subjects were in their early 40s, on average.

NSF patients were more likely to be taking anxiety and depression medications. One NSF patient had posttraumatic stress disorder, and two had sexual abuse histories, compared with none in the nondiagnostic and vasovagal groups. The NSF group had a shorter time to an event: 9 minutes versus 19 minutes among vasovagal patients.

Tilt-table testing was done after 6 hours of fasting, and the team used standard 22-channel EEG. Cognitive-behavioral therapy is the go-to treatment for NSF, Dr. Biaggioni said.

There was no industry funding, and the authors didn’t have any disclosures.

aotto@mdedge.com

SOURCE: Muldowney JA et al. Joint Hypertension 2019, Abstract P3061.

NEW ORLEANS – Limiting EEG during tilt-table testing to suspected pseudosyncope cases – instead of the common approaches, no EEG or EEG in everyone – greatly increases the chance of detecting the condition, according to an investigation from Vanderbilt University, Nashville.

Pseudosyncope, also known as nonsyncopal fainting (NSF), is a conversion disorder where people appear to faint, but don’t lose consciousness. It’s generally thought to be a physical manifestation of traumatic stress. Patients “aren’t faking it; they believe they are fainting,” said senior investigator Italo Biaggioni, MD, a professor of medicine and pharmacology at the university and director of the Vanderbilt Autonomic Dysfunction Center.

It’s “not benign. These patients stop working, stop driving, and need to depend on other people. They can have very dramatic episodes and hurt themselves” when they fall. “They are very disabled,” he said.

NSF is often misdiagnosed and mistreated, and sometimes unrecognized for years. Almost a third of the 39 NSF cases in Dr. Biaggioni’s series, for instance, were on anticonvulsants, and several had undergone cardiac catheterization. Often, NSF is treated as vasovagal syncope, but patients don’t respond to medications. A better way to identify it is needed. “By the time we get them, they’ve been through a lot.” Dr. Biaggioni said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

He and his team had a hunch that judicious use of EEG would help, so they limited EEG to suspected NSF cases in a series of 107 refractory syncope patients referred to Vanderbilt for head-up tilt-table testing; 39 (36%) had normal EEGs during an apparent loss of consciousness, as opposed to the slow-wave pattern of true loss of consciousness, and were diagnosed with NSF.

The 36% identified was a marked increase in incidence over more common approaches. Among 64 patients who had tilt-table testing without EEG at Vanderbilt, for instance, three (5%) were diagnosed with NSF. Historically, tilt table plus EEG in all comers has a diagnostic yield of around 18% for the condition. In short, “elective EEG monitoring during tilt-table testing” better “distinguishes between syncope” and NSF, the team concluded.

NSF is suggested by a history of more than 20 episodes of apparent fainting; episodes once a week or more; or losing consciousness for more than 5 minutes. Fainting with eyes closed, or while supine, is also suggestive.

The elective approach prevents inappropriate treatment but is also therapeutic in itself. “When we document with EEG that patients are not really fainting, and explain that to them, it automatically reduces the number of episodes,” Dr. Biaggioni said.

It also saves NSF patients from a nitroglycerin challenge and repeat tilt testing, which is the default in many places when the first round of testing doesn’t trigger an episode. Challenge testing provokes vasovagal syncope in around 10% of even healthy people, so it puts NSF patients at risk for a false positive. As a rule, “we don’t use provocative agents when we [suspect NSF],” he said.

In addition to the 39 NSF cases, 11 patients in the series were diagnosed with vasovagal syncope, and testing didn’t provoke an event in 57 (53%), which isn’t uncommon.

Baseline blood pressure and heart rates were similar across the three groups, and there were more women than men in each. Subjects were in their early 40s, on average.

NSF patients were more likely to be taking anxiety and depression medications. One NSF patient had posttraumatic stress disorder, and two had sexual abuse histories, compared with none in the nondiagnostic and vasovagal groups. The NSF group had a shorter time to an event: 9 minutes versus 19 minutes among vasovagal patients.

Tilt-table testing was done after 6 hours of fasting, and the team used standard 22-channel EEG. Cognitive-behavioral therapy is the go-to treatment for NSF, Dr. Biaggioni said.

There was no industry funding, and the authors didn’t have any disclosures.

aotto@mdedge.com

SOURCE: Muldowney JA et al. Joint Hypertension 2019, Abstract P3061.

The odds of adulthood insomnia are significantly higher among those with childhood behavioral problems, according to research published in JAMA Network Open.

klebercordeiro/Getty Images

Yohannes Adama Melaku, MPH, PhD, of the Adelaide (Australia) Institute for Sleep Health at Flinders University and coauthors drew data from the 1970 UK Birth Cohort Study. This study followed an initial cohort of 16,571 babies who were born during a single week, with follow-up at ages 5, 10, 16, 26, 30, 38, 42, and 46 years. For the purposes of this study, the investigators looked at participants who, at 42 years of age, were alive and not lost to follow-up and who responded to an invitation to be interviewed; the sample sizes in the analysis were 8,050 participants aged 5 years, 9,090 participants aged 10 years, 9,653 participants aged 16 years, and 9,841 participants aged 42 years.

Behavior was measured at ages 5 years and 16 years using the Rutter Behavioral Scale (RBS) and at age 10 years using a visual analog scale, and insomnia symptoms were assessed through interviewing participants in adulthood about duration of sleep, difficulty initiating sleep, difficulty maintaining sleep, and not feeling rested on waking. Participants were organized into normal behavior (less than or equal to 80th percentile on RBS), moderate behavioral problems (greater than the 80th percentile but less than or equal to the 95th percentile), and severe behavioral problems (above 95th percentile). The investigators then devised two models for their analysis: Model 1 adjusted for sex, parent’s social class and educational level, marital status, educational status, and social class, and model 2 adjusted for physical activity level and body mass index (BMI) trajectory (from 10 to 42 years), perceived health status, and number of noncommunicable diseases, although this latter model yielded fewer statistically significant results in some analyses.

Odds for difficulty initiating or maintaining sleep as an adult was increased among participants with severe behavioral problems at age 5 years in model 1 (adjusted odds ratio, 1.50; 95% confidence interval, 1.14-1.96; P = .004), as well as for those with severe problems at 10 years (aOR, 1.30; 95% CI, 1.14-1.63; P = .001), and at 16 years (aOR, 2.17; 95% CI, 1.59-2.91; P less than .001). The aORs also were higher individually for difficulty initiating sleep and for difficulty maintaining sleep in all age groups.

The association with adulthood insomnia was stronger in participants with externalizing behavioral problems such as lying, bullying, restlessness, and fighting than it was in those with internalizing behavioral problems such as worry, fearfulness, and solitariness.

“Although early sleep problems should be identified, we should additionally identify children with moderate to severe behavioral problems that persist throughout childhood as potential beneficiaries of early intervention with a sleep health focus,” the authors wrote.

One of the study’s limitations was a lack of standardized insomnia measures in the cohort study; however, the researchers suggested that the symptoms included reflect those of standardized measures and diagnostic criteria.

“This study is the first, to our knowledge, to suggest an unfavorable association of early-life behavioral problems with adulthood sleep health, underlining the importance of treating behavioral problems in children and addressing insomnia from a life-course perspective,” they concluded.

No study sponsor was identified. The authors reported no relevant financial disclosures.
 

cpalmer@mdedge.com

SOURCE: Melaku YA et al. JAMA Netw Open. 2019 Sep 6. doi: 10.1001/jamanetworkopen.2019.10861.

The odds of adulthood insomnia are significantly higher among those with childhood behavioral problems, according to research published in JAMA Network Open.

klebercordeiro/Getty Images

Yohannes Adama Melaku, MPH, PhD, of the Adelaide (Australia) Institute for Sleep Health at Flinders University and coauthors drew data from the 1970 UK Birth Cohort Study. This study followed an initial cohort of 16,571 babies who were born during a single week, with follow-up at ages 5, 10, 16, 26, 30, 38, 42, and 46 years. For the purposes of this study, the investigators looked at participants who, at 42 years of age, were alive and not lost to follow-up and who responded to an invitation to be interviewed; the sample sizes in the analysis were 8,050 participants aged 5 years, 9,090 participants aged 10 years, 9,653 participants aged 16 years, and 9,841 participants aged 42 years.

Behavior was measured at ages 5 years and 16 years using the Rutter Behavioral Scale (RBS) and at age 10 years using a visual analog scale, and insomnia symptoms were assessed through interviewing participants in adulthood about duration of sleep, difficulty initiating sleep, difficulty maintaining sleep, and not feeling rested on waking. Participants were organized into normal behavior (less than or equal to 80th percentile on RBS), moderate behavioral problems (greater than the 80th percentile but less than or equal to the 95th percentile), and severe behavioral problems (above 95th percentile). The investigators then devised two models for their analysis: Model 1 adjusted for sex, parent’s social class and educational level, marital status, educational status, and social class, and model 2 adjusted for physical activity level and body mass index (BMI) trajectory (from 10 to 42 years), perceived health status, and number of noncommunicable diseases, although this latter model yielded fewer statistically significant results in some analyses.

Odds for difficulty initiating or maintaining sleep as an adult was increased among participants with severe behavioral problems at age 5 years in model 1 (adjusted odds ratio, 1.50; 95% confidence interval, 1.14-1.96; P = .004), as well as for those with severe problems at 10 years (aOR, 1.30; 95% CI, 1.14-1.63; P = .001), and at 16 years (aOR, 2.17; 95% CI, 1.59-2.91; P less than .001). The aORs also were higher individually for difficulty initiating sleep and for difficulty maintaining sleep in all age groups.

The association with adulthood insomnia was stronger in participants with externalizing behavioral problems such as lying, bullying, restlessness, and fighting than it was in those with internalizing behavioral problems such as worry, fearfulness, and solitariness.

“Although early sleep problems should be identified, we should additionally identify children with moderate to severe behavioral problems that persist throughout childhood as potential beneficiaries of early intervention with a sleep health focus,” the authors wrote.

One of the study’s limitations was a lack of standardized insomnia measures in the cohort study; however, the researchers suggested that the symptoms included reflect those of standardized measures and diagnostic criteria.

“This study is the first, to our knowledge, to suggest an unfavorable association of early-life behavioral problems with adulthood sleep health, underlining the importance of treating behavioral problems in children and addressing insomnia from a life-course perspective,” they concluded.

No study sponsor was identified. The authors reported no relevant financial disclosures.
 

cpalmer@mdedge.com

SOURCE: Melaku YA et al. JAMA Netw Open. 2019 Sep 6. doi: 10.1001/jamanetworkopen.2019.10861.

The odds of adulthood insomnia are significantly higher among those with childhood behavioral problems, according to research published in JAMA Network Open.

klebercordeiro/Getty Images

Yohannes Adama Melaku, MPH, PhD, of the Adelaide (Australia) Institute for Sleep Health at Flinders University and coauthors drew data from the 1970 UK Birth Cohort Study. This study followed an initial cohort of 16,571 babies who were born during a single week, with follow-up at ages 5, 10, 16, 26, 30, 38, 42, and 46 years. For the purposes of this study, the investigators looked at participants who, at 42 years of age, were alive and not lost to follow-up and who responded to an invitation to be interviewed; the sample sizes in the analysis were 8,050 participants aged 5 years, 9,090 participants aged 10 years, 9,653 participants aged 16 years, and 9,841 participants aged 42 years.

Behavior was measured at ages 5 years and 16 years using the Rutter Behavioral Scale (RBS) and at age 10 years using a visual analog scale, and insomnia symptoms were assessed through interviewing participants in adulthood about duration of sleep, difficulty initiating sleep, difficulty maintaining sleep, and not feeling rested on waking. Participants were organized into normal behavior (less than or equal to 80th percentile on RBS), moderate behavioral problems (greater than the 80th percentile but less than or equal to the 95th percentile), and severe behavioral problems (above 95th percentile). The investigators then devised two models for their analysis: Model 1 adjusted for sex, parent’s social class and educational level, marital status, educational status, and social class, and model 2 adjusted for physical activity level and body mass index (BMI) trajectory (from 10 to 42 years), perceived health status, and number of noncommunicable diseases, although this latter model yielded fewer statistically significant results in some analyses.

Odds for difficulty initiating or maintaining sleep as an adult was increased among participants with severe behavioral problems at age 5 years in model 1 (adjusted odds ratio, 1.50; 95% confidence interval, 1.14-1.96; P = .004), as well as for those with severe problems at 10 years (aOR, 1.30; 95% CI, 1.14-1.63; P = .001), and at 16 years (aOR, 2.17; 95% CI, 1.59-2.91; P less than .001). The aORs also were higher individually for difficulty initiating sleep and for difficulty maintaining sleep in all age groups.

The association with adulthood insomnia was stronger in participants with externalizing behavioral problems such as lying, bullying, restlessness, and fighting than it was in those with internalizing behavioral problems such as worry, fearfulness, and solitariness.

“Although early sleep problems should be identified, we should additionally identify children with moderate to severe behavioral problems that persist throughout childhood as potential beneficiaries of early intervention with a sleep health focus,” the authors wrote.

One of the study’s limitations was a lack of standardized insomnia measures in the cohort study; however, the researchers suggested that the symptoms included reflect those of standardized measures and diagnostic criteria.

“This study is the first, to our knowledge, to suggest an unfavorable association of early-life behavioral problems with adulthood sleep health, underlining the importance of treating behavioral problems in children and addressing insomnia from a life-course perspective,” they concluded.

No study sponsor was identified. The authors reported no relevant financial disclosures.
 

cpalmer@mdedge.com

SOURCE: Melaku YA et al. JAMA Netw Open. 2019 Sep 6. doi: 10.1001/jamanetworkopen.2019.10861.

The early infusion of bone marrow cells could help patients recover from acute ischemic stroke, results from a single-arm, phase I trial demonstrated. Unlike autologous mesenchymal stem cells, mononuclear cells (MNCs) do not require passage in culture, which allows for testing in the early poststroke time therapy window.

Courtesy University of Texas, Houston

Bone marrow MNCs are attractive in regenerative medicine studies because they can be rapidly isolated; are enriched with hematopoietic, mesenchymal, and endothelial progenitor cells; and permit autologous applications. “The regenerative potential of bone marrow–derived MNCs is attributed to various mechanisms that impact stroke recovery,” researchers led by Sean I. Savitz, MD, wrote in a study published online Sept. 17 in Stem Cells. “These cells migrate to the site of injury, release cytokines and other trophic factors, decrease proinflammatory and upregulate anti-inflammatory pathways, and enhance angiogenesis, neurogenesis, and synaptogenesis.”

For the trial, Dr. Savitz, MD, director of the Institute for Stroke and Cerebrovascular Disease at UTHealth, Houston, and colleagues recruited 25 patients to receive an IV dose of their own bone marrow mononuclear cells within 72 hours after stroke onset, a time frame supported by previous preclinical studies. They followed the patients for 1 year and compared the results with a control group of 185 patients who received conventional poststroke treatment. Primary outcomes were study-related serious adverse events and the proportion of patients successfully completing study intervention.

The researchers reported results from 25 patients who received bone marrow MNCs. The mean age of patients in the MNC and control groups were 61 and 63 years, respectively, 53% were female, and 69% were white. No study-related adverse events were observed in the MNC group, but three (12%) had infarct expansion between enrollment and harvest and underwent elective hemicraniectomy after cell infusion.

Advanced magnetic resonance imaging revealed that the average mean fractional anisotropy (FA), a measure of structural integrity and directional coherence of axonal fibers, within the ipsilesional pons was decreased between 1 and 3 months after stroke, “which translated to a relative FA [rFA] comparable with prior reports at this time point,” the researchers wrote. “However, by 6 months, mean rFA began to increase and by 2 years it was significantly higher than at 1 month. This increasing trend in rFA may imply an increase in axonal and fiber coherence as well as thickness in myelin sheets, suggesting microstructural repair. However, without a comparable group of stroke patients not treated with MNCs, we cannot directly ascribe the white matter changes to MNC treatment.”

In light of the findings, the researchers concluded that MNCs “pose no additional harm in ischemic stroke patients when given during the acute phase, doses up to 10 million cells per kilogram are tolerated, and it is feasible to perform a bone marrow harvest and reinfusion of MNCs for a wide range of stroke patients. Well-designed RCTs are needed to further assess safety and efficacy of this novel investigational approach to enhance stroke recovery.”

The study was supported by grants from the National Institutes of Health. Dr. Savitz and many of his coauthors disclosed having numerous financial ties to the pharmaceutical and biotechnology industries.

dbrunk@mdedge.com

SOURCE: Vahidy F et al. Stem Cells. 2019 Sept. 17.

The early infusion of bone marrow cells could help patients recover from acute ischemic stroke, results from a single-arm, phase I trial demonstrated. Unlike autologous mesenchymal stem cells, mononuclear cells (MNCs) do not require passage in culture, which allows for testing in the early poststroke time therapy window.

Courtesy University of Texas, Houston

Bone marrow MNCs are attractive in regenerative medicine studies because they can be rapidly isolated; are enriched with hematopoietic, mesenchymal, and endothelial progenitor cells; and permit autologous applications. “The regenerative potential of bone marrow–derived MNCs is attributed to various mechanisms that impact stroke recovery,” researchers led by Sean I. Savitz, MD, wrote in a study published online Sept. 17 in Stem Cells. “These cells migrate to the site of injury, release cytokines and other trophic factors, decrease proinflammatory and upregulate anti-inflammatory pathways, and enhance angiogenesis, neurogenesis, and synaptogenesis.”

For the trial, Dr. Savitz, MD, director of the Institute for Stroke and Cerebrovascular Disease at UTHealth, Houston, and colleagues recruited 25 patients to receive an IV dose of their own bone marrow mononuclear cells within 72 hours after stroke onset, a time frame supported by previous preclinical studies. They followed the patients for 1 year and compared the results with a control group of 185 patients who received conventional poststroke treatment. Primary outcomes were study-related serious adverse events and the proportion of patients successfully completing study intervention.

The researchers reported results from 25 patients who received bone marrow MNCs. The mean age of patients in the MNC and control groups were 61 and 63 years, respectively, 53% were female, and 69% were white. No study-related adverse events were observed in the MNC group, but three (12%) had infarct expansion between enrollment and harvest and underwent elective hemicraniectomy after cell infusion.

Advanced magnetic resonance imaging revealed that the average mean fractional anisotropy (FA), a measure of structural integrity and directional coherence of axonal fibers, within the ipsilesional pons was decreased between 1 and 3 months after stroke, “which translated to a relative FA [rFA] comparable with prior reports at this time point,” the researchers wrote. “However, by 6 months, mean rFA began to increase and by 2 years it was significantly higher than at 1 month. This increasing trend in rFA may imply an increase in axonal and fiber coherence as well as thickness in myelin sheets, suggesting microstructural repair. However, without a comparable group of stroke patients not treated with MNCs, we cannot directly ascribe the white matter changes to MNC treatment.”

In light of the findings, the researchers concluded that MNCs “pose no additional harm in ischemic stroke patients when given during the acute phase, doses up to 10 million cells per kilogram are tolerated, and it is feasible to perform a bone marrow harvest and reinfusion of MNCs for a wide range of stroke patients. Well-designed RCTs are needed to further assess safety and efficacy of this novel investigational approach to enhance stroke recovery.”

The study was supported by grants from the National Institutes of Health. Dr. Savitz and many of his coauthors disclosed having numerous financial ties to the pharmaceutical and biotechnology industries.

dbrunk@mdedge.com

SOURCE: Vahidy F et al. Stem Cells. 2019 Sept. 17.

The early infusion of bone marrow cells could help patients recover from acute ischemic stroke, results from a single-arm, phase I trial demonstrated. Unlike autologous mesenchymal stem cells, mononuclear cells (MNCs) do not require passage in culture, which allows for testing in the early poststroke time therapy window.

Courtesy University of Texas, Houston

Bone marrow MNCs are attractive in regenerative medicine studies because they can be rapidly isolated; are enriched with hematopoietic, mesenchymal, and endothelial progenitor cells; and permit autologous applications. “The regenerative potential of bone marrow–derived MNCs is attributed to various mechanisms that impact stroke recovery,” researchers led by Sean I. Savitz, MD, wrote in a study published online Sept. 17 in Stem Cells. “These cells migrate to the site of injury, release cytokines and other trophic factors, decrease proinflammatory and upregulate anti-inflammatory pathways, and enhance angiogenesis, neurogenesis, and synaptogenesis.”

For the trial, Dr. Savitz, MD, director of the Institute for Stroke and Cerebrovascular Disease at UTHealth, Houston, and colleagues recruited 25 patients to receive an IV dose of their own bone marrow mononuclear cells within 72 hours after stroke onset, a time frame supported by previous preclinical studies. They followed the patients for 1 year and compared the results with a control group of 185 patients who received conventional poststroke treatment. Primary outcomes were study-related serious adverse events and the proportion of patients successfully completing study intervention.

The researchers reported results from 25 patients who received bone marrow MNCs. The mean age of patients in the MNC and control groups were 61 and 63 years, respectively, 53% were female, and 69% were white. No study-related adverse events were observed in the MNC group, but three (12%) had infarct expansion between enrollment and harvest and underwent elective hemicraniectomy after cell infusion.

Advanced magnetic resonance imaging revealed that the average mean fractional anisotropy (FA), a measure of structural integrity and directional coherence of axonal fibers, within the ipsilesional pons was decreased between 1 and 3 months after stroke, “which translated to a relative FA [rFA] comparable with prior reports at this time point,” the researchers wrote. “However, by 6 months, mean rFA began to increase and by 2 years it was significantly higher than at 1 month. This increasing trend in rFA may imply an increase in axonal and fiber coherence as well as thickness in myelin sheets, suggesting microstructural repair. However, without a comparable group of stroke patients not treated with MNCs, we cannot directly ascribe the white matter changes to MNC treatment.”

In light of the findings, the researchers concluded that MNCs “pose no additional harm in ischemic stroke patients when given during the acute phase, doses up to 10 million cells per kilogram are tolerated, and it is feasible to perform a bone marrow harvest and reinfusion of MNCs for a wide range of stroke patients. Well-designed RCTs are needed to further assess safety and efficacy of this novel investigational approach to enhance stroke recovery.”

The study was supported by grants from the National Institutes of Health. Dr. Savitz and many of his coauthors disclosed having numerous financial ties to the pharmaceutical and biotechnology industries.

dbrunk@mdedge.com

SOURCE: Vahidy F et al. Stem Cells. 2019 Sept. 17.

Of eight recommended prevention strategies for repeat severe pneumonia in children with neurologic impairment, only one – dental care – was found to be effective, according to findings published in Pediatrics.

Five of the remaining seven strategies – gastrostomy tube placement, chest physiotherapy, outpatient antibiotics before hospitalization, and clinic visit before and after index hospitalization – were associated with increased recurrence, Jody L. Lin, MD, of the department of pediatrics at Stanford (Calif.) University, and colleagues reported. Oral secretion management and gastric acid suppression were associated with increased risk, but to a lesser extent.

The researchers examined the outcomes of the prevention strategies because, although children with neurologic impairment are more susceptible to community-acquired pneumonia, current guidelines are based mostly on expert opinion. The study included 3,632 children aged 21 years or younger with neurologic impairment and at least one hospitalization for pneumonia, who were enrolled in the California Children’s Services program between July 1, 2009, and June 30, 2014.

Propensity-score matching based on factors such as age, sex, household income, as well as characteristics of index hospitalization, showed decreased odds of recurrence only with receipt of dental care (adjusted odds ratio, 0.64; 95% confidence interval, 0.49-0.85), whereas increased odds were seen with other recommended prevention strategies, such as chest physiotherapy (aOR, 2.03; 95% CI, 1.29-3.20), receipt of antibiotics before hospitalization (aOR, 1.42; 95% CI, 1.06-1.92), and clinic visit before (aOR, 1.30; 95% CI, 1.11-1.52) and after index hospitalization (aOR, 1.72; 95% CI, 1.35-2.20).

The greatest increased odds, however, were seen with new gastrostomy tube placement (aOR, 2.15; 95% CI, 1.63-2.85).

The investigators noted that the biggest limitation of this study was the potential for residual confounding by indication even after adjustment, whereby certain interventions were provided to patients deemed more clinically severe to begin with. A strength of the study is its longitudinal nature.

“Our results suggest that more attention should be paid to dental health for children with [neurologic impairment],” the researchers wrote, although they noted that dental care “remains the most common unmet health care need” for children with special health care needs.

The findings also “support a clinical trial of dental care for prevention of severe pneumonia in children with [neurologic impairment] and do not support the widespread use of gastrostomy tubes for that purpose,” they added.

The study was funded by the National Institutes of Health. Dr. Lin received support from the NIH and the Clinical Excellence Research Center. The authors reported that they had no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Lin JL et al. Pediatrics. 2019 Sep 19. doi: 10.1542/peds.2019-0543.

Of eight recommended prevention strategies for repeat severe pneumonia in children with neurologic impairment, only one – dental care – was found to be effective, according to findings published in Pediatrics.

Five of the remaining seven strategies – gastrostomy tube placement, chest physiotherapy, outpatient antibiotics before hospitalization, and clinic visit before and after index hospitalization – were associated with increased recurrence, Jody L. Lin, MD, of the department of pediatrics at Stanford (Calif.) University, and colleagues reported. Oral secretion management and gastric acid suppression were associated with increased risk, but to a lesser extent.

The researchers examined the outcomes of the prevention strategies because, although children with neurologic impairment are more susceptible to community-acquired pneumonia, current guidelines are based mostly on expert opinion. The study included 3,632 children aged 21 years or younger with neurologic impairment and at least one hospitalization for pneumonia, who were enrolled in the California Children’s Services program between July 1, 2009, and June 30, 2014.

Propensity-score matching based on factors such as age, sex, household income, as well as characteristics of index hospitalization, showed decreased odds of recurrence only with receipt of dental care (adjusted odds ratio, 0.64; 95% confidence interval, 0.49-0.85), whereas increased odds were seen with other recommended prevention strategies, such as chest physiotherapy (aOR, 2.03; 95% CI, 1.29-3.20), receipt of antibiotics before hospitalization (aOR, 1.42; 95% CI, 1.06-1.92), and clinic visit before (aOR, 1.30; 95% CI, 1.11-1.52) and after index hospitalization (aOR, 1.72; 95% CI, 1.35-2.20).

The greatest increased odds, however, were seen with new gastrostomy tube placement (aOR, 2.15; 95% CI, 1.63-2.85).

The investigators noted that the biggest limitation of this study was the potential for residual confounding by indication even after adjustment, whereby certain interventions were provided to patients deemed more clinically severe to begin with. A strength of the study is its longitudinal nature.

“Our results suggest that more attention should be paid to dental health for children with [neurologic impairment],” the researchers wrote, although they noted that dental care “remains the most common unmet health care need” for children with special health care needs.

The findings also “support a clinical trial of dental care for prevention of severe pneumonia in children with [neurologic impairment] and do not support the widespread use of gastrostomy tubes for that purpose,” they added.

The study was funded by the National Institutes of Health. Dr. Lin received support from the NIH and the Clinical Excellence Research Center. The authors reported that they had no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Lin JL et al. Pediatrics. 2019 Sep 19. doi: 10.1542/peds.2019-0543.

Of eight recommended prevention strategies for repeat severe pneumonia in children with neurologic impairment, only one – dental care – was found to be effective, according to findings published in Pediatrics.

Five of the remaining seven strategies – gastrostomy tube placement, chest physiotherapy, outpatient antibiotics before hospitalization, and clinic visit before and after index hospitalization – were associated with increased recurrence, Jody L. Lin, MD, of the department of pediatrics at Stanford (Calif.) University, and colleagues reported. Oral secretion management and gastric acid suppression were associated with increased risk, but to a lesser extent.

The researchers examined the outcomes of the prevention strategies because, although children with neurologic impairment are more susceptible to community-acquired pneumonia, current guidelines are based mostly on expert opinion. The study included 3,632 children aged 21 years or younger with neurologic impairment and at least one hospitalization for pneumonia, who were enrolled in the California Children’s Services program between July 1, 2009, and June 30, 2014.

Propensity-score matching based on factors such as age, sex, household income, as well as characteristics of index hospitalization, showed decreased odds of recurrence only with receipt of dental care (adjusted odds ratio, 0.64; 95% confidence interval, 0.49-0.85), whereas increased odds were seen with other recommended prevention strategies, such as chest physiotherapy (aOR, 2.03; 95% CI, 1.29-3.20), receipt of antibiotics before hospitalization (aOR, 1.42; 95% CI, 1.06-1.92), and clinic visit before (aOR, 1.30; 95% CI, 1.11-1.52) and after index hospitalization (aOR, 1.72; 95% CI, 1.35-2.20).

The greatest increased odds, however, were seen with new gastrostomy tube placement (aOR, 2.15; 95% CI, 1.63-2.85).

The investigators noted that the biggest limitation of this study was the potential for residual confounding by indication even after adjustment, whereby certain interventions were provided to patients deemed more clinically severe to begin with. A strength of the study is its longitudinal nature.

“Our results suggest that more attention should be paid to dental health for children with [neurologic impairment],” the researchers wrote, although they noted that dental care “remains the most common unmet health care need” for children with special health care needs.

The findings also “support a clinical trial of dental care for prevention of severe pneumonia in children with [neurologic impairment] and do not support the widespread use of gastrostomy tubes for that purpose,” they added.

The study was funded by the National Institutes of Health. Dr. Lin received support from the NIH and the Clinical Excellence Research Center. The authors reported that they had no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Lin JL et al. Pediatrics. 2019 Sep 19. doi: 10.1542/peds.2019-0543.