13 Critical Illness Polyneuropathy and 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.1 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.^1–5 Risk factors that have been suggested for CIP and CIM include:

• Sepsis/systemic inflammatory response syndrome (SIRS):^2,3,5,6 Sepsis/SIRS are proinflammatory states that result in the release of cytokines as well as microcirculatory changes. These inflammatory changes can result in CIP by direct injury to the nerve as well as increased permeability of the endoneurium to neurotoxins. The activation of proteosomes in the proinflammatory state can lead directly to muscle protein breakdown, leading to CIM. Elevations in proteosomes have been detected as early as 1 week into intensive care unit (ICU) treatment.⁷ Nerve conductions studies done as early as 3 days post-sepsis onset have shown findings consistent with CIP 2,4,6,8
  
• Neuromuscular blocking agents (NMBAs): The role of NMBAs as a risk factor for CIM has been debated. Some authors suggest that the use of NMBAs, particularly aminosteroidal (vecuronium, pancuronium, rocuronium) NMBAs or NMBAs used in conjunction with corticosteroids or aminoglycosides increase the risk of CIM.⁹ These agents have been found to cause pharmacological muscle denervation, resulting in upregulation of acetylcholine receptors and glucocorticoid receptors in muscle.^5,6
  
• Corticosteroids: The risk of developing CIM/CIP from steroid use is dose dependent with higher doses and longer uses. High-dose steroids contribute to muscle wasting by decreasing myosin synthesis and increasing muscle turnover, as well as triggering skeletal muscle apoptosis. Patients with sepsis may be at a higher risk of steroid-induced CIM, as glucocorticoid receptors of muscle may be unregulated in the septic state.6,7
  
• Hyperglycemia: Elevated blood sugars lead to insulin resistance that can prevent glucose uptake in skeletal muscle, leading to a depletion of energy stores. Tight control of blood sugars has been shown to reduce the risk of CIP.¹⁰

History and Examination

History

• CIM: Failure to wean from the ventilator, generalized weakness of subacute onset (reports of acute onset do exist)
  
• CIP: Failure to wean from the ventilator, generalized weakness onset over first 1 to 2 weeks in ICU
  
• Assess for history of sepsis, steroid use, neuromuscular blockade, antibiotic use, and hyperglycemia.

1. CIP/CIM
   
2. Guillain-Barré syndrome (GBS): GBS is an acute demyelinating polyneuropathy that typically begins as an ascending paralysis accompanied by areflexia and sometimes follows a diarrheal illness. 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. Nerve conduction studies in GBS should be consistent with a demyelinating neuropathy in the AIDP (acute inflammatory demyelinating polyneuropathy) subtype (i.e., severely prolonged distal motor latencies, severe motor conduction velocity slowing, severely prolonged F waves), often with an acquired demyelinating component (i.e., partial conduction blocks and abnormal temporal dispersion). The axonal variant of GBS seems to be less frequent in the Western world and more frequent in China and Japan.
   
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, a magnetic resonance imaging (MRI) scan of the cervical cord with and without contrast may be appropriate.
   
5. Underlying neuropathy-Toxins and medication effects: Often medications used in the ICU (i.e., neuromuscular blocking agents) can result in prolonged weakness and sedation. A nerve conduction study 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.

• Electromyography/nerve conduction study (EMG/NCS) findings:
  
  
  
  • CIP: CIP is an acute axonal sensorimotor polyneuropathy. Nerve conduction studies show amplitude reduction of both motor and sensory action potentials and normal or mildly slowed conduction velocities.
    
  • CIM: CIM is an acute primary myopathy (i.e., it is not due to muscle denervation). Routine electrodiagnostic studies often reveal nonspecific findings, including normal sensory nerve action potentials with small compound muscle action potentials and early recruitment, fibrillation potentials, and positive sharp waves on EMG.
    

    Studies that have employed both biopsy and advanced electrodiagnostic studies suggest that CIM is as common as CIP and that the two often coexist. Differentiation between the two based on physical exam or even basic electrodiagnostic testing can be extremely difficult.5,6

    
    

    Direct muscle stimulation (DMS) has been suggested as a technique to differentiate CIP and CIM. Compound muscle action potential (CMAP) amplitudes derived from direct muscle stimulation (DMS) may be inexcitable (absent) or decreased (<2 mV) in CIM, while they remain normal in CIP. However, nerve-evoked CMAPs are reduced in both CIP and CIM. Thus, a ratio of nerve-evoked CMAP to DMS CMAP would be >0.5 in patients with CIM and <0.5 in patients with CIP (Table 13.1).

  
  
• Muscle biopsy: Although biopsy is the gold standard for diagnosis of CIM, it is not commonly necessary. Both fiber types I and II are generally affected, but type II myofibers are sometimes more affected. Atrophic myofibers (predominantly type II) with basophilic cytoplasm on hemolytic and eosin (H&E) stain are seen under light microscopy. Electron microscopy shows loss of myosin filaments with relative sparing of actin filaments (patchy thick filament loss). The presence of necrosis is variable, ranging from absent to diffuse lesions described in acute necrotizing myopathy. Inflammatory changes are usually absent, and angulated fibers, rimmed vacuoles, and fatty degeneration may be seen. In patients with CIP, neuropathic features are seen on biopsy, including grouped atrophy, fiber-type grouping, and target fibers.
  
• Imaging studies: Computed tomography (CT) or MRI of the brain or spinal cord may be appropriate to rule out other etiologies when physical examination and electrodiagnostic studies are not conclusive or if electrodiagnostic studies are not available urgently. These studies may help to eliminate other emergent illnesses.
  
• Laboratory studies: Serum creatine phosphokinase (CPK) is usually normal or only mildly elevated in CIP/CIM. A lumbar puncture for cerebrospinal fluid (CSF) analysis may be appropriate only if the clinical picture is unclear. This may be especially helpful to differentiate CIP/CIM from Guillain-Barré syndrome. CSF studies should be normal in CIP/CIM.

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