Peripheral nervous system and neuromuscular disorders in the emergency department: A review

Guillain-Barré syndrome (GBS) and variants

The classic form of GBS, also called acute inflammatory demyelinating polyneuropathy (AIDP), presents with rapidly progressive quadriparesis or paraparesis and areflexia, usually within the setting of an antecedent infection or other physiological stressor.³ The immune response generates antibodies that cross-react with gangliosides in the nerve membrane, causing functional blockade or nerve damage. The nadir is often reached by the second or third week. Autonomic dysfunction can be seen in nearly 65% of patients. Severe pain is frequently reported at the time of onset of symptoms and could be attributed to radicular, neuropathic, or muscular pain. Neuropathic pain mimicking bilateral sciatica has been described at the onset of GBS. The diagnosis of GBS can be initially missed in cases with atypical presentations such as GBS variants, pure sensory complaints, or severe neuropathic pain. Moreover, symptoms can be more prominent than objective findings early in the course of the disease; for instance, areflexia may not be apparent in the first several days.

The spectrum of presentation of GBS is broad (Table 2). GBS variants include (a) lower-extremity paraparetic variant, (b) pharyngocervicobrachial variant, (c) pure motor variant, (d) Miller Fisher syndrome (ataxia, areflexia, ophthalmoplegia), (e) sensory ataxic variant, (f) pandysautonomia, and (g) bifacial palsy with distal paresthesias.⁴ AIDP is the most common subtype of GBS.

Respiratory weakness occurs in 12%–51% of patients with GBS.⁵ The Erasmus GBS Respiratory Insufficiency Score (EGRIS) is a clinical prediction model for the possibility of mechanical ventilation within the first week of admission based on: (a) days between onset and hospitalization, (b) presence of facial and/or bulbar weakness, and (c) severity of weakness.⁶

Electrodiagnostic tests help with localization, subtype differentiation, identification of atypical variants, and prognostication, although they may appear normal in the first week of GBS.⁷ Referral for nerve conduction studies/electromyography is required; however, these are often performed after hospitalization from the ED and are unlikely to influence treatment decisions in the acute setting.

Clinical features that should cast doubt on the diagnosis of GBS include fever at onset, persistent and marked asymmetry of weakness, sharp sensory level, hyperacute nadir, marked abnormalities in mentation, or the presence of cerebrospinal fluid (CSF) pleocytosis, which indicate an infectious process or vascular insult affecting different parts of the neuraxis.^{3, 7, 8} Similarly, systemic features such as abdominal pain, vomiting, eosinophilia, anemia, renal failure, and weight loss usually point to an alternate etiology such as porphyria, systemic vasculitis, or heavy metal intoxication. HIV seroconversion may present with a GBS-like syndrome. Other mimics of GBS include brainstem stroke, vitamin B1 (thiamine) deficiency, nerve root infiltration, infection, neurotoxic envenomation, electrolyte disturbances or autoimmune disorders (including myasthenia gravis [MG] or inflammatory myopathies).

Optimal supportive care including intensive care unit (ICU) monitoring, respiratory support, and management of autonomic dysfunction are crucial for improving outcomes. Immunotherapy is the mainstay of treatment, and it is indicated when independent ambulation for 10 m is difficult and when patients have rapidly progressing weakness, autonomic dysfunction, or bulbar or respiratory involvement.⁷ Both plasmapheresis and intravenous immunoglobulin (IVIG) have been shown to be beneficial, especially when initiated within 4 weeks (plasmapheresis) or 2 weeks (IVIG) of the onset of illness.⁹ These have been shown to shorten the time to independent ambulation and to weaning from ventilation.^{10, 11} Corticosteroids are unhelpful in GBS and have been associated with delayed recovery.¹² Poor prognosis has been described in the elderly and those with preceding diarrhea or severe disease at onset.¹³

Infectious and toxic acute neuropathies

Acute intermittent porphyria (AIP)

AIP is characterized by attacks of severe abdominal pain and a motor axonal neuropathy affecting mainly the proximal muscles of the upper limb, although it can also involve the bulbar and respiratory muscles.^{28, 29} The pathogenesis is attributed to the neurotoxicity of the heme pathway intermediates, which accumulate due to an enzymatic defect in the heme biosynthetic pathway. Autonomic disturbances can be prominent and lead to cardiac arrhythmias and sudden death. Neuropsychiatric manifestations, seizures, and hypertensive encephalopathy may also occur. Urine can turn red on standing due to formation of porphobilin. Urine testing for porphobilinogen and delta-aminolevulinic acid help in achieving an early diagnosis. AIP is treated with high glucose supplementation, hematin, givosiran, and avoiding precipitants.³⁰

Autoimmune neuromuscular junction dysfunction: MG

MG is a neuromuscular junction disorder characterized by episodic and fluctuating weakness. Although it can result in significant limb weakness, most commonly it presents with oculobulbar weakness with ptosis, diplopia, chewing difficulty, and/or dysphagia.³¹

The icepack test is a practical bedside test that can raise suspicion for MG in the ED. To perform an ice pack test, the palpebral opening is measured before and after an ice pack is applied for 2 min; an increase of at least 2 mm in the palpebral opening is considered positive (sensitivity 76%, specificity of 98%).³²

Myasthenic crisis is the most feared complication of MG, defined as neuromuscular weakness causing respiratory failure. Clinically, predictors of requiring intubation for airway protection include forced vital capacity (FVC) < 20% predicted, maximum inspiratory pressure (MIP) < −30 cm H₂O, maximum expiratory pressure (MEP) < 40 cm H₂O, low single-breath count, and hypercarbia (pCO₂ > 40–50).^{33, 34} Myasthenic crisis can be precipitated by infection, drugs, surgery, pregnancy, and other stressors. The most common drug triggers resulting in a myasthenic crisis are summarized in Table 3.³⁵ In patients with impending respiratory compromise, noninvasive ventilation (NIV) has been shown to decrease the number of intubations, ventilation days, hospital days, and decrease the time in ICU.³³ In those requiring intubation, rocuronium is preferred to succinylcholine. Patients with myasthenic crisis can be treated with either IVIG or plasma exchange depending on local practice patterns and availability. High-dose corticosteroids should be used with extreme caution with ICU monitoring or avoided as they can cause paradoxical worsening of MG especially in patients with bulbar weakness.

Other acute neuromuscular junction disorders: neurotoxic envenomation

Latrotoxin (black widow spider)

Black widow spider bite can result in severe pain, board-like rigidity, and progressive weakness. Weakness from latrotoxin is due to the toxin causing a massive presynaptic calcium influx resulting in a depletion of neurotransmitters at the motor endplate.⁴⁰ Management in severe cases include intravenous calcium, antivenom, muscle relaxation, and pain relief with opiods.⁴¹

Inflammatory myopathies

Polymyositis, dermatomyositis, and necrotising myopathy can all present with rapidly progressive weakness more profound in the proximal muscles compared to the distal ones.⁴³ Dermatomyositis can present with myalgias as well as skin changes such as Gottron's papules (erythematous, scaly indurations over the knuckles, elbows, and knees), heliotrope rash (purple discoloration in a butterfly distribution over the periorbital areas and cheek), and a “V” sign over the neck and chest.⁴⁴ Creatine kinase (CK) is usually elevated (though can be normal in dermatomyositis). Judicious use of immunotherapy is associated with favorable outcomes. Necrotizing myopathies carry a risk of rhabdomyolysis and renal failure.

Channelopathies

Periodic paralysis from potassium channelopathies can present with dramatic paralysis. Hypokalemic periodic paralysis can be inherited or secondary to thyrotoxicosis, renal tubular acidosis, or hyperaldosteronism.^{45, 46} Hypokalemic periodic paralysis is often precipitated by periods of exercise followed by rest, high carbohydrate intake, or sudden changes in temperature. Treatment for hypokalemic periodic paralysis is appropriate potassium replacement. Hyperkalemic periodic paralysis, on the other hand, is often precipitated by rest after strenuous exercise, cold, and fasting and is usually self-limited. Rarely does it require aggressive treatment unless there is critical hyperkalemia.⁴⁷

Identification of impending respiratory failure

Respiratory muscle weakness usually correlates with the severity of generalized weakness, and the strength of neck flexors correlates with diaphragmatic power.⁴⁸ Signs of impending respiratory failure may include tachypnea, use of accessory muscles of respiration, paradoxical breathing, inability to swallow or clear secretions, ineffective cough, inability to lift the head off the bed, and drowsiness/deteriorating sensorium.⁵ Importantly, patients with neuromuscular respiratory failure may not appear to be in overt respiratory distress, given hypoventilation (inability to increase respiratory rate or tidal volume)—breathlessness is often a late finding.⁴⁹ A single breath count less than 20 correlates with a markedly reduced vital capacity.⁴⁸ A weak cough is characteristic of neurogenic respiratory muscle weakness. Immediate onset of orthopnea on lying down is usually consistent with a neurogenic cause.⁵

Dysphagia in neuromuscular disorders may precede the overt manifestation of respiratory weakness and occurs in the oropharyngeal phase, characterized by symptoms that occur immediately upon swallowing.⁵⁰ Patients may complain of nasal regurgitation, cough while swallowing, or choking.

Once established, respiratory weakness can worsen rapidly, with bulbar weakness, pooling of secretions, and microaspirations further contributing to respiratory function decline. In GBS, diaphragmatic fatigue and fulminant respiratory failure can occur when the limb power remains static.⁵ While there should be a low threshold for intubation when acute respiratory failure is suspected, clinicians must also balance the risk of prolonged ventilation or low likelihood of extubation in patients with advanced disease course or other poor prognostic features.

Blood gas analysis, bedside spirometry, and end-tidal CO₂ can provide useful clues about the respiratory status. Subtle changes in blood gas analysis that may be overlooked include (a) minor declines in oxygenation due to atelectasis, (b) relative lack of hypocapnia despite tachypnea, and (c) elevated pH and bicarbonate indicating chronic hypoventilation.⁴⁸ It is important to note that hypoxia and hypercarbia may be late manifestations once respiratory failure is already well established. The presence of hypoxia may suggest atelectasis, aspiration, or other cardiopulmonary processes. Hypercarbia occurs due to muscle fatigue and reduction in tidal volumes.

A supine drop in the FVC by more than 20% indicates diaphragmatic weakness. Trends of change or decline in vital capacity may be more important than the absolute values.⁵ A drop in vital capacity by 50%–60% or more, to less than 15–20 mL/kg or to less than 1 L, is usually indicative of impending respiratory failure.⁴⁸ MIP may be underestimated when a weak seal is present due to facial weakness. Other parameters that may indicate a need for mechanical ventilatory support include a MIP less than −30 cm H₂O or a MEP less than 40 cm H₂O^{5, 51} (Table 4). The “20-30-40 rule” refers to these thresholds for FVC/MIP/MEP that can predict respiratory failure.⁵¹ Functional residual capacity (determined by the elastic recoil of chest wall and lung) is relatively preserved in pure muscle weakness and can help differentiate neurogenic respiratory weakness from restrictive lung disease.

In summary, clinicians should be wary of relying on hypoxia or respiratory symptoms to predict respiratory distress in the setting of neuromuscular weakness; instead, impending respiratory failure should be suspected in patients with bulbar or facial weakness, head-drop, poor performance on bedside spirometry, low single breath counts, autonomic dysfunction, rapid or deteriorating course, or substantial global weakness.^{7, 8, 52-54}

Oxygenation, neuromuscular blockade, and ventilation

NIV strategies are useful in situations with preserved bulbar function and lack of secretions and can help by improving gas exchange and reducing respiratory muscle fatigue. The optimal target of oxygenation in patients presenting with suspected acute exacerbation of chronic hypercapnic respiratory failure in a neuromuscular disorder remains to be ascertained. Up-titration of the oxygen fraction can result in worsening hypercarbia and acidemia should hypoventilation not be addressed.⁵⁵ This can compromise the respiratory drive, precipitating respiratory arrest. Studies support the use of oxygen administered through high-flow nasal cannula to improve oxygenation, reduce work of breathing, and improve dyspnea in patients with COPD with mild to moderate hypercapnia⁵⁶; however high-quality evidence for its use specifically in patients with neuromuscular respiratory failure is limited.

Nondepolarizing neuromuscular agents (e.g., rocuronium) are the preferred paralytic when intubating patients with neuromuscular respiratory failure. In patients with GBS, depolarizing agents (e.g., succinylcholine) carry a risk of hyperkalemic respiratory arrest,⁵⁷ and in patients with MG, rocuronium has a more predictable dose response. The rocuronium dose should be adjusted to 0.5 mg/kg for those with MG as there are fewer acetylcholine receptors to block to cause nondepolarizing paralysis.^{33, 54} Mechanical ventilation when required in addition to supportive therapy helps in tiding over the acute period of crisis in most disorders (apart from MND and muscular dystrophies, which eventually have poor long-term outcomes).

New-onset weakness or worsening of weakness while in the ICU can be due to critical illness myopathy (due to loss of myosin and myoglobin-related proteins in the limb and trunk muscles) or critical illness polyneuropathy (due to axonal degeneration). These disorders can occur independently or in combination, often in the setting of sepsis and concomitant steroid use, and manifest as difficulty in weaning from ventilation in addition to limb weakness.⁵⁸

Atypical presentations with neuromuscular respiratory failure

Hypercapnic respiratory failure can present as a dominant or isolated manifestation (without overt neuromuscular weakness) presenting a diagnostic and management challenge.⁵⁹ Moreover, symptoms like fatigue or orthopnea can be falsely attributed to cardiopulmonary illness in these patients.

A small proportion of patients with MG (approximately 14%) or MND (approximately 3%) have respiratory involvement as a dominant presenting feature.⁶⁰ Isolated respiratory involvement in MG, though rare, has been reported in a few case series.^{61, 62} Associated features described in cases of MND with respiratory onset include male predominance, neck weakness, fasciculations, and cachexia.^{63, 64} Mean survival up to 27 months has been reported with timely initiation of NIV.⁶⁵ Importantly, there are often ethical considerations regarding long-term ventilation in these patients; decisions regarding endotracheal intubation in the emergency setting may be especially challenging when advanced care directives have not been previously established.

Isolated phrenic neuropathy with diaphragmatic weakness has been associated with GBS, neuralgic amyotrophy, pneumonia, herpes zoster, drugs (e.g., amiodarone and chemotherapy), and malignancy and in the postoperative setting.^{66, 67} Patients with unilateral phrenic palsies are usually asymptomatic and often diagnosed due to an incidental radiological finding of an elevated hemidiaphragm. However, they can become symptomatic with coexistent cardiopulmonary disorders, abdominal distention, and pregnancy. A sizeable proportion of the patients have good functional recovery at 1-year follow-up.^{68, 69}

Approach to focal weakness: Radiculopathies, plexopathies, and neuropathies

The localization of focal weakness can be challenging. Musculoskeletal injuries and cortical lesions should be considered in the differential diagnosis for the patient presenting with weakness.^{70, 71} Radiculopathies need to be considered in the context of radicular pain, weakness involving specific myotomes with or without sensory involvement in the same dermatome, and focal areflexia. Focal cervical and lumbar radiculopathies are often secondary to compression due to disc herniation and root compression.⁷² Polyradiculopathies can occur due to nerve root inflammation (radiculitis/arachnoiditis) secondary to infections and meningeal inflammation. Leptomeningeal infiltration can be seen in malignancies and lymphoproliferative disorders. Diagnosis is usually confirmed by MRI and CSF analysis. Patients with suspected polyradiculopathies should be promptly referred to neurology.

Cauda equina syndrome presents with acute or subacute onset of lower limb pain, numbness, myotomal weakness, and/or bladder retention as well as bladder/bowel incontinence. A central lumbar disc is often the culprit and most cases occur due to trauma or injury. Cauda equina syndrome is a surgical emergency and timely intervention is required to prevent morbidity.⁷³

Motor and sensory deficits in a limb involving more than two nerves should raise the possibility of plexopathy. Causes of acute/subacute plexopathies include trauma, hemorrhage, inflammation, and infiltration. Brachial plexitis (also called neuralgic amyotrophy) is characterized by severe pain followed by weakness in the distribution of multiple nerves in the upper limbs. Brachial plexitis has restricted forms involving the phrenic, axillary, anterior and posterior interosseus nerves.⁷⁴ Herpetic plexitis or neuropathies may present with weakness and sensory loss or pain in the areas adjacent to the rash.⁷⁵

Focal neuropathy can occur from trauma, nerve compression, inflammation, and nerve ischemia secondary to vasculitis or atherosclerosis. Acute compressive neuropathy can occur in the setting of soft tissue edema, compartment syndrome, or hematoma. It may also occur as a surgical complication. The neuropathies of the upper limb can involve the median, ulnar, radial, anterior interosseus, posterior interosseus, axillary, suprascapular, and musculocutaneous nerves. The neuropathies of the lower limb can involve the sciatic, femoral, and peroneal nerves.

Rhabdomyolysis

The classic presenting triad in rhabdomyolysis of myalgia, weakness, and myoglobinuria is present in only around 10% of cases.⁷⁶ The biochemical hallmark of rhabdomyolysis is a marked elevation of serum CK, and its associated electrolyte disturbances include hyperkalemia, hyperphosphatemia, and hypocalcemia.^{77, 78} Rhabdomyolysis can result in renal failure, electrolyte derangements, compartment syndrome, metabolic acidosis, dysrhythmias, disseminated intravascular coagulopathy, hypovolemia, and liver dysfunction.⁷⁹

Rhabdomyolysis can occur secondary to exertion, trauma, heat-related illness, seizures, compartment syndrome, toxins, envenomation, medications (e.g., statins), and endocrinologic or metabolic derangements.⁸⁰ Underlying myopathy may be suggested by recurrent rhabdomyolysis, positive family history, or persistent muscle weakness along with elevations in CK beyond 8 weeks.⁸⁰

The principal treatment of rhabdomyolysis is fluid resuscitation, electrolyte replacement, and dialysis in the event of fulminant renal failure or related complications.

Malignant hyperthermia is a life-threatening hypermetabolic crisis, for which its hallmark features are hyperthermia, tachypnea, tachycardia, acidosis, myoglobinuria, coagulopathies, arrhythmias, and electrolyte derangements.⁸¹ Increases in end-tidal CO₂ can be an early warning of malignant hyperthermia. The usual precipitating factor is exposure to volatile anesthetic or succinylcholine in a susceptible individual. Mutations in RYR1, CACNA1S, and STAC3 have been associated with increased susceptibility for malignant hyperthermia.⁸²

Severe autonomic dysfunction

The manifestations of autonomic dysfunction are varied. Autonomic hyperactivity syndromes are often associated with tachycardia/bradycardia, labile blood pressure, diaphoresis and sweating abnormalities, urinary retention, constipation, or diarrhea.⁸³ There may be severe orthostatic intolerance due to postural hypotension. Cardiovascular autonomic dysfunction is associated with a higher risk of arrhythmias and sudden cardiac death. GBS can present with marked autonomic disturbances. Continuous monitoring of heart rate and blood pressure in an ICU setting may be warranted in severe cases of autonomic dysfunction.