Acute Neuromuscular Weakness In The Intensive Care Unit

Bobby Varkey Maramattom, MD, DM; Eelco F. M. Wijdicks, MD Section Editor(s): Dellinger, R. Phillip MD, FCCM


Crit Care Med. 2006;34(11):2835-2841. 

In This Article

Evaluation Of The Icu Patient With Neuromuscular Weakness

Important components of history are outlined in Table 2 . Clinical examination also provides invaluable clues. Specific findings that should be elicited include muscle wasting or swelling, muscle tenderness, fasciculations or myokymia, myotonia, presence of tendon reflexes, and skin lesions. Fasciculations are random single muscle fiber twitches visible in superficial muscles, especially over the limbs. The phenomenon of myokymia refers to an undulating rippling movement of muscle fibers beneath the skin that mimics a wriggling worm.[7] Myotonia is a delayed relaxation of muscle after voluntary contraction (action myotonia) or mechanical stimulation (percussion myotonia).[8] Facilitation of sluggish reflexes after repetitive tendon taps or brief isometric exercise is a clue to the Lambert-Eaton syndrome. Important skin lesions such as the heliotrope rash of dermatomyositis, purpura, telangiectasias, digital ulcers, splinter hemorrhages, or the palmoplantar hyperkeratosis and raindrop lesions of arsenic poisoning should be scrupulously looked for. A train of four stimulation may demonstrate a train of four fade or a posttetanic response, which might indicate a persistent neuromuscular (NM) blockade. In that case, it is worthwhile waiting for the NM blockade to wear off before reexamining the patient.

A simple mnemonic MUSCLES is helpful in remembering some of the most common causes of generalized weakness in the ICU ( Table 3 ).

A practical algorithm is also helpful in guiding the clinical approach to these patients (Fig. 1). Biopsy of nerve or muscle and ancillary investigations ( Table 4 ) can be invaluable in typing and subclassifying the neuromuscular pathology and can guide prognostication to some extent. Magnetic resonance imaging (MRI) of the brain and spine need to be ordered in selected cases when there is a suspicion of upper motor neuron involvement. Although clinical examination can be difficult in the ICU patient, findings such as an encephalopathy, cranial nerve involvement, hyperreflexia, spasticity, extensor plantar responses, sensory levels, or multifocal neurologic signs should prompt a request for MRI. Other indications include patients with polytrauma, coagulopathies, systemic malignancies, or infective causes of neuromuscular weakness such as West Nile virus or paralytic rabies.

Figure 1.

Algorithm for evaluation of generalized weakness in the intensive care unit (ICU). CK, creatine kinase; ESR, erythrocyte sedimentation rate; ABG, arterial blood gas; MRI, magnetic resonance imaging; Rx, prescription; EMG, electromyograph; AIDP, acute inflammatory demyelinating polyneuropathy; CIDP, chronic inflammatory demyelinating polyneuropathy; CIP, critical illness polyneuropathy; RNS, repetitive nerve stimulation.

Patients in a locked-in state sometimes pose a diagnostic conundrum. Such patients are often fully conscious but anarthric, quadriplegic, and able to communicate only through eye blinks or vertical eye movements. This state is classically described with a ventral pontine infarction, although it can be seen after midbrain infarction, hematomas, central pontine myelinolysis, trauma, and central nervous system infections.[9,10,11,12] It can also rarely occur in GBS, amyotrophic lateral sclerosis, myasthenia gravis, critical illness polyneuropathy, or critical illness myopathy (Fig. 2). These patients can appear comatose. Unless the clinician is vigilant, uses a structured neurologic examination, and specifically looks for this state or uses a coma scale specifically adapted to ICU patients that is capable of separating diverse states of consciousness (such as the FOUR [Full Outline of UnResponsiveness] score), this entity may go unrecognized.[13] Detection of the locked-in state will direct the further line of investigations. Computed tomography scans or MRI will identify most of the central nervous system lesions responsible for this state.

Figure 2.

Hematoxylin and eosin (HE) staining showing inflammatory cell infiltrate into muscle in critical illness myopathy.

Spinal Cord Disorders

The most common noncompressive myelopathy causing quadriparesis is transverse myelitis or myelopathy. Transverse myelitis or myelopathy is most often idiopathic or postinfectious but can also be due to infectious myelitis caused by viruses such as Coxsackievirus, herpes, or cytomegalovirus or bacteria including Mycoplasma or Legionella as well as multiple sclerosis, Devic's disease, collagen vascular diseases, or spinal cord infarction.[14]

Spinal cord infarction is a known complication of aortic dissection, acute aorto-iliac occlusion, and thoracoabdominal aortic surgeries. Spinal cord infarction can also occur after cardiac arrest and global hypotension. In such cases there is a predilection for the lumbosacral cord to be involved.[15] Such patients can potentially suffer a double hit with cortical watershed infarctions producing brachial paresis and spinal cord infarction resulting in paraplegia. Unexplained hypotension or bradycardia in an unconscious trauma patient should prompt evaluation of spinal cord injury with a whole-spine MRI if possible. MRI adequately delineates most myelopathies that produce generalized weakness.

Patients present with acute flaccid areflexic weakness that mimics GBS during the stage of spinal shock. Clinical clues such as early bowel or bladder dysfunction, a sensory level, neck pain, or impalpable lower limb pulses should alert the clinician to a myelopathy and the need for a spinal MRI. Transverse myelitis may respond to high-dose intravenous methylprednisolone and should be identified early.[16] Spinal cord infarction has no specific therapy and patients usually receive only supportive care. Infectious myelitis is treated with the appropriate antiviral or antibiotic regimen.

Anterior Horn Cell Disorders

Although acute poliomyelitis due to polio virus has nearly been eradicated, there are a number of viral mimics of acute poliomyelitis.[17] Notable among this is the West Nile virus (WNV), which is known to produce a meningo-encephalitis with an acute flaccid paralysis.[18] Severe WNV infection can also mimic GBS but is differentiated by fever; encephalopathy; predominantly proximal, asymmetric weakness; axonal pathology on nerve conduction studies;[19] and cerebrospinal fluid variables. The cerebrospinal fluid typically shows lymphocytic pleocytosis with elevated proteins. Enzyme-linked immunosorbent assay for immunoglobulin (Ig)M antibody to WNV is highly sensitive and should be considered. As IgM antibodies can persist for up to a year after primary infection, serial IgM titers or IgG avidity studies can help to differentiate primary infection from past infection.[20] MRI may show enhancement of the cauda equina, spinal cord signal changes, and cerebral parenchymal or leptomeningeal signal changes.[21] Treatment is mainly supportive, and no antiviral medications have any proven benefit in the management of WNV.

Of the other anterior horn cell disorders, amyotrophic lateral sclerosis is well known to present with respiratory failure due to primary involvement of the phrenic motor neurons.[22] The diagnosis is usually clear-cut on electrophysiological studies, and widespread denervation is seen on electromyogram. Although paraneoplastic motor neuron disorders can present with rapidly evolving respiratory weakness, they are uncommon.[23]


The most common variety of polyneuropathy encountered in the ICU nowadays is CIP[24] followed by CIM.

Sepsis, systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome are important in the development of these syndromes although additional factors such as use of NM blocking agents, corticosteroids, cytotoxic drugs, and status asthmaticus have also been identified in the development of CIP/CIM.[25,26,27,28,29] Together, these disorders are encountered in about 30-60% of ICU patients.[30,31,32] CIM may be the more common of the two disorders in ICU patients. CIP may occur as early as 2-5 days in the presence of sepsis or SIRS, but most often it takes =1 wk of mechanical ventilation before these syndromes develop.[30,32] One of the reasons for the delay is that most patients with SIRS or sepsis either have an underlying encephalopathy (septic encephalopathy) or are administered neuromuscular blocking agents or sedatives around the clock to facilitate mechanical ventilation.

The first neurologic consultation is requested when the critical care team finds it difficult to wean the patient from the ventilator and lung, chest wall, or cardiac causes of failure to wean have been excluded. The typical CIM/CIP patient has a flaccid quadriparesis and is often areflexic or hyporeflexic. Cranial nerves are often spared. Sensory examination is often difficult in these patients, and the differentiation between CIP and CIM often rests on electrophysiology. Compound muscle action potential amplitudes are reduced in both conditions; however, sensory nerve action potentials amplitudes are normal in CIM and reduced or absent in CIP. Phrenic nerve studies and needle electromyogram of the respiratory muscles can also establish CIM/CIP as the cause of failure to wean from the ventilator.

A number of terminologies such as acute quadriplegic myopathy, critical care myopathy, acute necrotizing myopathy of intensive care, thick filament myopathy, acute corticosteroid myopathy, acute myopathy in severe asthma, and acute pancuronium-associated myopathy have been used to allude to CIM. Lumpers prefer to term them all CIM and splitters prefer to subclassify CIM. Histopathologically, four subtypes of CIM have been identified on muscle biopsy-the necrotizing, cachectic, acute rhabdomyolysis, and the thick filament (myosin) loss type.[30,33,34,35] Histopathologic subtyping greatly influences the prognostic outcome of CIM as muscle recovery is poor in the necrotizing variant and relatively better in the other subtypes.

Muscle biopsies demonstrate characteristic features of muscle necrosis or selective loss of thick (myosin) myofilaments with preservation of thin (actin) myofilaments and Z discs without muscle necrosis in the thick filament loss type of CIM.[35] Creatine kinase levels are elevated in about 50% of patients with CIM if estimated early in the illness. Treatment of these syndromes is mainly supportive and rests on aggressive management of the underlying sepsis/SIRS. Fluid resuscitation, antibiotic therapy, surgical drainage of abscesses, and physiotherapy all have a role. Intravenous immunoglobulin has thus far not been promising in patients with CIP.[36] The long-term outcome following CIP/CIM ultimately depends on the underlying illness. If these are surmountable (the median hospital stay in patients with CIP is around 3 months), recovery from CIP can be surprisingly good; however, the outcome following CIM can be poor particularly in the necrotizing variants.[37,38]

Patients with GBS present with an ascending paralysis with respiratory and cranial nerve involvement and diffuse areflexia or hyporeflexia. Most patients show features of demyelination on nerve conduction studies and show a good response to intravenous immunoglobulin (IgIV) or plasma exchange. A proportion of patients develop regional variants of GBS or an axonal form of GBS, which may have a poorer prognosis (the acute motor axonal neuropathy or acute motor sensory axonal neuropathy variants). The clinical features of GBS are quite distinct from CIM/CIP and include weakness developing before ICU admission, history of a preceding upper respiratory or diarrheal illness, conspicuous cranial nerve involvement, albumino-cytological dissociation on cerebrospinal fluid examination, and demyelinating features on nerve conduction studies.[24] Some patients have a documented prior infection with certain serotypes of Campylobacter jejuni that evoke antiganglioside antibodies against the nodes of Ranvier.[39] Moreover, CIP occurs on the background of sepsis and SIRS in a patient who is being mechanically ventilating rather than developing de novo. A peculiar situation arises when patients with demyelinating variants of GBS develop sepsis or SIRS and resultant worsening of their neuropathy. Repeat electrophysiologic studies may show axonal degeneration. In such a situation, superadded CIP may be a more likely cause of worsening than axonal GBS.[30] In this case, treatment and management of sepsis and SIRS should take precedence over repeat IgIV or plasma exchange.

Other hospital-acquired polyneuropathies are rare but include acute vasculitic neuropathies, acute porphyria, drug-induced neuropathies, and the AIDS-associated cytomegalovirus polyradiculoneuropathy ( Table 5 ).

Neuromuscular Junction Disorders

Common myasthenic syndromes encountered in the ICU include myasthenia gravis, Lambert-Eaton myasthenic syndrome, prolonged neuromuscular blockade, and antibiotic-induced myasthenia. Oculobulbar involvement should raise the suspicion of myasthenia gravis and prompt a request for repetitive nerve stimulation studies and assessment of acetyl choline receptor antibody titers. Patients with myasthenia gravis can present in a crises with profound worsening of respiratory or other muscles. Common precipitants of crises include intercurrent infections, administration of drugs that impair neuromuscular junction transmission ( Table 1 ), myasthenic crises (undermedication), or cholinergic crises (overmedication). Although it is often difficult to distinguish between myasthenic and cholinergic crises, fasciculations, miosis, hypersalivation, lacrimation, diarrhea, and emesis are more suggestive of overmedication (cholinergic crises). To complicate matters, a poor response or even a hypersensitivity to anticholinesterase agents is observed in some seronegative myasthenic patients who are positive for antibodies to muscle-specific receptor tyrosine kinase.[40] Hypersensitivity is manifested by severe muscle fasciculations in the facial muscles, blurring of vision, sialorrhea, and abdominal cramping mimicking a cholinergic crises.[41] These patients may respond only to plasma exchange during their episodes of crises.[42]

IgIV and plasma exchange are often used as rescue therapies in myasthenic patients with crises.[43] Steroids, immunosuppressive medications, and thymectomy are alternative options in the long-term management of myasthenia gravis.

High-rate repetitive nerve stimulation studies and assessment of antivoltage gated calcium channel antibodies should be ordered if Lambert-Eaton myasthenic syndrome is suspected. Lambert-Eaton myasthenic syndrome responds variably to 3,4-diaminopyridine or IgIV.[44]

Competitive nondepolarizing neuromuscular blockers (NMB) are used in ICU patients to facilitate mechanical ventilation. All of these NMBs, including older amino steroids (pancuronium and vecuronium) and the newer benzylisoquinolinium NMBs such as atracurium,[45] cisatracurium,[46] and doxacurium, can induce prolonged NM blockade in ICU patients. NM blockade is also prolonged by metabolic acidosis and dyselectrolemia such as hypokalemia. NMBs also act synergistically with sepsis and SIRS in the pathogenesis of CIP and CIM.

Uncommon neuromuscular junction disorders seen in the ICU include botulism, tick paralysis, and hypermagnesemia. Botulism involves autonomic functions in addition to producing flaccid paralysis and areflexia. Hence patients often have internal and external ophthalmoplegia, dry mouth, and a paralytic ileus. Repetitive nerve stimulation studies may show features of presynaptic blockade. Clostridium botulinum or its toxin can be detected in stool, serum, wound cultures, or food samples by cultures or mouse bioassays. However, these are cumbersome procedures and not widely available. Although the mainstay of treatment is mechanical ventilation, it is imperative that the disease be diagnosed early to ensure that trivalent antitoxin is administered before the toxin binds to presynaptic nerve terminals. If administered early enough, the antitoxin reduces the mortality, morbidity, and length of hospital stay associated with botulism.[47] Tick paralysis is found mostly in North America and Australia. It mimics GBS with an ascending motor paralysis, preserved sensations, and areflexia. Complete ophthalmoplegia provides a clue toward tick paralysis. Careful search and removal of the tick, which may be embedded in scalp hair, can result in rapid resolution of the paralysis. Hypermagnesemia mimics Lambert-Eaton myasthenic syndrome with respiratory failure, generalized weakness, and diminished reflexes.[48] It is seen more often in patients with renal failure who consume magnesium-containing laxatives or antacids or eclamptic patients who are administered magnesium sulfate.


Among myopathies, the most common variety to be encountered in the ICU is probably CIM. Among other acquired myopathies, inflammatory myopathies deserve a special mention, of which two types are encountered frequently in the ICU: dermatomyositis and polymyositis. Dermatomyositis has a more malignant course than polymyositis and is easier to recognize by virtue of its characteristic skin rash. The rash is often erythematous, periorbital, and purplish (heliotrope) and may spread into the neck and back in a shawl sign. It can be hyperpigmented or salt and pepper as in dark-skinned people. Rashes over the knuckles (Gottron's sign) or subcutaneous calcifications may also be seen. Muscle enzymes (creatine kinase) are elevated in the majority of cases, and electromyogram and muscle biopsy should establish the diagnosis. Autoantibodies such as anti-Jo-1 antibodies and antibodies to the polymyositis/scleroderma nucleolar antigen complex are of limited clinical relevance. Nevertheless, they are often ordered along with autoantibody panels to exclude other conditions as well as to increase the level of diagnostic certainty.

Corticosteroids are the cornerstone of therapy. Patients with respiratory failure may require pulse therapy with intravenous methyl prednisolone with subsequent conversion to oral prednisolone.[49] Addition of steroid sparing agents such as methotrexate or azathioprine should be considered at the outset itself.[50,51] IgIV is used as a second-line agent in dermatomyositis especially when drug resistance is encountered or disease remains active.[52,53]

Among the electrolyte disorders, potassium disturbances are the most common disturbances that produce weakness. Hypokalemic periodic paralysis due to familial periodic paralysis or thyrotoxic periodic paralysis presents with recurrent weakness. Rarely, patients with hypokalemic periodic paralysis can progress to respiratory failure.[54] Acquired hypokalemia from causes such as gastroenteritis can also result in weakness and respiratory failure.[55] Serum K+ levels are often <3.5 mEq/L, and these patients respond well to oral or intravenous potassium loading. Potassium should be coadministered only with normal saline as glucose infusions worsen hypokalemia. Other, more rare, electrolyte disturbances include severe hypophosphatemia.[56]

Rhabdomyolysis can be precipitated by ischemic arterial occlusion, compartment syndromes, or trauma and presents with swollen, tender muscles, focal weakness, and extreme elevations of creatine kinase levels (>10,000 IU). Rhabdomyolysis may also coexist with generalized weakness in one of the subtypes of CIM. It is important to check whether the patient is receiving any of the drugs that predispose to muscle necrosis such as statins, fibrates, colchicine, or zidovudine.


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