Differential Diagnosis of Neurologic Weakness in the ICU

Neurologic causes of profound weakness in an ICU patient include disorders of the central nervous system (CNS) and the peripheral nervous system (PNS) (Box 37–1). Some of these are primary neurologic disorders that result in admission to the ICU, whereas others occur while the patient is hospitalized for unrelated medical conditions (Box 37–2). One of the most common CNS diagnoses leading to weakness in the ICU is encephalopathy. Encephalopathy in the ICU often is multifactorial, secondary to a multitude of causes including electrolyte and metabolic disturbances, sepsis, and medications. Other CNS disorders can manifest as generalized weakness, including stroke, especially of the posterior circulation, seizures, anoxia, subarachnoid hemorrhage, and infectious meningitis. The spinal cord is part of the CNS, and spinal cord disorders also can present as generalized weakness. Infarction, demyelination, or unrecognized trauma in the high cervical cord can present acutely as a flaccid quadriparesis with decreased or absent reflexes and loss of sensation. Remember that an acute CNS disorder often is associated initially with decreased tone and reduced reflexes (i.e., cerebral or spinal shock) and can mimic a PNS problem early on.

In the PNS, profound weakness can occur from a lesion anywhere in the motor unit, from the motor neuron (anterior horn cell) to the motor nerve, neuromuscular junction (NMJ), and muscle. Acute motor neuron disease is very uncommon and occurs only in the setting of paralytic poliomyelitis. As discussed in Chapter 28, poliomyelitis is a clinical syndrome that occurs from infection by several viruses, with West Nile virus now added to the list. Patients with chronic motor neuron disorders, such as amyotrophic lateral sclerosis (ALS), occasionally present to the ICU when the neurologic condition has not been previously recognized or diagnosed, and the patient comes to medical attention because of a concurrent acute medical problem, usually pneumonia. The typical scenario is that of a patient with bulbar-onset ALS who has undergone an exhaustive medical evaluation looking for a gastrointestinal or ENT etiology of the speech and swallowing dysfunction. The impaired speech and swallowing eventually lead to aspiration and an accompanying pneumonia, which superimposed on respiratory muscle weakness from the unrecognized ALS quickly leads to respiratory compromise and the need for intubation. It is only then, in the ICU, as the patient is recovering from the pneumonia but cannot be weaned from the ventilator, that it becomes more apparent that there is more generalized weakness that had not been appreciated earlier.

Moving down the motor unit, the most well-known acute neuropathy that results in marked weakness and respiratory compromise is Guillain–Barré syndrome (GBS). GBS is an acquired motor and sensory polyradiculoneuropathy that usually is demyelinating. Other variants have been described, including axonal forms, one of which is motor and sensory, and the other pure motor. GBS probably has an autoimmune etiology, often triggered by an infection either days or a few weeks earlier. Patients typically present with ascending numbness and weakness over several days, often with simultaneous paresthesias of the fingers and toes. Weakness may affect bulbofacial and respiratory muscles. Some patients present more abruptly, over hours, with associated early respiratory weakness. Other than GBS, it is rare to see an acute neuropathy as the cause for admission to the ICU. Notable exceptions include porphyria and some toxic (e.g., arsenic) neuropathies, which can mimic the presentation of GBS.

The most common severe neuropathy seen in the ICU patient is critical illness polyneuropathy (CIP). CIP usually occurs in patients who have been admitted to the ICU for a primary medical illness, most often sepsis and multiple organ failure. In contrast to GBS, which is usually demyelinating, CIP is an axonal sensorimotor polyneuropathy thought to be due to a complication of the systemic inflammatory response syndrome (SIRS). SIRS is a severe systemic response that can be caused by sepsis, but is also seen in other settings including trauma, burns, major organ failure and/or as a consequence of major procedures. SIRS is thought to be present in most patients hospitalized in the ICU for longer than one week. In SIRS, significant cellular and humoral responses are thought to alter the microcirculation in the body, including the microcirculation to nerve and muscle. These responses include changes in endothelial and inflammatory cells, in addition to the expression of numerous cytokines and coagulation factors, among other changes. In prospective studies of ICU patients studied with serial nerve conduction studies, CIP can occur as early as within 3 days after the onset of sepsis. In most patients, CIP is preceded by a septic encephalopathy (aka, toxic metabolic encephalopathy) which is extremely common in ICU patients. CIP usually comes to medical attention only when the patient begins to improve from their primary medical illness but is found to have profound weakness and sensory loss or fails to wean from the ventilator. As CIP results in axonal degeneration, recovery is typically very slow and often incomplete, especially in severe cases. Indeed, in some cases, clinical and electrophysiologic evidence of CIP may remain for years after an ICU admission; rare patients remain profoundly disabled.

CIP is reported to be very common in ICU patients, and can occur by itself, or more commonly in association with critical illness myopathy (CIM). Indeed, the two occur so commonly together, depending on how closely the patient is examined clinically and electrically, that some have advocated the name critical illness polyneuromyopathy to describe the neuromuscular syndrome that commonly occurs in the ICU. In one study of ICU patients with SIRS, 50% developed a neuromuscular disorder. Of these, 80% had both CIP and CIM, 10% had CIP alone, and 10% had CIM alone.

In addition to severe polyneuropathies, mononeuropathies of one or both phrenic nerves can directly result in respiratory compromise. Phrenic neuropathies may be idiopathic, presumably autoimmune and postinfectious, similar in etiology to other mononeuropathies such as Bell’s palsy. In addition, phrenic neuropathy can occur rarely as part of neuralgic amyotrophy, either in isolation or more commonly in a more widespread pattern of multiple mononeuropathies. The other situation where unilateral or bilateral phrenic neuropathies occur is as a complication of thoracic surgery. Some cases of phrenic neuropathy following coronary artery bypass surgery may be due to cold-induced injury occurring secondary to the use of topical cooling with ice slush for prevention of myocardial ischemia.

Moving next to the NMJ, several disorders should be considered in the ICU setting. The one disorder of NMJ that presents acutely as rapidly progressive weakness in an adult is botulism. The typical presentation is one of descending paralysis, often associated with gastrointestinal and autonomic symptoms. Of course, a large number of chemical and biologic toxins can poison the NMJ acutely, among them organophosphates, spider venom, and “nerve gas.”

Although myasthenia gravis (MG) typically is diagnosed in an outpatient presenting with ptosis, double vision, slurred speech, and fluctuating weakness, an occasional previously undiagnosed patient may present to the ICU in acute primary respiratory failure. This can occur from selective involvement of the diaphragm and other muscles of respiration or, similar to the patient with unrecognized ALS, bulbar weakness leading to aspiration and pneumonia, quickly followed by respiratory failure.

Patients with Lambert–Eaton myasthenic syndrome (LEMS) are distinctly uncommon in the ICU. First, the disorder is extremely rare. Second, the disorder usually presents subacutely over months, and respiratory muscles are not typically involved. Clinically, it is most often confused with a myopathy. However, rare patients with LEMS present to the ICU as a failure to wean after elective surgery. In these cases, LEMS probably is unmasked when the patient receives a calcium channel blocker or an NMBA at the time of surgery.

Rare patients without any underlying NMJ or muscle disorder fail to extubate as a result of delayed clearance of an NMBA given during anesthesia in preparation for surgery. Most often, these patients have renal insufficiency or frank renal failure and thus fail to clear the NMBA effectively from their system.

The final component of the motor unit is the muscle. By far, the most common muscle disorder seen in the ICU is critical illness myopathy (CIM), also known as acute quadriplegic myopathy, thick myosin filament myopathy, and intensive care myopathy, among many other names. CIM occurs most often in the setting of high-dose intravenous steroids used in conjunction with NMBAs. Rarely, it is seen in association with only one of the two; exceptional cases have been reported in sepsis and multiple organ failure in the absence of steroids and NMBAs. Pathologically, there is dissolution of the thick myosin filaments in most cases. Rarely, there is a necrotizing myopathy on muscle biopsy. One of the most common clinical situations in which CIM occurs is in patients with status asthmaticus, with estimates as high as a third of patients developing some component of CIM. These patients typically are intubated and treated with high-dose intravenous methylprednisolone. Because intubation often is difficult in these patients, pharmacologic paralysis with NMBAs is common. As the asthma improves, it becomes apparent that the patient is flaccid, areflexic, and profoundly weak. Once intubated, the patient may fail to wean for a prolonged period of time. CIM recovers in most patients in 3 to 6 months. However, in patients with SIRS, CIM often occurs in conjunction with CIP. When both are present, the recovery is much longer and may result in permanent disability because of the CIP component.

Other myopathies seldom cause respiratory arrest or severe generalized weakness in the ICU. Rarely, severe cases of inflammatory myopathy (i.e., polymyositis or dermatomyositis) may result in profound generalized weakness. Likewise, severe toxic myopathies are uncommon in the ICU, although rare cases of rhabdomyolysis associated with alcohol, drugs, or other toxins can present as profound weakness. Periodic paralysis, especially hypokalemic periodic paralysis, presents as severe, rapidly evolving weakness during an attack, but only rarely does it affect the respiratory muscles. Finally, although extremely rare, the myopathy associated with adult-onset acid maltase deficiency characteristically affects respiratory and abdominal muscles and can present as a primary neuromuscular cause of respiratory insufficiency.