Neuromuscular Diseases in Geriatric Patients: Part II

This two-part article on neuromuscular diseases in geriatric patients focuses on the conditions that occur with regularity in older persons or have a striking effect on their lives. Part I, published in the February 2010 issue of the Journal, discussed cervical spondylotic radiculomyelopathy, lumbar spondylosis, amyotrophic lateral sclerosis, Guillain-Barré syndrome, and acquired demyelinating polyneuropathies. Part II focuses on myasthenia gravis, inclusion body myositis, polymyositis, and polymyalgia rheumatica.

Myasthenia Gravis

The hallmark of this autoimmune disease is fatigable strength that improves with rest.¹ Presentation may be: (1) primarily ocular: ptosis and extraocular movement abnormality leading to diplopia; (2) bulbar: weakness of muscles of mastication leading to fatigable chewing and prolonged meal times, dysphagia, regurgitation of liquids into the nasal passages, and nasal speech due to palatal weakness; or (3) generalized: usually symmetric proximal limb weakness, neck extensor weakness presenting as head drop or diaphragmatic weakness. In 15% of patients, the disease remains largely confined to the extraocular muscles and eyelids. The remaining 85% of patients have generalized myasthenia gravis. Occasionally, patients will present with respiratory failure (myasthenic crisis) or failure to wean from mechanical ventilation after they have been intubated for an unrelated reason. Anti-MuSK (muscle-specific kinase) seropositive patients have a higher frequency of bulbar involvement and respiratory crises.^2,3 There is no sensory involvement, and deep tendon reflexes are unaffected. The prevalence of myasthenia gravis is between 50-125 cases per million population, and the incidence is bimodal; the first peak is in females in their second or third decade, and the second peak is in males in their sixth or seventh decade.¹

Serum anti-acetylcholine receptor (AChR) antibody testing (binding, blocking, and modulating), anti-MuSK antibody testing, nerve conduction studies (NCS) including repetitive nerve stimulation and electromyography ± single-fiber electromyogram (EMG) are the diagnostic cornerstones for this disease. AChR antibody testing has 99% specificity and 80-90% sensitivity in patients with generalized myasthenia.^4,5 In patients who are initially seronegative, it may be worth repeating the antibody testing in 12 months, as a Mayo Clinic cohort found that 15.2% of initially seronegative patients became senopositive with testing at later dates.⁵ In patients with purely ocular myasthenia gravis, seropositivity drops to approximately 60%. In AChR antibody-negative myasthenia gravis, the antibody involved is directed toward an epitope located on or near the AChR (eg, antibodies against MuSK), which are found in 20-38%^3,5 of “seronegative” patients, or against striated muscle (present in 85% of thymoma patients). Between 10-15% of patients will have a thymic neoplasm uncovered on chest computed tomography, and 65% of the remaining patients will have a thymic hyperplasia.⁴

NCS and EMG eliminate neurogenic or myopathic causes for the muscle weakness. Repetitive nerve stimulation, whereby a peripheral nerve is stimulated at a frequency of 2-3 Hz and the ensuing compound muscle action potentials (CMAPs) recorded, will show a 10% (or greater) decrement in the amplitude of the CMAP. This is characteristic of a postsynaptic disorder and is positive in over 70% of patients with myasthenia gravis; the sensitivity is increased by studying muscles that are clinically involved. Single-fiber EMG, which has greater than 90% sensitivity, is of particular value in ocular myasthenia gravis.

Other diagnostic tests include the icepack test, in which an icepack is applied over a ptotic eye for as long as the patient can tolerate (usually minutes). In myasthenic patients, this simple maneuver often produces an appreciable improvement in the degree of ptosis, which one can quantify by measuring the interpalpebral distance.⁶The edrophonium test (Tensilon test) entails incremental administration of a total dose of 10 mg of an intravenous acetylcholinesterase inhibitor.⁷ This increases the availability of acetylcholine in the synaptic cleft, allowing for repeated binding to the limited number of receptors. A positive test requires a quantifiable end point demonstrating improved muscle strength (ie, subjective improvement does not constitute a positive test).

Electron microscopy of the neuromuscular junction reveals reduction in the area of the nerve terminal, oversimplification of the postsynaptic cleft with a reduction in the number of acetylcholine receptors, scarcity or absence of the secondary synaptic clefts, and widening of the primary clefts.⁸ The number of presynaptic vesicles and quanta are normal. This occurs because circulating antibodies are directed against the acetylcholine receptor, blocking the binding of acetylcholine, reducing the number of receptors through cross-linkage and increased degradation, ⁹ and inducing complement-mediated destruction of the postsynaptic folds.⁴ The result is insufficient end plate potentials to generate action potentials, resulting in accumulation of blocked potentials, which is clinically manifested as fatigable muscle strength.

The name conveys the deadly nature of this disease; prior to the advent of mechanical ventilation and the development of modern Intensive Care Units, the mortality rate approached 30%. If the disease remains confined to its ocular form, then the probability that it will generalize decreases over time (approximately 15% after 2 yr).¹⁰ Spontaneous early remissions can occur, but the possibility of a relapse remains and the disease may be progressive when it recurs. A later age of onset is associated with an increased risk of respiratory crisis.

Treatment options are divided into symptomatic, immunosuppressant, and surgical. Pyridostigmine is for symptom control and typically used in a dose of 30-90 mg every 4-6 hours as needed; it has the advantage of fewer cholinergic and central nervous system side effects as compared with other anticholinesterase agents. Overdose can result in a cholinergic crisis; manifestations include nausea, vomiting, pallor, diaphoresis, bronchorrhea, salivation, miosis, and bradycardia, which responds to atropine.

Prednisone may induce a steroid crisis (worsening weakness); therefore, it should be introduced slowly in the form of a ramp, starting at 15-20 mg daily and slowly titrating up to 60 mg daily.¹¹ Improvement occurs slowly, over weeks, and once maximum beneficial effect is reached, it can be tapered slowly to a minimum effective dose (eg, 20 mg qod). Initiating prednisone prior to thymectomy may interfere with healing of the sternal wound afterwards.

Plasmapheresis may be used before and after surgery, or for severe or refractory cases. A typical protocol consists of five exchanges over a 7-10–day period, and improvement is usually noted within 1 week,^12,13 making it a suitable treatment modality for patients in crisis. The effect usually lasts for a couple of months.

A recent randomized, placebo-controlled, masked study in 51 patients with worsening myasthenia gravis found a clinically meaningful improvement at 14 days post-treatment with intravenous immunoglobulin (IvIG) 2 g/kg. This was observed in patients with a higher Quantitative Myasthenia Gravis Score for Disease Severity, but not in patients with a lower score (milder disease) or purely ocular myasthenia gravis.¹⁴

The oral agent azathioprine can be used as a adjunct to steroids or alone with a target dose of 2-3 mg/kg/day; the improvement is noticed over months (12-18 mo) rather than weeks but may facilitate a steroid taper. Mycophenolate has also been used as a steroid-sparing agent, and possibly as monotherapy in milder cases; however, recent randomized controlled trials have called into question the efficacy of this drug in myasthenia gravis.^15,16 Pulsed cyclophosphamide can be used in severe refractory cases.

With regard to ocular myasthenia gravis, the recent report of the American Academy of Neurology (AAN) Quality Standards Subcommittee states that the evidence “does not support or refute the use of corticosteroids and/or azathioprine to reduce the risk of progression to generalized myasthenia gravis (Level U).”¹⁷ However, other authors recommend the use of corticosteroids in ocular myasthenia gravis.^18,19

New therapies on the horizon include oral antisense oligonucleotides, which cause targeted gene transcription inhibition.²⁰ An open-label study looking at long-term tacrolimus (FK506) for approximately 2.5 years in 79 cyclosporine- and prednisone-dependent patients achieved pharmacologic remission in 87% of patients who had undergone prior thymectomy.²¹ Case reports of successful rituximab treatment in MuSK–positive myasthenia gravis that was refractory to conventional immunosuppression are also in the literature.²²

In patients with thymoma, thymectomy is indicated to prevent tumor spread, but in patients with thymic hyperplasia—especially those over the age of 50 years—there are no published data addressing this issue. The AAN Quality Standards Subcommittee, after an evidence-based review, concluded that there is Class 2 evidence to support thymectomy as an option to increase the probability of remission or improvement in nonthymomatous autoimmune myasthenia gravis.²³ A 25% lower remission rate was found in patients with late-onset disease as compared with early-onset disease.

Ultimately, the treatment or combination of treatments are influenced by the patient’s age, severity of disease, comorbidities, and side-effect profiles of the drugs. Management by an experienced neurologist is necessary to optimize treatment.

Inclusion Body Myositis

Inclusion body myositis (IBM) produces progressive limb weakness over years; the median time from onset to diagnosis is 6 years. It is the most common acquired myopathy in those over the age of 50 years,² affecting more males than females. Interestingly, it was not described as a distinct entity until 1971 when Yunis and Samaha² proposed the term inclusion body myositis. However, in 1967 Chou²⁶ had described the ultrastructural feature of this disease in a biopsy from a 66-year-old man thought to have chronic polymyositis.

The characteristic phenotype is weakness and atrophy of wrist and finger flexors, quadriceps, and foreleg muscles.^24,27 The patient often reports instability of gait (especially when descending stairs), reduced grip strength with a hollowed appearance of forearm muscles, and foot drop. Assymetric muscle involvement is often observed,²⁸ which can lead to a misdiagnosis of motor neuron disease. Dysphagia is present in 40%²⁹ and facial weakness in one-third.²⁴ IBM should be considered in patients with head drop due to erector spine weakness.³⁰ Sensory testing is abnormal in up to one-third (confirmed by nerve conduction velocity [NCV]) of patients, and early loss of the patellar reflexes occurs. Autoimmune disorders are present in up to 15% of patients with IBM (eg, systemic lupus erythematosus [SLE],³¹ Sjögren’s syndrome³²), but myocardial involvement is not observed, nor is there increased risk of malignancy.

A modest rise in creatine kinase is seen (< 10 times baseline) but may be normal,²⁹ and a positive antinuclear antibody (ANA) test is reported in up to 20% of patients. EMG shows increased spontaneous and insertional activity, small polyphasic motor unit action potentials, and early recruitment of motor units (ie, a myopathic picture). Muscle biopsy is frequently pursued in order to confirm the diagnosis. Rimmed vacuoles, cytoplasmic inclusions, fiber atrophy, and endomysial inflammation are the cardinal light microspcopy features.²⁴ The cytoplasm of the myocytes, which contain rimmed vacuoles and inclusions, stains positive for amyloid. The inflammatory cells are CD8 T cells and macrophages (similar to polymyositis). Electron microscopy reveals cytoplasmic and intranuclear tubulofilaments measuring 15-21 nm in diameter.³³ Initially thought to be a inflammatory myopathy (like dermatomyositis and polymyositis), it is now proposed that IBM may be a degenerative process with a secondary inflammatory response.^34,35 There is accumulation of proteins, namely, β-amyloid,³⁶ amyloid precursor protein, apolipoprotein E,37 hyperphosphorylated tau, and ubiquitin38 within the muscle fibers in IBM—the same proteins found in the brains of patients with Alzheimer’s disease.³⁹ The question of whether these proteins are “cause” or “effect” in the primary pathogenesis in IBM is as yet unanswered.

Unfortunately, there is no effective therapy, as the results of trials with immunosuppressant therapies, including prednisone,⁴ IvIG,⁴¹ and methotrexate,⁴² have been disappointing. Supportive treatment with physical and occupational therapy, assistive walking devices/wheelchairs, cricopharyngeal myotomy⁴³ for severe dysphagia, and patient support groups help improve quality of life for these patients. Patients with later-onset (60-79 yr) disease progress more rapidly, requiring a walker in 6 years as compared to those with earlier-onset (40-59 yr) disease, who take 10 years to require a walker.⁴⁴

Polymyositis

Adult-onset polymyositis (PM) typically occurs during the fifth or sixth decade but can present in any decade. The clinical picture is marked by neck flexor and proximal symmetrical limb weakness, evolving over weeks or months. Distal limb muscles or muscles of facial expression may be affected but to a lesser degree. Dysphagia occurs in about one-third of patients denoting oropharyngeal and upper-esophageal weakness. Sensory examination and deep tendon reflexes are normal. Cardiac involvement (myocarditis) occurs in up to one-third, presenting as congestive cardiac failure or conduction abnormalities.⁴⁵ Other systemic involvement includes interstitial lung disease, which is reported in 10% of patients (50% of whom are seropositive for anti-Jo-1 antibodies), and 25-50% of patients with PM are found to have polyarthritis. Skin lesions (erythema of the periorbital area, anterior neck and chest, extensor surface of elbows and fingers) are not associated with polymyositis, and if present should raise suspicion for dermatomyositis.The risk of malignancy may be higher than in the non-PM population but is lower than with dermatomyositis.

Creatine kinase is 5-50 times baseline; monitoring levels can be used to help gauge a patient’s response to therapy but does not correlate with the degree of weakness. ANA is positive in up to 40% of patients. Erythrocyte sedimentation rate (ESR) can be normal in 50% of patients. EMG is very useful in diagnosis, showing increased insertional and spontaneous activity, small polyphasic motor unit action potentials, and early recruitment in affected muscles—typically the iliopsoas and proximal upper-extremity muscles. Magnetic resonance imaging (MRI) of muscles is not routinely performed but can show inflammatory changes in affected muscle groups.

PM is the result of a cell-mediated immune response, with myocytes being the target.⁴⁶ Increased fiber size variability, endomysial inflammation with invasion of non-necrotic fibers, fiber necrosis, and regeneration are the cardinal light microscopy features of PM. Classically, the inflammatory cell population is described as consisting of antigen-specific CD8 T cells and macrophages. However, more recently a B-cell antigen-specific response was found in patients with PM.⁴ The trigger of this attack is as yet unidentified.

Immunosuppressive therapies produce remission; this is known through clinical experience despite the lack of randomized controlled trials demonstrating this.⁴⁷ A minority of patients may have a monophasic illness, permitting permanent withdrawal of immunosuppressant medication, but most patients require treatment for the remainder of their lives. Amato and Griggs⁴⁸ suggest starting prednisone at a dose of 1.0-1.5 mg/kg/day (up to a maximum dose of 100 mg/day), with a change to alternate-day dosing after 2-4 weeks, if possible. Gradual reduction to alternate-day dosing by decreasing the dose by 10 mg/week on alternate days may be undertaken. Patients are maintained at this dose until they return to baseline strength or plateau, and then a gradual taper of 5 mg every 2-3 weeks is suggested. (The reader is referred to the original article for further recommendations on the rate of steroid taper.⁴⁸) Careful attention to osteopenia and other steroid-induced side effects needs to be maintained for the duration of treatment. Azathioprine, IvIG, and mycophenolate are all used as second-line or steroid-sparing agents. In patients who are anti-Jo-1–positive or who have interstitial lung disease, methotrexate is avoided because of the known complication of pulmonary fibrosis with this medication.

Polymyalgia Rheumatica

Polymyalgia rheumatica (PMR), one of the protean manifestations of giant cell arteritis (GCA), presents as severe proximal limb pain, stiffness, and aching of “tissues” rather than joints,⁴⁹ plus an elevated ESR. While PMR is seen in 40-50% of patients with GCA, it can also exist in a primary form independent of GCA and is three times more common.⁴⁹ The patient’s symptoms may be diffuse or asymmetrical, with the shoulders most frequently affected, followed by hip and neck. This picture may be accompanied by constitutional symptoms of fever, weight loss, anemia, headache, fatigue, joint swelling, and pitting edema of hands and feet.⁵⁰ PMR has a predilection for females (66.6% in Olmsted County series), and mean age at incidence was 72 years.⁵¹ Annual incidence over a 30-year period was 58.7 per 100,000 population age 50 years or more. The incidence of GCA has been found to climb from 1.54/100,000/year in the sixth decade to 20.7/100,000/year by the eighth decade.⁵²

Laboratory testing in PMR shows an elevated ESR (> 40 mm/h) in 93% of patients.⁵³ Even though the ESR may be normal (< 30 mm/hr),⁵ in the majority of patients, it is a good surrogate of disease activity and is routinely used to monitor response to treatment. Creatine kinase levels are normal, and the patient may be anemic.

Pathogenesis is unknown, but arthroscopy and MRI have shown synovitis, bursitis (especially subacromial/subdeltoid), and inflammation of periarticular structures and their muscular attachments.⁵⁴ Possession of the HLA-DRB1-04 allele increases the risk of developing GCA.⁴⁹

Prognosis is that of a self-limiting condition lasting 6-24 months. Treatment with steroids produces a dramatic response⁵⁵ but may have to be continued at a low dose for a long period of time (12 mo or more). One author suggests commencing with oral prednisone 20 mg if there is no suspicion of temporal arteritis.⁵⁵ Relief of pain should occur within days, with reconsideration of the diagnosis if this does not occur. Tapering of steroids should occur every 2 weeks in small decrements, using response of shoulder and hip pain along with ESR as guides.⁵⁶ If there is concurrent GCA, then treatment with high-dose steroids (1 mg/kg/day) is required.

Conclusion

Neuromuscular disease is both common in older persons and often treatable. Although sometimes straightforward, most often diagnosis and management require a neurologist’s input. The Table summarizes the core clinical features, suggested work-up, and usual treatments employed in the conditions discussed.

The authors report no relevant financial relationships.

Dr. Gleeson is from St. Francis Hospital, Hartford, CT; and Dr. Wolfson is Professor and Chair, Department of Neurology, University of Connecticut School of Medicine, Farmington, and Chief of Neurology, Hartford Hospital, Hartford, CT.

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