Critical Illness Myopathy and Neuropathy

Michio Hirano

Louis H. Weimer

INTRODUCTION

Although critically ill individuals in intensive care units are typically weak due to their severe medical illnesses, a subgroup of patients develops critical illness myopathy (CIM), critical illness polyneuropathy (CIP), or both. The first case of acute quadriplegic myopathy (AQM, later renamed CIM) was reported in 1977 by MacFarlane and Rosenthal in a 24-year-old woman who received high-dose corticosteroids for status asthmaticus. In 1984, Bolton and colleagues described five critically ill patients with sepsis and multiorgan failure who developed severe sensorimotor peripheral neuropathies. Since then, hundreds of patients with CIM and CIP have been reported.

EPIDEMIOLOGY

Although incidence rates of CIM and CIP vary in reported series based on patient populations and detection methods, the disorders appear frequently common in the intensive care unit (ICU) setting. In one report, about 25% of patients in the ICU developed weakness, whereas electrophysiologic studies have detected neuromuscular abnormalities in up to 84% of patients. Among patients with sepsis or systemic inflammatory response syndrome (SIRS), the incidence has been estimated to be 70% and virtually 100% in patients with septic shock or sepsis plus coma. In most case series, the incidence of CIM has been greater than CIP; however, some patients manifest both.

PATHOBIOLOGY

For CIM, corticosteroids, nondepolarizing neuromuscular blocking agents, or both are considered the prime inciting factors, but it has appeared in some individuals who received neither agent. Patients undergoing treatment for status asthmaticus, organ transplantation, and severe trauma seem to be particularly vulnerable. In contrast, for CIP, sepsis, SIRS, and multiorgan failure are risk factors. Other factors that may contribute to CIM and CIP include severity of the illness, duration of ICU stay, duration of organ dysfunction, renal failure, neurologic failure, hyperosmolarity, hyperglycemia, and vasopressor and catecholamine supportive treatment.

Pathophysiologic mechanisms responsible for these conditions are not fully understood. In patients with CIM, direct muscle stimulation has shown a loss of muscle fiber excitability, which has been attributed to voltage-gated sodium channel fast inactivation, based on animal models of steroid-treated denervated muscle as well as biopsied muscle. Enhanced expression of ubiquitin, lysosomal enzymes, and calcium-activated proteases (calpains) has been observed in muscle and could play a pathogenic role. These catabolic pathways may be activated in muscle by induction of transforming growth factor-β/mitogen activated protein kinase pathways. Immune activation by cytokines may also contribute to the myopathy.

Although direct evidence is lacking, CIP has been attributed to microcirculation defects including increased vessel permeability and vasodilation leading to the axonal degeneration. Peripheral nerve biopsies from CIP patients have revealed expression of E-selectin in the vascular endothelium of epineural and endoneurial vessels. Because E-selectin is not normally expressed in vascular endothelium, its presence may increase nerve microvasculature permeability, which would allow circulating neurotoxins to enter the endoneurium and promote endoneural edema.

CLINICAL MANIFESTATIONS

In CIM, severe quadriplegia and muscle atrophy commence 4 to more than 100 days after initiation of intensive care therapy. The weakness may be primarily distal or proximal but is usually diffuse; many patients lose tendon reflexes. Ophthalmoparesis and facial muscle weakness are occasionally present. Persistent respiratory muscle weakness complicates weaning patients from mechanical ventilation. Patients often manifest diffuse muscle atrophy, which can be severe. Improvement is generally evident in 1 to several months in most individuals who survive their critical illness, but protracted recovery or persistent deficits are common.

CIP presents as acute distal limb weakness and sensory loss with diminished or absent tendon reflexes. Involvement of the phrenic and intercostal nerves causes respiratory muscle weakness that often requires prolonged mechanical ventilation therapy (Table 91.1).

DIAGNOSIS

Diagnosis of CIM and CIP is typically suspected when patients have unexplained severe limb weakness, inability to weak patients off mechanical ventilation, or both. Marked muscle atrophy is common in CIM, whereas areflexia and stocking-glove sensory loss (in alert patients) are characteristic of CIP. CIM and CIP must be distinguished from the persistent weakness that may follow administration of nondepolarizing blocking agents to a person with impaired hepatic metabolism, reduced renal excretion, or both.

In patients with CIM, laboratory studies have shown normal or elevated serum creatine kinase levels. Nerve conduction studies (NCS) demonstrate absent or low-amplitude compound motor action potentials with decreased duration. Sensory nerve action potentials are normal, reduced, or absent but frequently hampered by technical constraints in the ICU environment and by limb edema. Electromyography (EMG) variably shows signs of denervation from muscle necrosis and myogenic or normal motor unit action potentials; however, motor unit and recruitment analysis are frequently suboptimal owing to severe weakness, encephalopathy, sedation, or other confounding factors. Direct muscle stimulation has shown a loss of muscle fiber excitability.

Muscle biopsies demonstrate myopathic changes. Three distinct histologic features have been described in skeletal muscle biopsies;
the abnormalities may be present in isolation or in variable combinations. Muscle fiber atrophy, often more prominent in type 2 fibers, is routinely seen. In patients with markedly elevated creatine kinase levels, necrosis of muscle fibers has been observed. The most striking feature revealed by electron microscopy is loss of thick (myosin) filaments, corroborated by antimyosin-antibody stains and reduced myosin mRNA levels but is not seen in many cases.

TABLE 91.1 Major Characteristics of Critical Illness Myopathy and Critical Illness Polyneuropathy

	Critical Illness Myopathy (CIM)	Critical Illness Polyneuropathy (CIP)
Clinical features	Weakness, typically diffuse including respiratory muscles. Muscle atrophy is common.	Distal limb weakness and sensory loss with diminished or absent tendon reflexes. Respiratory muscle weakness is common.
Risk factors	Treatment with corticosteroid, nondepolarizing neuromuscular blocking agent, or both	Sepsis, systemic inflammatory response syndrome (SIRS), multiorgan failure
Nerve conduction study and electromyography abnormalities	Myogenic abnormalities	Neurogenic abnormalities with signs of acute denervation
Muscle biopsy findings	Myofiber atrophy predominantly affecting type 2 fibers. Loss of thick (myosin) filaments is characteristic but is not always seen.	Signs of acute denervation
Treatment	Reduce exposure to corticosteroids and nondepolarizing neuromuscular blocking agents.	Intensive insulin treatment to maintain normal blood glucose levels