Neuromuscular disorders are diseases that affect the peripheral nervous system in any location from the anterior horn cells in the spinal cord, peripheral nerves, neuromuscular junction (NMJ), to the muscles. Identifying and treating neuromuscular disorders is of special concern for hospital providers, as patients with these conditions may develop acute episodes of generalized weakness, leading to respiratory failure and difficulty weaning from mechanical ventilation. The following discussion will focus on identification and management of various neuromuscular disorders. Additional discussion of classification and localization will enable providers to better diagnose the disease process. The remainder of the chapter will focus on causes of acute weakness and management of these disorders in acute and hospital settings.

Neuromuscular disorders are diseases that affect the peripheral nervous system. These disease states can affect any location from the anterior horn cells in the spinal cord, peripheral nerves, neuromuscular junction (NMJ), to the muscles.

Motor neuron disorders (MND)

MNDs are a group of progressive disorders caused by dysfunction of the anterior horn cells. Motor neurons are necessary in controlling voluntary muscle activity including speaking, swallowing, breathing, and ambulation. MNDs occur in both adults and children, and may be present at birth in children with inherited or familial forms of the disease. Although some forms of MNDs are inherited, the majority are sporadic. MNDs are often classified as to whether they lead to dysfunction of upper motor neurons (UMNs), lower motor neurons (LMNs), or both.

Acquired disorders of the lower motor neuron include poliomyelitis and West Nile virus infection. Most patients who are infected with these viruses are usually asymptomatic; however, a minority will develop neurological involvement. Patients may present with nonspecific symptoms such as headache, myalgias, malaise, and sore throat. A select number of patients with poliomyelitis develop severe neck, back and muscle pain along with asymmetric muscle weakness and atrophy. West Nile virus can lead to neuroinvasive disease causing encephalitis picture with acute asymmetric flaccid paralysis. Patients may also develop tremor and Parkinsonian features such as rigidity and bradykinesia.

The most common MND in adults is amyotrophic lateral sclerosis (ALS), which affects both UMN and LMN. Primary lateral sclerosis selectively affects only UMN. LMN-predominant disorders include progressive muscular atrophy, progressive bulbar palsy, and spinobulbar muscular atrophy (Kennedy disease). Presenting in infancy or childhood, spinal muscular atrophy (SMA) is caused by degeneration of LMN secondary to defects in gene SMN1, leading to muscle wasting and skeletal muscle weakness. Although genetic testing is available for SMA, no specific testing is available to diagnose most MNDs, although electrodiagnostic testing is often useful.

Neuropathy

Peripheral nerves include cranial nerves (excluding cranial nerves I and II), spinal nerve roots, dorsal root ganglia, peripheral nerve branches, and the autonomic nervous system. Damage to peripheral nerves can occur at the level of the axon or myelin sheath. In generalized polyneuropathies, disruption of the axon leads to degeneration of the axon distal to the injury site in a length-dependent manner, in turn leading to sensory symptoms involving the tips of the toes progressing proximally, with distal more than proximal weakness. Peripheral neuropathies can be caused by a number of underlying conditions and are most commonly secondary to vitamin B12 deficiency, alcohol abuse, and diabetes mellitus.

Acquired demyelinating neuropathies may be classified as acute (Guillain–Barré syndrome [GBS]) and chronic (in the case of chronic inflammatory demyelinating polyradiculoneuropathy [CIDP]). Multifocal causes of neuropathies include diabetes mellitus, vasculitis, multifocal motor neuropathy with conduction block (MMNCB), sarcoidosis, leprosy, and HIV.

Damage that occurs to the myelin sheath in neuropathies can be inflammatory or hereditary. Hereditary neuropathies (such as Charcot–Marie–Tooth disease) are more slowly progressive with diffuse involvement of myelin. Electromyography (EMG) and nerve conduction studies (NCSs) can be used to confirm the presence of neuropathy and differential type of fiber involvement (ie, axonal versus demyelinating).

Neuromuscular junction (NMJ) disorders

NMJ disorders characteristically present with fluctuating weakness. These disorders can be classified into congenital, toxic (botulism), metabolic, and immune-mediated (myasthenia gravis [MG] and Lambert–Eaton myasthenic syndrome [LEMS]). Disorders of the NMJ junction preferentially affect proximal, bulbar, or extraocular muscles. Involvement of respiratory musculature can also occur, leading to respiratory failure. Diagnostic evaluation may include nerve conduction studies (NCS), repetitive stimulation, and single-fiber EMG.

Myopathy

In myopathies, dysfunction of muscle fibers causes weakness. Muscle pain or myalgias may also occur. Myopathies can be classified into inherited or acquired. Inherited forms of myopathy include muscular dystrophies, congenital myopathies, mitochondrial myopathies, and metabolic myopathies. Acquired myopathies include inflammatory and toxic myopathies. Laboratory testing including creatine kinase (CK) level, genetic testing, EMG, and muscle biopsy may be useful in determining the cause of the myopathy. Treatment is dependent on etiology and may range from supportive measures to targeted therapy.

UMNs run from cell bodies in the frontal lobe and descend in the ventral aspect of the brainstem and in the corticospinal tracts in the spinal cord, eventually synapsing on anterior horn cells. Central disease states can be secondary to demyelination, space-occupying lesions, trauma, infections, or spinal cord lesions. In the case of cerebral lesions, these disorders often demonstrate other signs of cortical disease such as aphasia, visual loss, sensory loss, or lateralizing weakness. On examination, UMN signs such as spasticity, hyperreflexia, and Babinski sign may be seen.

LMNs originate in the anterior horn cells of spinal cord (exception being cranial nerves) and terminate in the neuromuscular junction. The examination in LMN diseases discloses hypotonia, hyporeflexia, and muscle atrophy. Other signs of LMN disease include fasciculations, which are characterized by fine movements of the muscle under the skin. Fasciculations are caused by denervation of motor units, leading to acetylcholine hypersensitivity at the motor endplate. Atrophy of the affected muscle usually occurs simultaneously with fasciculations.

Signs of both UMN and LMN may be seen in diseases of the spinal cord. Although UMN is involved in the case of spinal shock, patients may present with LMN signs of hypotonia, with UMN signs developing later on.

Weakness is a common complaint in the setting of neurologic evaluation. Complaints of weakness can occur on any level of the motor system from the cortex to muscle fibers, from dysfunction of the central or peripheral nervous system. Causes of generalized weakness can range from disuse atrophy from prolonged immobilization to motor neuron disease. Establishing the distribution of weakness on examination can provide key clues to localizing the lesion and differentiating the disease state (Table 16-1).

Weakness confined to specific muscle groups can be classified as asymmetric or symmetric.

Asymmetric weakness

Examples of asymmetric causes of weakness include: cerebrovascular or spinal cord disease, mononeuropathy multiplex, compressive neuropathy, demyelinating disorders, and disuse atrophy.

Symmetric weakness

Symmetric weakness can be further classified as distally or proximally predominant. With distal weakness, decreased grip strength, weakness of wrist flexion or extension, decreased foot and toe dorsiflexion, and plantar flexion strength are seen. Patients often complain of difficulty closing or opening jars, and foot drop. Distal motor weakness is more commonly seen in early motor neuron disease or peripheral neuropathy.

Proximal weakness affects axial muscle groups, including the shoulder and hip girdle muscles. Patients may complain of difficulty holding their head up and demonstrate weakness while flexing or extending the neck against resistance. Additional clues such as difficulty climbing stairs, arising from a chair, combing hair, or lifting objects above the head may be seen. Conditions leading to proximally predominant weakness include botulism, most types of myopathy, and MG.

History⁷

The clinical history is of the utmost importance in providing clues toward diagnosis. Important questions to consider during history of suspected neuromuscular disorders should include history of preexisting neuromuscular or systemic disorders, dietary profile, and potential exposure to drugs or neurotoxins. In critically ill patients with severe weakness, considering systemic causes is especially important. Patients with history of sepsis, asthma, pneumonia, and multiorgan failure are more prone to critical illness polyneuropathy and critical illness myopathy.

Specific questions based on disease entity are as follows.

Peripheral neuropathy

History of recent vaccine or viral illness may occur in setting of GBS.

Dietary factors and drug exposure are important to ask as patients with botulism may have history of consuming home-canned goods. Shellfish consumption may lead to acute-onset weakness from saxitoxin. Arsenic intoxication can cause peripheral nerve toxicity associated with encephalopathy. Those who rely on well water may be at risk for arsenic poisoning. The diagnosis of tick paralysis should be considered in a patient with recent woodland exposure.

Motor neuron disease

History of muscle cramping, fasciculation, wasting, dysphagia, dysarthria, or pre-existing muscle weakness may point toward motor neuron disease. Rarely, a family history of motor neuron disease is present.

Neuromuscular disorders

A history of ptosis and diplopia may be suggestive of MG. Patients may report weakness that worsens as the day progresses. Difficulty chewing, speaking, or swallowing may also be present, and should clue the provider into MG as a possible diagnosis.

Inquiring about a prior history of episodes of weakness is also important; patients with MG might experience worsening of symptoms in the setting of systemic illness. Additionally, familial periodic paralysis and inborn errors of glycogen and lipid metabolism should be considered in patients with prior history of episodic weakness.

Myopathy

Asking about drug exposure is imperative for patients presenting with myopathy, as the symptoms may be secondary to a number of drugs including statins, colchicine, chloroquine, and cyclosporine.

Physical examination^8,9

Respiratory status

Neuromuscular disorders such as MG, GBS, ALS, and certain myopathies may lead to impaired ventilation and hypercapnic respiratory failure. Involvement of neck muscles on neck flexion and weakness of infraspinatus correlate with diaphragmatic paralysis from phrenic nerve involvement. Decreased tongue movement, weakness during cough, and weak pharyngeal muscles point to impairment in protecting the airway.

Mental status

Severe weakness can lead to mental status changes due to a variety of causes. In patients with diaphragmatic weakness, CO₂ retention may lead to encephalopathy. Patients with myopathies due to electrolyte disturbances (alterations in glucose, sodium, potassium, or calcium) can develop mental status changes ranging from lethargy to coma. In patients presenting with myopathies and mental status changes, evaluating for electrolyte abnormalities is recommended.

Cranial Nerves

The finding of diplopia on examination points to neuromuscular junction defect, after CNS pathology is ruled out. Diplopia and ptosis is a common physical finding with MG, occurring in up to 50% of patients. Dysarthria may suggest motor neuron disease such as amyotrophic lateral sclerosis and is also frequently seen in MG. Myopathies and GBS can also present with dysarthria and eye movement abnormalities, although seen less frequently. Facial weakness may be seen in patients with MG, botulism, GBS, and certain myopathies (eg, facioscapulohumeral dystrophy [FSHD]).

Motor examination

Motor examination should include assessing tone, muscle bulk, and muscle strength. Any involuntary movements should be taken note of, such as tics, tremors, or fasciculations. The presence of fasciculations may suggest lower motor neuron involvement and is seen in ALS.

Distribution of muscle weakness is an important localizing finding and is discussed above in “distribution of weakness.” Briefly, proximal symmetric weakness is consistent with a myopathy or neuromuscular junction disorder. Repetitive movements may increase the weakness in MG (fatigable weakness). Distally predominant weakness is typically seen in generalized polyneuropathies (though is usually diffuse in GBS).

Evaluation should also include understanding whether the weakness is occurring in an ascending or descending pattern. GBS and tick paralysis (from Dermacentor ticks) are characterized by an ascending pattern weakness, while weakness in botulism occurs in a descending pattern.

Sensory examination

Sensory loss may be due to disorders of the central or peripheral nervous system. The sensory examination includes testing for pain sensation (pin prick), light touch sensation, and position sense. Identifying the distribution of sensory loss is important in localization.

If sensory loss is seen bilaterally, polyneuropathies and spinal cord disease should be considered. Polyneuropathies can be caused by various diseases, illnesses, or drugs. Sensory loss in a stocking-glove pattern is characteristic of a length-dependent axonal neuropathy such as diabetes. Asymmetric sensory loss is seen with involvement of individual peripheral nerves as may occur in mononeuritis multiplex.

Reflexes

Examining muscle stretch reflexes can help in determining a central versus peripheral cause. Exaggerated reflexes suggest an UMN lesion as can be seen with disorders of the central nervous system (eg, spinal cord compression) or in ALS. The loss of reflexes suggests a neuropathic lesion affecting either sensory or motor fibers (eg, in GBS). Reflexes are generally preserved in muscle disease unless it is severe. In MG, reflexes are preserved, while in Lambert–Eaton myasthenic syndrome (LEMS), reflexes are reduced or absent.

Laboratory evaluation

For patients who present with generalized weakness, electrolyte testing is mandatory. Hyper- or hypokalemia, hypermagnesemia, and hypophosphatemia can all lead to severe, generalized weakness. In addition, generalized weakness may also be seen in patients with severe hypo- or hyperglycemia.

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  Suspected peripheral nerve disease

  
  
  
  
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    Testing of complete blood count, glucose level, glycated hemoglobin (HbA1C), serum and urine protein electrophoresis, antinuclear antibody levels, VDRL/RPR, vitamin B12 and methylmalonic acid level, renal and hepatic function tests, and sedimentation rate is advised. HIV testing may be warranted given a patient’s risk factors.

    
    
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    CSF analysis may enable diagnosis of patients with presumed GBS.

    
    
    
    
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      CSF analysis shows elevated protein with normal cell count, referred to as albumin-cytologic dissociation.

      
      
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      In myelitis, CSF analysis may reveal high protein, although in half of patients the protein levels are normal.

    
    

  
  
  
  
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  Neuromuscular junction disorders

  
  
  
  
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    Botulism

    
    
    
    
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      Confirmation includes serum findings of botulism toxin in serum, stool of patient, or food recently consumed.

      
      
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      CSF findings are normal.

    
    
    
    
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    MG

    
    
    
    
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      Anti-acetylcholine receptor (AchR) antibody testing has a high specificity and is positive in up to 85% of patients with generalized MG.

      
      
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      Anti-MuSK antibody is detected in up to half of myasthenia patients without AchR antibodies.

      
      
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      Other antibody testing includes antistriated muscle antibody and antistriational antibody present in a majority of patients with MG and thymoma.

      
      
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      It is important to check thyroid function studies in patients with suspected myasthenia as well as dysthyroid disease, which often co-occurs and, if untreated, can aggravate symptoms.

    
    

  
  
  
  
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  Muscle disease

  
  
  
  
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    Serum creatine kinase (CK) is a sensitive marker for muscle damage and is the most commonly used enzyme in diagnosis and course of muscle disease. CK is increased in primary muscle disease, with levels of >10,000 U/L seen in rhabdomyolysis and acute necrotizing myopathy.

    
    
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    In patients with history of periodic paralysis with worsening weakness, immediate potassium level should be drawn. Those with hypokalemic periodic paralysis often have potassium values less than 3.0 mEq/L.

    
    
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    Other blood tests important in evaluation of myopathy are aldolase, AST, ALT, and LDH.

  
  

Imaging

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  In patients presenting with acute onset of weakness, imaging of the brain and spinal cord may be performed to rule out central nervous system (CNS) pathology.

  
  
  
  
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    Bilateral lower extremity weakness warrants magnetic resonance imaging (MRI) of the spine (with and without gadolinium), to rule out spinal cord compression. Although the sensitivity of MRI is superior to CT, in patients unable to undergo MRI, CT myelogram is an option.

  
  
  
  
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  Myasthenia gravis

  
  
  
  
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    Plain chest radiographs may identify a thymoma as an anterior mediastinal mass.

    
    
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    Chest computed tomography or MRI is used to rule out thymoma or thymic enlargement in all cases of MG.

    
    
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    MRI of the brain and orbitis used to evaluate for mass lesions compressing the cranial nerves or a brainstem lesion, which may be mistaken for ocular MG.

  
  

Electrophysiologic testing^7,10–18

Electrodiagnostic testing provides valuable information aiding in establishing diagnosis and localization of disorders of the peripheral nervous system. Routine electrophysiologic testing can be achieved in a reliable fashion for ICU patients using portable equipment, although it is technically demanding.

Nerve conduction studies

Nerve conduction studies (NCSs) are essential in assessing peripheral nerve function and in differentiating axonal damage versus demyelination. Sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) represent the summated electrical activity of individual nerve fibers activated by nerve stimulation. Surface electrodes are used to record the electrical activity from nerve excitation. Electrodes are placed over a muscle or a distal sensory nerve. Amplitude, area, duration, latencies of SNAPs and CMAPs, F wave latencies, and conduction velocities of sensory and motor nerves are measured. The distribution of abnormalities allows for localization and diagnosis.

Electromyography (EMG)

EMG assesses the physiologic function of the motor unit from anterior horn cell to the muscle. Activation of anterior horn cell leads to depolarization of muscle fibers. Electrical activity from these muscle fibers summates to generate a motor unit action potential (MUAP), which is used to characterize disease processes into neurogenic, myopathic, or normal. Each muscle studied is evaluated with four measures: insertional activity, spontaneous activity at rest, MUAP waveform analysis during minimal voluntary contraction, and MUAP analysis during maximal voluntary muscle contraction to assess MUAP recruitment (Table 16-2).

Myopathic versus neurogenic disorders on EMG

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  Neurogenic disorders

  
  
  
  
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    Reduced interference pattern with maximal voluntary activity due to fewer motor units (ie, reduced recruitment).

    
    
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    Increased amplitude and duration of MUAPs.

    
    
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    Increased MUAP polyphasia and satellite potentials.

  
  
  
  
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  Myopathic disorders

  
  
  
  
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    Normal interference pattern as a normal number of motor units are activated, but may see early recruitment.

    
    
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    Decreased MUAP amplitude and duration due to reduced muscle fibers in each motor unit.

    
    
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    Polyphasic MUAPs.

  
  

Peripheral nerve disease

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  Pathologic mechanisms that affect peripheral nerves include axonal degeneration and demyelination.

  
  
  
  
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    Reduced amplitudes of CMAPs or SNAPs are seen in axonal degeneration.

    
    
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    Reduced conduction velocity and prolonged latencies are seen in demyelination.

    
    
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    Conduction block may occur with demyelinating lesions.

    
    
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    Fibrillation potentials may be seen on EMG with ongoing lesions, and neurogenic MUAPs indicate a chronic process.

  
  
  
  
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  GBS

  
  
  
  
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    NCSs are consistent with demyelination.

    
    
    
    
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      Prolonged distal latencies.

      
      
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      Conduction block and slowing.

      
      
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      Temporal dispersion.

      
      
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      Prolongation or absence of F responses and H reflexes.

    
    

  
  

Neuromuscular disease

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  MG

  
  
  
  
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    Repetitive nerve stimulation shows a decremental motor amplitude by the fourth response in a train of 6 or 10, exceeding 10% with stimulation rates at 2–3 Hz.

  
  
  
  
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  LEMS

  
  
  
  
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    Repetitive nerve stimulation at low rates of 2–3 Hz produces a decremental motor response similar to MG.

    
    
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    Repetitive nerve stimulation at high rates (30–50 Hz) causes increments in baseline amplitude and area. Brief voluntary contraction produces a marked increase in CMAP amplitude (post-exercise facilitation) due to calcium accumulation in the presynaptic nerve terminal.

  
  
  
  
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  Botulism

  
  
  
  
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    Electrophysiologic evaluation findings in botulism are similar to Lambert–Eaton myasthenic syndrome.

    
    
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    A decremental response may be seen with slow repetitive nerve stimulation, with an incremental response seen after fast repetitive nerve stimulation.

    
    
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    Sensory conduction studies are normal. CMAP amplitudes are decreased with normal latencies and conduction velocities.

  
  

Muscle disease

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  Normal motor and sensory nerve conduction studies.

  
  
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  Low CMAPs due to loss in muscle bulk.

  
  
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  Fibrillation potentials may be seen on EMG in myopathies with muscle membrane instability (eg, inflammatory myopathies).

  
  
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  Short-duration, low-amplitude, polyphasic MUAPs.

Motor neuron disease

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  Reduced CMAP amplitudes.

  
  
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  Intact sensory responses.

  
  
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  Widespread fibrillation potentials.

  
  
  
  
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    ALS

    
    
    
    
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      Requires denervation in two territories of each of three limbs (or bulbar muscles).

      
      
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      EMG shows fasciculations, fibrillations, positive sharp waves, and enlarged voluntary unit motor (neurogenic) potentials.

      
      
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      CMAPs may be reduced with preserved SNAPs.

    
    

  
  

Muscle and nerve biopsy¹⁹

Muscle biopsy

In patients with unexplained weakness, muscle biopsy can be used to distinguish between myopathies and neuropathies. Muscle biopsy can be used to differentiate between certain myopathies including inflammatory, metabolic, congenital, and muscular dystrophies. Findings of muscle biopsy in neurogenic disorders are characterized by angulated atrophic fibers, fiber type grouping, denervation atrophy, target fibers, and nuclear clumping. In myopathies, findings may include myofiber necrosis, myophagocytosis, regeneration, segmental necrosis of muscle fibers, and fibrosis.

Morphological findings on muscle biopsy in different diseases

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  Critical illness myopathy

  
  
  
  
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    Myopathic features with muscle fiber atrophy and disruption of myofibrillar architecture.

    
    
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    Absent inflammatory cells.

    
    
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    Electron microscopy shows diagnostic selective loss of thick myosin filaments.

    
    
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    Segmental necrosis of muscle fibers are seen in most causes of myoapthy.

  
  
  
  
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  Inflammation and vasculitis

  
  
  
  
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    Polymyositis

    
    
    
    
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      Lymphocytic infiltration of endomysium.

      
      
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      Abnormal muscle fibers are scattered throughout the fascicle (not grouped to one portion, as in dermatomyositis).

      
      
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      No signs of vasculopathy or immune complex deposition.

    
    
    
    
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    Dermatomyositis

    
    
    
    
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      Perimysial inflammatory infiltrate with vascular C5b-9 deposition in the perimysial blood vessels.

      
      
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      Perifasicular atrophy and fibrosis.

      
      
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      Abnormal muscle fibers grouped to one portion of the fascicle.

    
    
    
    
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    Inclusion body myositis

    
    
    
    
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      Characterized by inflammation.

      
      
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      Vacuolar inclusions

    
    
    
    
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    Other myopathies, such as scleroderma, mixed connective tissue disorder, Sjogren syndrome, and facioscapulohumeral dystrophy, may be associated with lesser degree of inflammation.

  
  
  
  
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  Vasculitis

  
  
  
  
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    Inflammatory vascular destruction can occur in systemic disease.

    
    
    
    
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      Granulomatous myopathy may be seen in systemic sarcoidosis.

    
    

  
  

Changes in muscle protein and histochemical stains

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  Presence or absence of structural proteins detected by special enzyme staining can be helpful in the diagnosis of various forms of muscular dystrophy.

Abnormalities of mitochondria

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  Mitochondrial myopathies

  
  
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  Classic hallmark of mitochondrial diseases is subsarcolemmal and inter myofibrillar accumulation of mitochondria, which can be visualized by light microscopy using Gomori trichrome stain.

  
  
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  Mitochondria appear as bright red against the blue background of the myofibers, leading to the term “ragged red fibers.”

Disorders of neuromuscular junction

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  Motor point biopsy, which includes the motor endplate, and electron microscopy can be used to evaluate nerve terminals in NMJ diseases.

  
  
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  Biopsy is rarely required in the diagnosis of NMJ diseases.

Nerve biopsy

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  Generally of limited use in identifying the etiology of polyneuropathies.

  
  
  
  
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    Enables identification of inflammatory, vasculitis, and amyloid neuropathies.

    
    
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    May find evidence of focal inflammation, demyelination, axonal destruction, sarcoidosis, amyloidosis, leprosy, and vasculitis.

  
  
  
  
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  Sural nerve at the ankle is the preferred site for cutaneous nerve biopsy. However, superficial peroneal nerve combined with muscle biopsy of peroneus brevis gives higher yield in cases of vasculitis.

  
  
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  Nerve biopsy should only be used when diagnosis is unclear as a final step, as the procedure may lead to dysesthesias of the lateral foot, wound infections, and thrombophlebitis.