Chapter 6: Neuromuscular Diseases

Acute bilateral weakness can be due to either a central or peripheral lesion. When approaching such a patient, it is advisable to develop a methodology beginning with brain and spinal cord etiologies and moving peripherally, ruling out possibilities based on examination, imaging, and laboratory findings. The acuity of the presentation, symmetry, and pattern of weakness can be helpful. Generalized fatigue due to cardiopulmonary disease, anemia, malignancy, depression, and fibromyalgia, for example, can overlay objective muscle weakness. Similarly, pain can limit the motor examination. A broad overview of possibilities using the mnemonic VINDICATE is listed in Table 6-1.

The reflex examination can further assist with localization. Reflexes are brisk with central lesions of the brain and spinal cord, but can initially be absent or reduced with spinal cord lesions. Reflexes are preserved/normal with postsynaptic neuromuscular junction disease, but can be reduced with presynaptic disease. Reflexes are normal with myopathy. Fasciculations are specific to neuropathic disease.

Focusing on three common entities, a more specific differential diagnosis can be generated for each: myasthenia gravis, Guillain-Barré syndrome, and critical illness polyneuropathy/myopathy.

Myasthenia Gravis

1. Myasthenic crisis can present as a forme fruste of myasthenia gravis (MG). MG is an autoimmune disease of the neuromuscular junction characterized by a T-cell–dependent response targeted to the postsynaptic acetylcholine receptor or receptor-associated proteins. Weakness is confined to voluntary muscles (sparing smooth and cardiac muscles) and is variable in focus and degree. Breathing and swallowing may become significantly involved, with severe consequences leading to respiratory failure requiring mechanical intubation. Respiratory insufficiency due to MG is referred to as myasthenic crisis. It can begin with oropharyngeal weakness with or without appendicular symptoms and progress to crisis within hours to days, often in the context of infection or aspiration and occasionally following surgery. Half of patients with recently diagnosed MG will have a crisis within the first year and another 20% within the second year from diagnosis. Patients with long-standing MG are also at risk for crisis.

2. Cholinergic crisis can occur from excess acetylcholine esterase inhibitor. It is characterized by salivation, lacrimation, urination, diarrhea, gastrointestinal upset, and emesis (SLUDGE), miosis, bronchospasm, and flaccid weakness. Although a Tensilon (a solution of edrophonium chloride) challenge can distinguish cholinergic crisis from myasthenia, this test can be dangerous and often is not necessary.

3. Lambert-Eaton myasthenic syndrome is a presynaptic autoimmune attack of voltage-gated calcium channels, associated with cancer in 50% to 70% (typically small-cell lung cancer); limb symptoms more prominent than ocular/bulbar symptoms (5% with bulbar findings); facilitation with exercise; autonomic dysfunction; reduced reflexes; and respiratory failure uncommon.

4. Botulism is caused by a neurotoxin produced by Clostridium botulinum that permanently blocks presynaptic acetylcholine release at the neuromuscular junction. It is characterized by symmetric descending paralysis with dilated pupils (50%) and dysautonomia but no sensory deficit. It can be treated with trivalent equine antitoxin.

5. Tick paralysis results in presynaptic neuromuscular blockade. Associated ticks include Rocky Mountain wood tick, American dog tick, Lone Star tick, black-legged tick, Western black-legged tick, Gulf Coast tick, and Australian Ixodes holocyclus tick. It typically can present as ascending paralysis, ophthalmoparesis, bulbar dysfunction, ataxia, and reduced reflexes. It has a rapid course of progression (hours to days) and is accompanied by ataxia, but no sensory symptoms.¹ Complete cure can occur with tick removal.

6. Snake venom from the tiger snake, taipan snake, and Brazilian rattlesnake causes presynaptic blockade; and postsynaptic blockade is caused by alpha-bungarotoxin from the venom of kraits and is also due to the venom of cobras, mambas, coral snakes, and sea snakes. Other snakes with venom affecting the neuromuscular junction include copperheads, cottonmouths, moccasins, rattlesnakes, vipers, adders, boomslangs, and twig snakes. Snake venom initially affects cranial nerves resulting in ptosis, ophthalmoplegia, dysarthria, and dysphasia followed by progressive limb weakness.

7. Organophosphate toxicity. Organophosphates (eg, malathion, parathion, sarin, soman) inactivate acetylcholine esterase causing SLUDGE, miosis, bronchospasm, blurred vision, and bradycardia. It is characterized by confusion, optic neuropathy, extrapyramidal effects, dysautonomia, fasciculations, seizures, cranial nerve palsies, and weakness due to continued depolarization at the neuromuscular junction. Delayed polyneuropathy can occur 2 to 3 weeks after exposure. It is treated with atropine, pralidoxime (2-PAM), and benzodiazepines. Succinylcholine should be avoided.

8. Guillain-Barré syndrome can present with areflexia and ophthalmoplegia (Miller-Fisher variant) or ascending weakness, facial weakness, diplopia, and areflexia. It is often demyelinating, but can be axonal. Early loss of F waves is seen on electromyography (EMG). It is treatable with plasmapheresis or IV immunoglobulin.

9. Neurotoxic fish poisoning is caused by tetrodotoxin (from the puffer fish) and saxitoxin (from the organisms that cause red tide), both of which block neuromuscular transmission. Ciguatera toxin (from red snapper, grouper, barracuda) affects voltage-gated sodium channels of muscles and nerves and produces a characteristic metallic taste in the mouth and hot-cold reversal.

10. Diphtheria, caused by Corynebacterium diphtheriae, is associated with a thick gray pharyngeal pseudomembrane, atrioventricular (AV) block, endocarditis, myocarditis, lymphadenopathy, neuropathy with craniopharyngeal involvement, proximal to distal weakness, and decreased reflexes.

Guillain-Barré Syndrome

1. GBS is a heterogeneous group of immune-mediated polyneuropathies with motor, sensory, and dysautonomic features. It is the most common cause of acute flaccid paralysis in the United States with a frequency of 1 to 3 per 100,000 people and occurs in all age groups. The pathophysiology of GBS is thought to be related to molecular mimicry triggered by recent infection producing an autoimmune humeral- and cell-mediated response against the ganglioside surface molecules of peripheral nerves. A typical history involves acute symmetric ascending weakness, often beginning in the proximal legs. Weakness beginning in the arms or face occurs in 10%, but eventually 50% of patients have facial or oropharyngeal weakness. Paresthesias in the hands and feet are reported in 80% of patients, as is lower back pain. Diplopia occurs in 15% due to oculomotor weakness. Dysautonomia occurs in 70% (tachycardia/bradycardia, wide swings in blood pressure, orthostasis, tonic pupils, urinary retention, ileus/constipation, hypersalivation, and anhidrosis). Respiratory failure requiring intubation occurs in 30% (Table 6-2)

2. Polyneuropathies include the following:

   • Acute motor neuropathies due to arsenic, lead poisoning, or porphyria.

   • N-hexane (glue sniffing).

   • Peripheral nerve vasculitis (presents as, eg, mononeuritis multiplex and can be due to polyarteritis nodosa, Churg-Strauss syndrome, rheumatoid arthritis, lupus).

   • Neuropathy due to Lyme disease, sarcoidosis, paraneoplastic disease, and critical illness polyneuropathy.

   • Diphtheria, caused by Corynebacterium diphtheriae, is associated with a thick gray pharyngeal pseudomembrane, AV block, endocarditis, myocarditis, lymphadenopathy, neuropathy with craniopharyngeal involvement, proximal to distal weakness, and decreased reflexes.

   • Ciguatera toxin (red snapper, grouper, barracuda) affects voltage-gated sodium channels of muscles and nerves and produces a characteristic metallic taste in the mouth and hot-cold reversal.

3. Neuromuscular junction disease. There is no sensory involvement in any disorder of neuromuscular transmission. This group of diseases includes the following:

   • MG

   • Lambert-Eaton myasthenic syndrome

   • Botulism

   • Organophosphate toxicity. Delayed polyneuropathy can occur 2 to 3 weeks after exposure. Treat with atropine, pralidoxime (2-PAM), and benzodiazepines. Avoid succinylcholine.

   • Neurotoxic fish poisoning. Caused by tetrodotoxin (from puffer fish), and saxitoxin (from organisms that cause red tide), both of which block neuromuscular transmission.

4. Muscle disorders. Critical illness myopathy and acute polymyositis can mimic GBS. Can differentiate with EMG/nerve conduction study (NCS).

5. Spinal cord disorders. Acute myelopathy can cause weakness, numbness, and acutely depressed deep tendon reflexes along with bowel and bladder dysfunction. Back pain is common in GBS and spinal cord disorders. Magnetic resonance imaging (MRI) can easily distinguish between the two (enhancement of nerve roots can occur with GBS).

6. Brainstem disease with multiple cranial neuropathies (stroke, Bickerstaff-Cloake brainstem encephalitis, rhombencephalitis, basilar meningitis, carcinomatous meningitis, Wernicke encephalopathy).

Critical Illness Polyneuropathy/Myopathy

1. Critically ill patients are at risk for developing severe weakness secondary to critical illness polyneuropathy (CIP) and/or critical illness myopathy (CIM). Weakness may progress to severe quadriparesis and muscle wasting.² The incidence of CIP/CIM in critically ill patients has been reported as 33% to 44% of patients with prolonged admission to critical care settings. The incidence increases to nearly 70% when considering only patients with sepsis.^2-6

2. GBS. Coincidental occurrence of GBS in a critically ill patient is relatively rare. However, if the history is suspicious, a lumbar puncture can be done (best yield is 1 to 2 weeks from symptom onset). Elevated protein without elevation in leukocytes would be suspicious for GBS. Cerebrospinal fluid (CSF) studies should be normal in CIP/CIM.

3. Cachetic myopathy. Critically ill patients can develop a subacute myopathy due to protein catabolism and disuse. Patients develop weakness and muscle atrophy. Type II muscle atrophy is seen histologically.

4. Spinal cord lesions. A lesion to the cervical spinal cord can result in tetraparesis and should be considered if the clinical setting is appropriate. Lesions in the cord can initially cause flaccid paresis with decreased reflexes, followed subacutely by hyperreflexia and increased tone. A sensory level may be evident in a patient who is able to participate in a sensory examination. If the history or examination is suspicious, an MRI of the cervical cord with and without contrast may be appropriate.

5. Underlying neuropathy. Toxins and medication effects: Often medications used in the intensive care unit (ICU) (ie, neuromuscular-blocking agents) can result in prolonged weakness and sedation. An NCS may help in this case. For patients who have been treated with neuromuscular-blocking agents, “a train of four” (slow repetitive stimulation at 2 to 3 Hz at the median or ulnar nerve) may be used to determine if the medication's effect is persisting.

Electrophysiology

An electrophysiology examination consists of NCSs, needle EMG, and neuromuscular junction testing. Frequently, the EMG is not particularly useful for the first few weeks after symptom onset and many practitioners will wait at least 3 weeks prior to performing a needle study.

However, NCS examination can provide some insight early in the disease course. The NCS consists of peripheral motor nerve compound muscle action potential (CMAP) and sensory nerve action potential (SNAP). Decreased nerve conduction amplitude implies an axonal process, while slowed conduction velocities, distal latencies, temporal dispersion, and conduction block indicate a demyelinating process.

Late responses, F and H waves, can add additional information to the NCS. F waves represent the very proximal portion of the nerve and are generated by supramaximal stimulation of a motor nerve while recording over a muscle. An H reflex is typically a tibial reflex (patellar reflex arc) and represents the sensory and motor nerves of the entire reflex arc. Both amplitude and latency are measured bilaterally and greater than 50% difference between side-to-side amplitudes is considered abnormal.

The needle examination assesses muscle activity at rest, with mild voluntary contraction, and with maximal voluntary muscle contraction. During the needle examination the practitioner assesses for:

1. Insertional activity (increased in denervated muscle, decreased when muscle is replaced by fat or connective tissue)

2. Spontaneous activity (fibrillation potentials and sharp waves suggest recent denervation or muscle necrosis)

3. Recruitment (reduced recruitment with rapid firing occurs when there is damage to the axon, neuron, or when a large number of motor units are lost. Poor activation occurs with central disorders when there is a decreased number of motor units recruited and firing is slow. Early recruitment occurs in the context of myopathy.)

4. Motor unit potential duration (long duration is seen with lower motor neuron disorders, while short-duration motor units are common with myopathies, but may be seen in neuromuscular disorders and the early phases of reinnervation after neuropathy)

5. Motor unit potential amplitude (long-duration, high-amplitude motor units are seen with chronic neurogenic disorders, while small-amplitude, short-duration motor units are common to myopathic disorders)

6. Motor unit polyphasia (five or more phases constitute polyphasia, which can be seen in both myopathic and neurogenic disorders)

Electrophysiology, CSF, imaging, and serologic studies for MG, GBS, CIP/CIM are listed in Tables 6-3 and 6-4.

Direct muscle stimulation (DMS) has been suggested as a technique to differentiate CIP and CIM in patients who cannot generate a motor unit owing to extreme weakness or altered mental status.⁷ Comparing CMAP amplitudes generated by motor nerve stimulation to CMAP amplitudes generated by direct muscle stimulation can help identify a myopathy as opposed to an isolated neuropathy. CMAP amplitudes derived from DMS may be inexcitable (absent) or decreased (less than 2 mV) in CIM,⁸ while they remain normal in isolated CIP. When neuropathy alone is present, CMAP amplitudes produced by muscle stimulation are normal, but CMAP amplitudes produced by nerve stimulation are small. When CMAP amplitudes are low for both nerve and muscle stimulation, a myopathy is present and, thus, the ratio of nerve-evoked CMAP to muscle-evoked CMAP amplitude is greater than 0.5. When CIP is present alone, a ratio of nerve-evoked CMAP to DMS CMAP would be less than 0.5.

The risk factors for MG, GBS, and CIP/CIM are given in Table 6-5.

Consider intubation early. MG and GBS patients can deteriorate rapidly. Check vital capacity (VC) and negative inspiratory force (NIF). If VC is less than 10 to 15 mL/kg or less than 1 L and/or the NIF is weaker than –20 cm H₂O or rapidly worsening, the patient should be intubated. Beware that patients with bulbar dysfunction often cannot form a proper seal for respiratory testing and results can sometimes appear worse than the patient's true respiratory status. Multiple VC/NIF measurements should be made to capture the patient's best effort. Poor pulmonary function assessment: Ask the patient to count as rapidly and as high as he/she can in one breath. Every 10 numbers counted roughly equates to 1 L of VC. If the patient cannot count to 10, intubation should be pursued. Similarly, oxygen saturation can be falsely reassuring. Most patients retain Co₂ prior to becoming hypoxia. Hypoxia is a late sign of respiratory failure in neuromuscular disease. If the patient is already hypoxic, the physician should proceed to intubation without delay. Patients with myasthenic crisis and many GBS patients should be monitored in an ICU setting (Tables 6-6 and 6-7).

Every day of strict bed rest leads to a 1% decline in muscle strength.⁹ Casting can lead to a 25% decline in muscle strength within 7 days.¹⁰ As assessed by MRI or computed tomography (CT), muscle mass decreases by 1.5% to 2.0% per day after 2 to 3 weeks of bed rest.¹¹ A decrease in the size of muscle fibers is primarily responsible for this decrease in mass.¹² The underlying mechanisms of muscle atrophy and fiber injury are due to oxidative stress, down regulation of protein synthesis, and activation of calpain, caspase, and ubiquitin, which are involved in degradation of contractile fibers.¹³ Mobility therapy has been shown to prevent muscle degeneration in healthy volunteers randomized to receive bed rest with or without resistance exercise training. Healthy volunteers who did not participate in an exercise regimen had a significant decrease in muscle protein synthesis as measured by needle biopsy after infusions of radiolabeled phenylalanine.¹⁴ Early mobility of ICU patients (including patients who were sedated and received passive stretch therapy) has been shown to shorten ICU and hospital length of stay, improve functional outcomes, and reduce delirium.^15,16 Based on histologic data,¹⁷ passive stretching alone decreases muscle atrophy.

Diaphragm weakness and dysfunction are very common in patients receiving mechanical ventilation due to the same mechanisms described above.^18-20 Strategies for expedited liberation from the ventilator have been suggested by the Centers for Disease Control and Prevention (CDC) and the Institute for Healthcare Improvement and Joint Commission.²¹ Two major components of this strategy include daily sedation vacation and assessment for readiness to wean. Daily sedation interruption has been shown to reduce the duration of mechanical ventilation and length of stay in the ICU.²² Daily spontaneous breathing trials or pressure support (PS) trials have also been shown to reduce the duration of mechanical ventilation.^23,24 Conversely, the use of a controlled mechanical ventilation mode, which does not allow for any patient respiratory effort, has been shown to cause muscle atrophy and severe diaphragm weakenss.^25,26 In animal models, PS ventilation has been shown to reduce mechanical ventilation–induced proteolysis and diaphragm weakness.²⁷ The coupling of sedation vacation and spontaneous breathing trials resulted in a shorter duration of mechanical ventilation, shorter ICU length of stay, and lower mortality rate in the Wake Up and Breathe Trial.²⁸

Most ICUs use a PS mode for weaning. Although this mode, adjusted to a respiratory rate less than 25 breaths/min, was found to be inferior to a once-daily T-piece trial in one randomized study²³ a separate randomized trial found that a PS mode titrated to a respiratory rate less than 35 breaths/min was superior to T-piece trials in regard to reduction in mechanical ventilation time.²⁹ A meta-analysis revealed that both PS and T-piece modes are similar in time to ventilator liberation, but synchronized intermittent mechanical ventilation (SIMV) mode appears to be the worst method of mechanical ventilation weaning.^24,30 A PS mode may be safer than a T-piece mode because most ventilators provide back-up ventilation in patients who become apneic or fail their spontaneous breathing trial.

There is a paucity of literature addressing ventilation weaning in patients who undergo tracheotomy. Although early tracheotomy in a select group of patients projected to require mechanical ventilation for more than 14 days has been shown to reduce mortality rate, pneumonia, mechanical ventilation time, and ICU length of stay,³⁷ there have been no studies addressing weaning strategies in tracheotomized patients. Most studies address extubation and require patients to either be noncomatose and/or able to clear their secretions prior to extubation. Most neurointensivists extrapolate from published weaning trials when addressing liberation from the ventilator in patients who have undergone tracheotomy. This means that even patients who are projected to undergo tracheotomy (owing to mental status or weakness) should undergo daily sedation vacation and spontaneous breathing trials. Daily spontaneous breathing trials may reduce diaphragm and muscle atrophy and allow patients to wean off the ventilator more rapidly than patients who are not afforded daily weaning trials.

Myasthenic Crisis

Mortality rate from myasthenic crisis is less than 5%; however, the mean duration of mechanical ventilation is 2 weeks. Predictors for prolonged mechanical ventilation and ICU/hospital length of stay include preintubation HCO₃ greater than or equal to 30 mL/dL, peak VC on days 1 to 6 postintubation of less than 25 mL/kg, and age older than 50 years. The need for more than 2 weeks of mechanical ventilation per number of risk factors is: 0/3 = 0%, 1/3 = 21%, 2/3 = 46%, 3/3 = 88%.²

GBS

The course of GBS is usually progressive for the first 2 weeks of illness, followed by 2 to 4 weeks of a plateau phase, and then a recovery phase. Disease progression for more than 8 weeks is consistent with the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Poor prognostic factors include older age, rapid onset, preceding diarrheal illness, respiratory failure, and distal CMAP amplitudes less than 20% of normal. Overall, 85% of GBS patients achieve a full functional recovery within 6 to 12 months. The mortality rate is generally less than 5%, but up to 15% of patients may have neurologic sequelae. Of those who become ventilator-dependent, the mortality rate is 20%. Outcome depends on the GBS variant. Patients with acute idiopathic demyelinating polyneuropathy (AIDP) typically do better than axonal variants, with remyelination occurring over several weeks to months. In a small fraction of AIDP patients there is superimposed axonal degeneration leading to incomplete or delayed recovery. Relapses occur in up to 10% of GBS patients, and 2% of patients develop CIDP.

CIM/CIP

Patients with CIP/CIM may be more difficult to wean from mechanical ventilation and require prolonged rehabilitation. The mortality rate of patients with CIP has been reported as ranging from 26% to 71% and may be significantly higher than for patients with similar underlying illness without evidence of CIP.^4,5 Patients who survive their underlying illness may recover some strength within weeks to months; however, many may have residual functional deficits. In one review, 68.4% of patients discharged from the ICU with CIP/CIM regained the ability to breathe and walk independently, while 28.1% had persistent severe disability.⁵