Acute bilateral weakness can be due to either central or peripheral lesions. 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 and the 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 shown 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.

By focusing on three common entities, a more specific differential diagnosis can be generated for each (Table 6-2).

Myasthenia Gravis

1. 
   

   Myasthenic crisis can present as a forme fruste of myasthenia gravis (MG), which 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 muscle) 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 after diagnosis. Patients with long-standing MG are also at risk for crisis.

   
   
2. 
   

   Cholinergic crisis can occur from excess acetylcholine esterase inhibitor and is characterized by SLUDGE (salivation, lacrimation, urination, diarrhea, GI upset, and emesis), miosis, bronchospasm, and flaccid weakness. Though a tensilon challenge can distinguish cholinergic crisis from MG, 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, is associated with cancer in 50% to 70% (typically, small cell lung cancer), has limb symptoms more prominent than ocular/bulbar symptoms (5% with bulbar findings), and can include facilitation with exercise, autonomic dysfunction, and reduced reflexes; however, respiratory failure is uncommon.

   
   
4. 
   

   Botulism is cause by a neurotoxin produced from Clostridium botulinum, which permanently blocks presynaptic acetylcholine release at the neuromuscular junction, and causes symmetrical descending paralysis with dilated pupils (50%), as well as dysautonomia, but no sensory deficit. It can be treated with trivalent equine antitoxin.

   
   
5. 
   

   Tick paralysis results in presynaptic neuromuscular blockade. Associated ticks include the 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. Typical symptoms include ascending paralysis, ophthalmoparesis, bulbar dysfunction, ataxia, and reduced reflexes. The patient can present with ascending paralysis, ophthalmoparesis, bulbar dysfunction, and reduced reflexes and has a rapid course of progression (hours to days) that is accompanied by ataxia, but no sensory symptoms.¹ Complete cure can occur with tick removal.

   
   
6. 
   

   Snake venom from the venom of the tiger snake, taipan and Brazilian rattle snakes causes presynaptic blockade. Postsynaptic blockade is due to α-bungarotoxin from the krait and venom from cobras, mambas, coral snakes, and sea snakes. Other snakes with venom affecting the neuromuscular junction include copperheads, cottonmouths, moccasins, rattlesnakes, vipers, adders, the boomslang, and twig snake. Snake venom initially affects cranial nerves, resulting in ptosis, ophthalmoplegia, dysarthria, and dysphasia followed by progressive limb weakness.

   
   
7. 
   

   Organophosphate toxicity (eg, malathion, parathion, sarin, soman) inactivates acetylcholine esterase causing SLUDGE, miosis, bronchospasm, blurred vision, and bradycardia and also causes 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. Treat with atropine, pralidoxime (2-PAM), and benzodiazepines. Avoid succinylcholine.

   
   
8. 
   

   Guillain-Barré syndrome (GBS) can present with areflexia and ophthalmoplegia (Miller-Fisher variant) or ascending weakness, facial weakness, diplopia, and areflexia and is often demyelinating, but can be axonal. Early loss of F waves is seen on electromyography (EMG). It is caused by tetrodotoxin (pufferfish) and saxitoxin (red tide), both of which block neuromuscular transmission. 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.

   
   
9. 
   

   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% as a result of 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%.

   
   
2. 
   

   Polyneuropathies include the following:

   
   
   
   
   • 
     

     Acute motor neuropathies due to arsenic, lead poisoning, and porphyria.

     
     
   • 
     

     N-hexane (glue sniffing).

     
     
   • 
     

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

     
     
   • 
     

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

     
     
   • 
     

     Diphtheria caused by C diphtheriae, 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.

   
   
   
   
   • 
     

     MG

     
     
   • 
     

     Lambert-Eaton myasthenic syndrome

     
     
   • 
     

     Botulism

     
     
   • 
     

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

     
     
   • 
     

     Neurotoxic fish poisoning. Caused by tetrodotoxin (pufferfish) and saxitoxin (red tide), which block neuromuscular transmission.

   
   
4. 
   

   Muscle disorders. Critical illness myopathy and acute polymyositis can mimic GBS and can be differentiated with an EMG and a 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, and Wernicke encephalopathy).

Critical Illness Neuropathy/Myopathy

1. 
   

   Critical illness neuropathy/myopathy. 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 almost 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 patient has history of suspicious symptoms, a lumbar puncture can be done (the best yield is 1-2 weeks from symptom onset). Elevated protein levels 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—effects of toxins and medication. Often medications used in the ICU (ie, neuromuscular blocking agents) can result in prolonged weakness and sedation. A nerve conduction study may be helpful for patients who have been treated with neuromuscular blocking agents. “A train of four” (slow repetitive stimulation at 2-3 Hz at the median or ulnar nerve) maybe used to determine if the medication’s effect is persisting.