10/15/2019

Neuromuscular Diseases Primer

K. H. VINCENT LAU, MD ASSISTANT PROFESSOR IN NEUROLOGY BOSTON MEDICAL CENTER

40TH ANNUAL NEUROREHABILITATION CONFERENCE ON TRAUMATIC BRAIN INJURY, STROKE AND OTHER NEUROLOGICAL DISORDERS

Disclosures

No conflict of interest to disclose

Objectives

By the end of the session, participants should be able to: ▪ Describe the neuro-axis and name a representative disorder in each level of the axis ▪ Describe the diagnosis, management and expected course of five neuromuscular disease

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Neuro-axis

▪ Brain and brainstem (stroke) ▪ Spinal cord (cord compression) ▪ Anterior horn cells (amyotrophy lateral sclerosis) ▪ Nerve roots (Guillain-Barre syndrome - GBS) ▪ Plexus (lumbosacral plexopathy) ▪ Peripheral nerve (GBS, critical illness neuropathy) ▪ Neuromuscular junction (myasthenia gravis) ▪ Muscle (myositis, critical illness myopathy)

Neuromuscular Diseases

1. Guillain Barre syndrome

2. Critical illness neuropathy and myopathy

3. Inflammatory myopathies

4. Amytrophic lateral sclerosis

5. Myasthenia gravis

Guillain-Barre syndrome: Introduction

▪ Most common cause of acute or subacute flaccid weakness ▪ Monophasic (occurs once in lifetime and rarely recurs) ▪ “Ascending” weakness, usually with numbness and tingling ▪ Symptoms generally nadir within 4 weeks ▪ Risk of respiratory compromise during course of illness ▪ Treat with intravenous immunoglobulin (IVIg) or plasmapheresis ▪ May have prolonged disability

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Guillain-Barre syndrome: Epidemiology

▪ After eradication of polio, is now the most common cause of acute or subacute flaccid weakness worldwide ▪ 0.5-2 per 100,000 (lifetime risk 1/1000!) ▪ Men > women

Guillain-Barre syndrome: Clinical features

▪ Weakness and numbness in lower extremities, “ascending” ▪ 90% reach peak weakness by 4 weeks ▪ Neuropathic pain usually at lower back or thighs (66%) ▪ Cranial nerves weakness (50%) incl ophthalmoparesis (20%) ▪ Respiratory failure (30%) ▪ Autonomic involvement: tachycardia/bradycardia, hypertension/hypotension, urinary retention, gastric hypomotility ▪ Often with preceding illness (70% have respiratory illness or gastroenteritis within 10-14 days, most often Campylobacter) ▪ Neurological examination: extremities weakness, mild sensory changes, decreased reflexes (possible facial weakness)

Guillain-Barre syndrome: Variants

▪ Demyelinating types: ▪ Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) ▪ Most common type of GBS (85-90% of all cases) ▪ Miller Fisher syndrome – clinical triad of: ▪ Ophthalmoparesis/ophthalmoplegia ▪ Areflexia ▪ Ataxia ▪ Axonal variants: ▪ Acute motor axonal neuropathy (AMAN) – more in children ▪ Acute motor and sensory axonal neuropathy (AMSAN) – poor prognosis

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Guillain-Barre syndrome: Diagnosis

▪ Clinical presentation ▪ Lumbar puncture: cerebrospinal fluid (CSF) shows “albuminocytologic dissociation” ▪ MRI lumbar spine with and without contrast may show nerve root enhancement; helpful to exclude alternative diagnoses ▪ Electromyography and nerve conduction studies (EMG/NCS) – may show demyelination ▪ Differential diagnoses: ▪ Critical illness neuropathy and myopathy (based on history) ▪ Tick paralysis (more predominantly motor, normal CSF) ▪ Acute intermittent porphyria (usually with psych sxs, prior attacks) ▪ HIV infection (CSF with white blood cells)

Guillain-Barre syndrome: Management

▪ Intravenous immunoglobulin (IVIg) or plasmapheresis ▪ Monitor for respiratory failure, cardiac arrhythmias, autonomic dysfunction ▪ Frequent forced vital capacity and negative inspiratory force ▪ Neuropathic pain medication (e.g. gabapentin, pregabalin, tricyclic) ▪ Early physical therapy and occupational therapy

Guillain-Barre syndrome: Prognosis

▪ Mortality 3-7% (respiratory, autonomic failure, infection) ▪ Full recovery or minor deficits in 87% ▪ Residual bilateral foot drop (ankle-foot orthoses) ▪ Most recovery occurs over first year, but may occur up to >3 years ▪ May have residual numbness and pain, persistent fatigue ▪ Poor prognostic factors: ▪ Late age ▪ Preceding diarrhea or C. jejuni infection ▪ Need for intubation and ventilator support

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Guillain-Barre syndrome: Rehabilitation

▪ “Early rehabilitation intervention ensures medical stability, appropriate treatment and preventive measures to minimise long term complications. Specific problems include deep venous thrombosis prevention, complications of immobility, dysautonomia, de-afferent pain syndromes, muscle pain and fatigue. Longer-term issues include psychosocial adjustment, return to work and driving, and resumption of the role within the family and community. Effective communication between the GP and rehabilitation physicians is imperative for improved functional outcomes and successful social reintegration.”

Khan F. Rehabilitation in Guillian Barre syndrome. Aust Fam Physician. 2004 Dec;33(12):1013-7.

Critical illness neuropathy/myopathy: Introduction

▪ Causes of weakness and difficulty with weaning off mechanical ventilation in intensive care settings ▪ Subtypes: ▪ Critical illness neuropathy or polyneuropathy (CIN) ▪ Critical illness myopathy (CIM) ▪ Critical illness polyneuromyopathy (CIPNM) ▪ Early recognition may lead to earlier management and better outcomes

Critical illness neuropathy/myopathy: Epidemiology

▪ Prevalence depends on underlying disease and degree of involvement: ▪ E.g. multiorgan dysfunction - perhaps close to 100% ▪ E.g. sepsis/systemic inflammatory response syndrome – >70% ▪ E.g. status asthmaticus – 33% develop CIM

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Critical illness neuropathy/myopathy: Clinical feat.

▪ Weakness: ▪ CIM – proximal > distal weakness and atrophy (sensory spared) ▪ CIN - distal > proximal weakness, sensory changes and limited atrophy ▪ CIPNM – combination of proximal > distal weakness, distal sensory loss and variable atrophy ▪ Gradual loss of reflexes ▪ Respiratory failure, inability to wean from ventilator ▪ Secondary to ICU diagnoses, e.g. status asthematicus, sepsis, trauma ▪ Risk factors: systemic inflammatory response syndrome, multiorgan dysfunction, mechanical ventilation, possibly hyperglycemia (unclear if steroid use or neuromuscular blockade truly risk factors)

Critical illness neuropathy/myopathy: Pathophys.

▪ CIN – unclear mechanism, hypotheses include microcirculatory injury from systemic inflammation or vascular permeability ▪ CIM – myosin loss and contractile apparatus dysfunction ▪ Neurophysiological findings can be seen within hours of admission to ICU

Critical illness neuropathy/myopathy: Diagnosis

▪ Exclude neuromuscular causes e.g. GBS, Lambert Eaton, botulinum toxin, ongoing neuromuscular blockade (usually need EMG/NCS) ▪ Exclude non-neuromuscular causes e.g. primary pulmonary or cardiovascular, central nervous system ▪ Consider muscle biopsy if EMG/NCS difficult to interpret ▪ In CIP would show neurogenic changes ▪ in CIM would show myogenic changes (specifically loss of type 2 greater than type 1 muscle fibers)

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Critical illness neuropathy/myopathy: Management

▪ Modify the modifiable risk factors: ▪ Tight glucose control – only intervention with clear benefit ▪ Treat sepsis ▪ Immunotherapy not yet demonstrated to improve outcomes ▪ Early ICU mobility

Critical illness neuropathy/myopathy: Prognosis

▪ Results in increased length of stay, more ventilator-dependent days than without diagnosis ▪ May have worsened hospital mortality (conflicting data) ▪ May have ongoing noticeable weakness at time of discharge (20%) ▪ CIM has better prognosis than CIN; in one study: ▪ 11/12 of patients with CIM had complete recovery at 6 months ▪ Only 2/7 of patients with CIN/CIPNM had complete recovery ▪ Note conflicting data with another prior study ▪ Recovery can continue up to 24 months

Critical illness neuropathy/myopathy: Rehabilitation

▪ No randomized control trials, but it is thought that early ICU mobility can decrease length of stay ▪ One case series: ▪ Group A: 19 patients received 30 minutes a day x 5 days of PT Group B: 35 patients received intermittent PT ▪ Result: Group A, 32% discharged home; Group B, 11% ▪ Earlier mobility does not appear to change rate of ICU-acquired weakness ▪ Direct muscle stimulation x 30 minutes daily showed decreased loss of cross-sectional area of muscle mass

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Critical illness neuropathy/myopathy: Rehabilitation

▪ “There are no published RCTs or quasi-RCTs that examine whether physical rehabilitation interventions improve activities of daily living for people with CIP and CIM. Large RCTs, which are feasible, need to be conducted to explore the role of physical rehabilitation interventions for people with CIP and CIM.”

Mehrholz J, Pohl M, Kugler J, Burridge J, Mückel S, Elsner B. Physical rehabilitation for critical illness myopathy and neuropathy: an abridged version of Cochrane Systematic Review. Eur J Phys Rehabil Med. 2015 Oct;51(5):655-61. Epub 2015 Jul 9.

Inflammatory Myositis: Introduction

▪ Largest group of potentially treatable myopathies in adults and children ▪ Heterogeneous, with four subtypes: ▪ Dermatomyosits ▪ Polymyositis ▪ Necrotizing autoimmune myositis ▪ Inclusion-body myositis (IBM) ▪ All cause proximal weakness except IBM has special pattern ▪ All treated with immunotherapy except IBM (no treatment)

Inflammatory Myositis: Clinical features

▪ Proximal weakness (except IBM) – difficulty getting up from a chair, climbing steps, lifting objects, with eventual atrophy ▪ IBM: weakness in finger flexors, quadriceps and ankles (may also have facial weakness) ▪ May have head drop and dysphagia ▪ May have respiratory muscles in advanced cases ▪ Myalgia and muscle tenderness (especially with antisynthetase syndrome) ▪ No ocular involvement

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Inflammatory Myositis: Clinical features (con’t)

▪ Extramuscular manifestations: ▪ Systemic: fever, arthralgia, Raynaud’s ▪ Cardiac: arrhythmias, ventricular dysfunction ▪ Pulmonary: interstitial lung disease (especially with certain antibodies, namely anti-histidyl-tRNA synthetase (anti-Jo-1) or anti-melanoma differentiation associated protein ▪ Skin (in dermatomyositis) ▪ Malignancy (in dermatomyositis) ▪ Overlap myositis – antisynthetase antibodies

Inflammatory Myositis: Epidemiology

▪ Overall about 1 in 100,000 ▪ Dermatomyositis – about 1 in 50,000 ▪ Polymyositis – fluctuating prevalence due to misdiagnosis and recategorization, generally less than dermatomyositis ▪ Necrotizing autoimmune myositis – up to 19% of all inflammatory myopathies ▪ IBM – 50-70 per million

Inflammatory Myositis: Diagnosis

▪ Clinical history, tempo, muscle and extramuscular involvement ▪ Creatine kinase level (very high in necrotizing) ▪ EMG/NCS ▪ MRI (muscle edema/myofasciitis) ▪ Muscle biopsy ▪ Antibodies ▪ Dermatomyositis - Anti-Mi-2, anti-MDA-5, anti-TIF-1gamma, anti-NXP-2 ▪ Polymyositis - Anti-Jo in 75% of all antisynthetases in antisynthetase syndrome ▪ Necrotizing autoimmune myositis - SRP or HMGCR ▪ IBM - anti-cNA1

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Inflammatory Myositis: Pathophysiology

▪ Idiopathic, but presumed autoimmune ▪ Dermatomyositis – perifascicular, perimysial, perivascular inflammation ▪ Polymyositis – invasion of healthy muscle fibers

Inflammatory Myositis: Management

▪ Dermatomyositis, polymyositis, necrotizing autoimmune myositis ▪ Oral prednisone 1mg/kg up to 100mg daily ▪ If very weak at onset, intravenous methylprednisolone 1g daily x 3-5 days ▪ After 3-4 weeks, taper prednisone ▪ Steroid-sparing: azathioprine, mycophenolate, methotrexate or cyclosporine ▪ If with interstitial lung disease, consider cyclophosphamide or tacrolimus ▪ If dermatomyositis, consider topical steroids ▪ If steroids not helpful, consider intravenous immune globulin therapy (2g over 2-5 days) ▪ Inclusion body myositis: does not respond to immunotherapy (maybe because of amyloid aggregates)

Inflammatory Myositis: Rehabilitation

▪ Exercise generally does not worsen muscle inflammation ▪ Focus on non-fatiguing exercises with emphasis on endurance and aerobic exercises ▪ Passive movement of weak muscles may help prevent contractures ▪ IBM: ▪ Occupational therapy for finger flexion weakness ▪ May need ankle foot orthoses as disease progresses ▪ May need assistive devices ▪ Fall prevention

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Amyotrophic Lateral Sclerosis: Introduction

▪ Fatal neurodegenerative disease ▪ Genetic and possible environmental causes ▪ Incurable but important symptomatic strategies exist

Amyotrophic Lateral Sclerosis: Clinical features

▪ Painless progressive weakness ▪ Most commonly limb onset (20-30% bulbar onset) ▪ Combination of: ▪ Lower motor dysfunction – weakness, atrophy, fasciculations ▪ Upper motor dysfunction – spasticity, hyperreflexia ▪ Spread to adjacent limbs ▪ Diagnosis may be delayed by a year

Amyotrophic Lateral Sclerosis: Epidemiology

▪ Mean age of onset: 55 years old ▪ Incidence 5 per 100,000 in United States ▪ Cumulative lifetime risk of ALS is 1 in 300 or 1 in 400

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Amyotrophic Lateral Sclerosis: Diagnosis

▪ Exclude treatable causes and mimics: ▪ Nerve conduction studies and electromyography ▪ Ongoing and denervation changes in multiple levels (bulbar, cervical, thoracic, lumbar) ▪ Clinically definite, clinically probable, clinically possible, clinically suspected ▪ Lab work (controversy) ▪ MRI brain and cervical spine

Amyotrophic Lateral Sclerosis: Pathophysiology

▪ Degeneration of motor neuron cells in ▪ Spinal cord ▪ Cranial motor nuclei in brainstem ▪ Motor cortex ▪ Genetics: ▪ C9orf72 gene – 40% of all familial ALS, 10% of sporadic ALS ▪ SOD1 gene – first ALS gene discovered

Amyotrophic Lateral Sclerosis: Management

▪ Multidisciplinary care at dedicated center ▪ Physical therapy, occupational therapy, speech therapy, swallow studies, social work, palliative care, nursing, physician ▪ Medications: ▪ Riluzole – confer 2- to 3-month survival benefit – better with bulbar onset, younger at age onset, longer diagnostic delay ▪ Edaravone – intravenous; mortality benefit unclear ▪ Treat symptoms: ▪ Sialorrhea – amitriptyline, atropine eye drops, glycopyrrolate, scopolamine (botulinum toxin, salivary gland irradiation) ▪ Spasticity – stretching; baclofen and tizanidine ▪ Pseudobulbar affect – consider dextromethorphan/quinidine

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Amyotrophic Lateral Sclerosis: Management (con’t)

▪ Maintain weight (weight loss negative prognostic factor) – high calorie and protein-rich diets, nutritional shakes ▪ Medical alert systems ▪ Communication strategies – after verbal ability is lost, can use pen or eWriter, consider text to speech technologies and eyegaze augmentative communication strategies ▪ Noninvasive ventilation (start when forced vital capacity < 50% predicted) ▪ Initiate end-of-life decision making discussions early

Amyotrophic Lateral Sclerosis: Prognosis

▪ Median survival 20-48 months after symptom onset ▪ Quality-of-life discussions ▪ “Anchors” ▪ Noninvasive ventilation ▪ Feeding tube ▪ Palliative care ▪ Hospice care

Amyotrophic Lateral Sclerosis: Rehabilitation

▪ Types of exercises: ▪ Flexibility – prevent/manage contractures, reduce pain/spasticity ▪ Start early in disease course ▪ Strengthening – maintain muscle strength ▪ Do not exercise muscles that do not have antigravity strength ▪ Avoid high-resistance and eccentric exercises ▪ “Start low, go slow” ▪ Aerobic – reduce deconditioning, improve mood, sleep, quality of life ▪ Perform at moderate, sub-maximum level ▪ Patient should be able to talk comfortably while exercising ▪ Consider community-based programs e.g. adaptive golf

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Amyotrophic Lateral Sclerosis: Rehabilitation (con’t)

▪ “Despite the fatal outcome of the disease process, ALS multidisciplinary care is intrinsically “rehabilitative” where rehabilitation is defined as the process of assisting people to reach their fullest potential despite the presence of a disability. Therefore, in ALS, the goal… shifts from “cure” to “care”. The disease, while “incurable”, is clearly worth treating, and invites as much creativity as possible to enhance function throughout the course of a disease that is quite dynamic and diverse.”

Paganoni S, Karam C, Joyce N, Bedlack R, Carter G. Comprehensive Rehabilitative Care Across the Spectrum of Amyotrophic Lateral Sclerosis. NeuroRehabilitation. NeuroRehabilitation. 2015; 37(1):53–68.

Myasthenia gravis: Introduction

▪ Arguably best understood human autoimmune disease in terms of pathophysiology ▪ Characterized by fatigable weakness (may fluctuates by activity level and time of day) ▪ Treated with immunotherapy ▪ Great prognosis overall, but may need lifelong immunotherapy ▪ Myasthenic exacerbations may lead to respiratory failure (“myasthenic crises”)

Myasthenia gravis: Epidemiology

▪ Incidence 9-30 out of 1 million ▪ More women < 50, more men > 50 ▪ Ocular MG more common in prepubertal juvenile

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Myasthenia gravis: Pathophysiology

▪ Antibodies against neuromuscular junction ▪ Normally, nerve depolarization causes release of acetylcholine into synaptic cleft ▪ Acetylcholine binds to its receptor (AChR), opening AChR channels ▪ Cations go through AChR channels, causing muscle fiber action potential and eventual muscle movement ▪ Normally there is extra acetylcholine (and AChR) to make sure the process goes smoothly ▪ In MG, antibodies (most commonly AChR binding antibody) attack the AChR or its surrounding supportive structures, reducing the numbers ▪ When the system is stressed (patient is using muscles actively), it is overwhelmed and the muscle is clinically “fatigable” ▪ Antibodies may be secreted by thymoma in 10-20% of cases

Myasthenia gravis: Clinical features

▪ Weakness ▪ Proximal > distal ▪ Arms > legs ▪ Symmetric (asymmetric in 5%) ▪ Fatigable ▪ Dysphagia ▪ Fatigable dysarthria ▪ Fatigable weakness of chewing (jaw closure harder than jaw opening) ▪ Laryngeal involvement with stridor ▪ Neck weakness (flexor > extensor)

Myasthenia gravis: Diagnosis

▪ Exam: ▪ Upgaze for 60 seconds - watch for repeated blinking (looking for fatigable ptosis – usually occurs by 15-30 seconds) ▪ Cogan eyelid twitch sign (twitching of upper eyelid seen when eyes moved from downgaze to neutral position) ▪ Single breath count test (goal at least 20) – listen for fatigable dysarthria ▪ Weakness more in deltoids/triceps (myopathy more in deltoids/biceps) ▪ Ice pack test (2-5 minutes crushed ice in bag over ptotic eyelid) ▪ EMG repetitive stimulation, single fiber ▪ Acetylcholinesterase receptor antibodies

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Myasthenia gravis: Management

▪ Pyridostigmine ▪ Prednisone ▪ Azathioprine or mycophenolate ▪ Exacerbations or crises: IVIg or plasmapheresis ▪ Thymectomy

Myasthenia gravis: Prognosis and Rehabilitation

▪ Prognosis is overall excellent, although many patients need lifelong therapy ▪ Rehabilitation is important after exacerbation if involved prolonged ICU stay or ventilation

References

▪ Alexanderson H. Exercise in inflammatory myopathies, including inclusion body myositis.

▪ Dalakas MC. Inflammatory Muscle Diseases. Curr Rheumatol Rep. 2012;14(3):244-51. N Engl J Med. 2015 Jul 23;373(4):393-4.

▪ Donofrio PD. Guillain-Barré Syndrome. Continuum (Minneap Minn). 2017;23(5, Peripheral Nerve and Motor Neuron Disorders):1295-1309.

▪ Goutman SA. Diagnosis and Clinical Management of Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders. Continuum (Minneap Minn). 2017 Oct;23(5, Peripheral Nerve and Motor Neuron Disorders):13-1359.

▪ Mehrholz J, Pohl M, Kugler J, Burridge J, Mückel S, Elsner B. Physical rehabilitation for critical illness myopathy and neuropathy: an abridged version of Cochrane Systematic Review. Eur J Phys Rehabil Med. 2015 Oct;51(5):655-61. Epub 2015 Jul 9.

▪ Nicolle MW. Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome. Continuum (Minneap Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1978-2005.

▪ Paganoni S, Karam C, Joyce N, Bedlack R, Carter G. Comprehensive Rehabilitative Care Across the Spectrum of Amyotrophic Lateral Sclerosis. NeuroRehabilitation. NeuroRehabilitation. 2015; 37(1):53–68.

▪ Shepherd S, Batra A, Lerner DP. Review of Critical Illness Myopathy and Neuropathy. Neurohospitalist. 2017;7(1):41-48.

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