CHAPTER 33: NEUROLOGIC CRITICAL CARE, INCLUDING HYPOXIC-ISCHEMIC ENCEPHALOPATHY, AND SUBARACHNOID HEMORRHAGE

Life-threatening neurologic illness may be caused by a primary disorder affecting any region of the neuraxis or may occur as a consequence of a systemic disorder such as hepatic failure, multisystem organ failure, or cardiac arrest (Table 33-1). Neurologic critical care focuses on preservation of neurologic tissue and prevention of secondary brain injury caused by ischemia, hemorrhage, edema, herniation, and elevated intracranial pressure (ICP). Management of other organ systems proceeds concurrently and may need to be modified in order to maintain the overall focus on neurologic issues.

Brain edema

Swelling, or edema, of brain tissue occurs with many types of brain injury. The two principal types of edema are vasogenic and cytotoxic. Vasogenic edema refers to the influx of fluid and solutes into the brain through an incompetent blood-brain barrier (BBB). In the normal cerebral vasculature, endothelial tight junctions associated with astrocytes create an impermeable barrier (the BBB), through which access into the brain interstitium is dependent upon specific transport mechanisms. The BBB may be compromised in ischemia, trauma, infection, and metabolic derangements. Vasogenic edema results from abnormal permeability of the BBB, and typically develops rapidly following injury. Cytotoxic edema results from cellular swelling, membrane breakdown, and ultimately cell death. Clinically significant brain edema usually represents a combination of vasogenic and cytotoxic components. Edema can lead to increased ICP as well as tissue shifts and brain displacement or herniation from focal processes (Chap. 19). These tissue shifts can cause injury by mechanical distention and compression in addition to the ischemia of impaired perfusion consequent to the elevated ICP.

Ischemic cascade and cellular injury

When delivery of substrates, principally oxygen and glucose, is inadequate to sustain cellular function, a series of interrelated biochemical reactions known as the ischemic cascade is initiated (see Fig. 32-2). The release of excitatory amino acids, especially glutamate, leads to influx of calcium and sodium ions, which disrupt cellular homeostasis. An increased intracellular calcium concentration may activate proteases and lipases, which then lead to lipid peroxidation and free radical–mediated cell membrane injury. Cytotoxic edema ensues, and ultimately necrotic cell death and tissue infarction occur. This pathway to irreversible cell death is common to ischemic stroke, global cerebral ischemia, and traumatic brain injury.

Penumbra refers to areas of ischemic brain tissue that have not yet undergone irreversible infarction, implying that these regions are potentially salvageable if ischemia can be reversed. Factors that may exacerbate ischemic brain injury include systemic hypotension and hypoxia, which further reduce substrate delivery to vulnerable brain tissue, and fever, seizures, and hyperglycemia, which can increase cellular metabolism, outstripping compensatory processes. Clinically, these events are known as secondary brain insults because they lead to exacerbation of the primary brain injury. Prevention, identification, and treatment of secondary brain insults are fundamental goals of management.

An alternative pathway of cellular injury is apoptosis. This process implies programmed cell death, which may occur in the setting of ischemic stroke, global cerebral ischemia, traumatic brain injury, and possibly intracerebral hemorrhage. Apoptotic cell death can be distinguished histologically from the necrotic cell death of ischemia and is mediated through a different set of biochemical pathways; apoptotic cell death occurs without cerebral edema and therefore is often not seen on brain imaging. At present, interventions for prevention and treatment of apoptotic cell death remain less well defined than those for ischemia.

Excitotoxicity and mechanisms of cell death are discussed in more detail in Chap. 30.

Cerebral perfusion and autoregulation

Brain tissue requires constant perfusion in order to ensure adequate delivery of substrate. The hemodynamic response of the brain has the capacity to preserve perfusion across a wide range of systemic blood pressures. Cerebral perfusion pressure (CPP), defined as the mean systemic arterial pressure (MAP) minus the ICP, provides the driving force for circulation across the capillary beds of the brain. Autoregulation refers to the physiologic response whereby cerebral blood flow (CBF) is regulated via alterations in cerebrovascular resistance in order to maintain perfusion over wide physiologic changes such as neuronal activation or changes in hemodynamic function. If systemic blood pressure drops, cerebral perfusion is preserved through vasodilation of arterioles in the brain; likewise, arteriolar vasoconstriction occurs at high systemic pressures to prevent hyperperfusion, resulting in fairly constant perfusion across a wide range of systemic blood pressures (Fig. 33-1). At the extreme limits of MAP or CPP (high or low), flow becomes directly related to perfusion pressure. These autoregulatory changes occur in the microcirculation and are mediated by vessels below the resolution of those seen on angiography. CBF is also strongly influenced by pH and Paco₂. CBF increases with hypercapnia and acidosis and decreases with hypocapnia and alkalosis because of pH related changes in cerebral vascular resistance. This forms the basis for the use of hyperventilation to lower ICP, and this effect on ICP is mediated through a decrease in both CBF and intracranial blood volume. Cerebral autoregulation is a complex process critical to the normal homeostatic functioning of the brain, and this process may be disordered focally and unpredictably in disease states such as traumatic brain injury and severe focal cerebral ischemia.

Cerebrospinal fluid and intracranial pressure

The cranial contents consist essentially of brain, cerebrospinal fluid (CSF), and blood. CSF is produced principally in the choroid plexus of each lateral ventricle, exits the brain via the foramens of Luschka and Magendie, and flows over the cortex to be absorbed into the venous system along the superior sagittal sinus. In adults, approximately 150 mL of CSF are contained within the ventricles and surrounding the brain and spinal cord; the cerebral blood volume is also ~150 mL. The bony skull offers excellent protection for the brain but allows little tolerance for additional volume. Significant increases in volume eventually result in increased ICP. Obstruction of CSF outflow, edema of cerebral tissue, or increases in volume from tumor or hematoma may increase ICP. Elevated ICP diminishes cerebral perfusion and can lead to tissue ischemia. Ischemia in turn may lead to vasodilation via autoregulatory mechanisms designed to restore cerebral perfusion. However, vasodilation also increases cerebral blood volume, which in turn then increases ICP, lowers CPP, and provokes further ischemia (Fig. 33-2). This vicious cycle is commonly seen in traumatic brain injury, massive intracerebral hemorrhage, and large hemispheric infarcts with significant tissue shifts.

HYPOXIC-ISCHEMIC ENCEPHALOPATHY

This occurs from lack of delivery of oxygen to the brain because of extreme hypotension (hypoxia-ischemia) or hypoxia due to respiratory failure. Causes include myocardial infarction, cardiac arrest, shock, asphyxiation, paralysis of respiration, and carbon monoxide or cyanide poisoning. In some circumstances, hypoxia may predominate. Carbon monoxide and cyanide poisoning are sometimes termed histotoxic hypoxia because they cause a direct impairment of the respiratory chain.

Clinical manifestations

Mild degrees of pure hypoxia, such as occur at high altitudes, cause impaired judgment, inattentiveness, motor incoordination, and, at times, euphoria. However, with hypoxia-ischemia, such as occurs with circulatory arrest, consciousness is lost within seconds. If circulation is restored within 3–5 min, full recovery may occur, but if hypoxia-ischemia lasts beyond 3–5 min, some degree of permanent cerebral damage usually results. Except in extreme cases, it may be difficult to judge the precise degree of hypoxia-ischemia, and some patients make a relatively full recovery after even 8–10 min of global cerebral ischemia. The brain is more tolerant to pure hypoxia than it is to hypoxia-ischemia. For example, a PaO₂ as low as 20 mmHg (2.7 kPa) can be well tolerated if it develops gradually and normal blood pressure is maintained, whereas short durations of very low or absent cerebral circulation usually result in permanent impairment.

Clinical examination at different time points after a hypoxic-ischemic insult (especially cardiac arrest) is useful in assessing prognosis for long-term neurologic outcome. The prognosis is better for patients with intact brainstem function, as indicated by normal pupillary light responses and intact oculocephalic (doll’s eyes), oculovestibular (caloric), and corneal reflexes. Absence of these reflexes and the presence of persistently dilated pupils that do not react to light are grave prognostic signs. A low likelihood of a favorable outcome from hypoxic-ischemic coma is strongly suggested by an absent pupillary light reflex or extensor or absent motor response to pain on day 3 following the injury, excluding patients with metabolic disturbances and those treated with high-dose barbiturates or hypothermia, which confound interpretation of these signs. Electrophysiologically, the bilateral absence of the N20 component of the somatosensory evoked potential (SSEP) in the first several days also conveys a poor prognosis. A very elevated serum level (>33 μg/L) of the biochemical marker neuron-specific enolase (NSE) is indicative of brain damage after resuscitation from cardiac arrest and predicts a poor outcome. However, at present, SSEPs and NSE levels may be difficult to obtain in a timely fashion, with SSEP testing requiring substantial expertise in interpretation and NSE measurements not yet standardized. Recent studies suggest that the administration of mild hypothermia after cardiac arrest (see “Treatment”) may affect the time points when these clinical and electrophysiologic predictors become reliable in identifying patients with a very low likelihood of clinically meaningful recovery. For example, the false-positive rate for incorrect prediction of poor neurologic outcome may be as high as 21% (95% confidence interval [CI] 8–43%) for patients treated with mild hypothermia who exhibit 3-day motor function no better than extensor posturing. Long-term consequences of hypoxic-ischemic encephalopathy include persistent coma or a vegetative state (Chap. 19), dementia, visual agnosia (Chap. 22), parkinsonism, choreoathetosis, cerebellar ataxia, myoclonus, seizures, and an amnestic state, which may be a consequence of selective damage to the hippocampus.

Pathology

Principal histologic findings are extensive multifocal or diffuse laminar cortical necrosis (Fig. 33-4), with frequent involvement of the hippocampus. The hippocampal CA1 neurons are vulnerable to even brief episodes of hypoxia-ischemia, perhaps explaining why selective persistent memory deficits may occur after brief cardiac arrest. Scattered small areas of infarction or neuronal loss may be present in the basal ganglia, hypothalamus, or brainstem. In some cases, extensive bilateral thalamic scarring may affect pathways that mediate arousal, and this pathology may be responsible for the persistent vegetative state. A specific form of hypoxic-ischemic encephalopathy, so-called watershed infarcts, occurs at the distal territories between the major cerebral arteries and can cause cognitive deficits, including visual agnosia, and weakness that is greater in proximal than in distal muscle groups.

Diagnosis

Diagnosis is based on the history of a hypoxic-ischemic event such as cardiac arrest. Blood pressure <70 mmHg systolic or Pao₂ <40 mmHg is usually necessary, although both absolute levels and duration of exposure are important determinants of cellular injury. Carbon monoxide intoxication can be confirmed by measurement of carboxyhemoglobin and is suggested by a cherry red color of the venous blood and skin, although the latter is an inconsistent clinical finding.

TREATMENT

METABOLIC ENCEPHALOPATHIES

Altered mental states, variously described as confusion, delirium, disorientation, and encephalopathy, are present in many patients with severe illness in an intensive care unit (ICU). Older patients are particularly vulnerable to delirium, a confusional state characterized by disordered perception, frequent hallucinations, delusions, and sleep disturbance. This is often attributed to medication effects, sleep deprivation, pain, and anxiety. The presence of delirium is associated with worsened outcome in critically ill patients, even in those without an identifiable CNS pathology such as stroke or brain trauma. In these patients, the cause of delirium is often multifactorial, resulting from organ dysfunction, sepsis, and especially the use of medications given to treat pain, agitation, or anxiety. Critically ill patients are often treated with a variety of sedative and analgesic medications, including opiates, benzodiazepines, neuroleptics, and sedative-anesthetic medications, such as propofol. In critically ill patients requiring sedation, use of the centrally acting α₂ agonist dexmedetomidine may reduce delirium and shorten the duration of mechanical ventilation compared to the use of benzodiazepines such as lorazepam or midazolam. The presence of family members in the ICU may also help to calm and orient agitated patients, and in severe cases, low doses of neuroleptics (e.g., haloperidol 0.5–1 mg) can be useful. Current strategies focus on limiting the use of sedative medications when this can be done safely.

In the ICU setting, several metabolic causes of an altered level of consciousness predominate. Hypercarbic encephalopathy can present with headache, confusion, stupor, or coma. Hypoventilation syndrome occurs most frequently in patients with a history of chronic CO₂ retention who are receiving oxygen therapy for emphysema or chronic pulmonary disease. The elevated PaCO₂ leading to CO₂ narcosis may have a direct anesthetic effect, and cerebral vasodilation from increased PaCO₂ can lead to increased ICP. Hepatic encephalopathy is suggested by asterixis and can occur in chronic liver failure or acute fulminant hepatic failure. Both hyperglycemia and hypoglycemia can cause encephalopathy, as can hypernatremia and hyponatremia. Confusion, impairment of eye movements, and gait ataxia are the hallmarks of acute Wernicke’s disease (see below).

SEPSIS-ASSOCIATED ENCEPHALOPATHY

Pathogenesis

In patients with sepsis, the systemic response to infectious agents leads to the release of circulating inflammatory mediators that appear to contribute to encephalopathy. Critical illness, in association with the systemic inflammatory response syndrome (SIRS), can lead to multisystem organ failure. This syndrome can occur in the setting of apparent sepsis, severe burns, or trauma, even without clear identification of an infectious agent. Many patients with critical illness, sepsis, or SIRS develop encephalopathy without obvious explanation. This condition is broadly termed sepsis-associated encephalopathy. Although the specific mediators leading to neurologic dysfunction remain uncertain, it is clear that the encephalopathy is not simply the result of metabolic derangements of multiorgan failure. The cytokines tumor necrosis factor, interleukin (IL)-1, IL-2, and IL-6 are thought to play a role in this syndrome.

Diagnosis

Sepsis-associated encephalopathy presents clinically as a diffuse dysfunction of the brain without prominent focal findings. Confusion, disorientation, agitation, and fluctuations in level of alertness are typical. In more profound cases, especially with hemodynamic compromise, the decrease in level of alertness can be more prominent, at times resulting in coma. Hyperreflexia and frontal release signs such as a grasp or snout reflex (Chap. 22) can be seen. Abnormal movements such as myoclonus, tremor, or asterixis can occur. Sepsis-associated encephalopathy is quite common, occurring in the majority of patients with sepsis and multisystem organ failure. Diagnosis is often difficult because of the multiple potential causes of neurologic dysfunction in critically ill patients and requires exclusion of structural, metabolic, toxic, and infectious (e.g., meningitis or encephalitis) causes. The mortality rate of patients with sepsis-associated encephalopathy severe enough to produce coma approaches 50%, although this principally reflects the severity of the underlying critical illness and is not a direct result of the encephalopathy. Patients dying from severe sepsis or septic shock may have elevated levels of the serum brain injury biomarker S-100β and neuropathologic findings of neuronal apoptosis and cerebral ischemic injury. Successful treatment of the underlying critical illness almost always results in substantial improvement of the encephalopathy. However, although severe disability to the level of chronic vegetative or minimally conscious states is uncommon, long-term cognitive dysfunction clinically similar to dementia is being increasingly recognized in some survivors.

CENTRAL PONTINE MYELINOLYSIS

This disorder typically presents in a devastating fashion as quadriplegia and pseudobulbar palsy. Predisposing factors include severe underlying medical illness or nutritional deficiency; most cases are associated with rapid correction of hyponatremia or with hyperosmolar states. The pathology consists of demyelination without inflammation in the base of the pons, with relative sparing of axons and nerve cells. MRI is useful in establishing the diagnosis (Fig. 33-5) and may also identify partial forms that present as confusion, dysarthria, and/or disturbances of conjugate gaze without quadriplegia. Occasional cases present with lesions outside of the brainstem. Therapeutic guidelines for the restoration of severe hyponatremia should aim for gradual correction, i.e., by ≤10 mmol/L (10 meq/L) within 24 h and 20 mmol/L (20 meq/L) within 48 h.

WERNICKE’S DISEASE

Wernicke’s disease is a common and preventable disorder due to a deficiency of thiamine. In the United States, alcoholics account for most cases, but patients with malnutrition due to hyperemesis, starvation, renal dialysis, cancer, AIDS, or rarely gastric surgery are also at risk. The characteristic clinical triad is that of ophthalmoplegia, ataxia, and global confusion. However, only one-third of patients with acute Wernicke’s disease present with the classic clinical triad. Most patients are profoundly disoriented, indifferent, and inattentive, although rarely they have an agitated delirium related to ethanol withdrawal. If the disease is not treated, stupor, coma, and death may ensue. Ocular motor abnormalities include horizontal nystagmus on lateral gaze, lateral rectus palsy (usually bilateral), conjugate gaze palsies, and rarely ptosis. Gait ataxia probably results from a combination of polyneuropathy, cerebellar involvement, and vestibular paresis. The pupils are usually spared, but they may become miotic with advanced disease.

Wernicke’s disease is usually associated with other manifestations of nutritional disease, such as polyneuropathy. Rarely, amblyopia or myelopathy occurs. Tachycardia and postural hypotension may be related to impaired function of the autonomic nervous system or to the coexistence of cardiovascular beriberi. Patients who recover show improvement in ocular palsies within hours after the administration of thiamine, but horizontal nystagmus may persist. Ataxia improves more slowly than the ocular motor abnormalities. Approximately half recover incompletely and are left with a slow, shuffling, wide-based gait and an inability to tandem walk. Apathy, drowsiness, and confusion improve more gradually. As these symptoms recede, an amnestic state with impairment in recent memory and learning may become more apparent (Korsakoff’s psychosis). Korsakoff’s psychosis is frequently persistent; the residual mental state is characterized by gaps in memory, confabulation, and disordered temporal sequencing.

Pathology

Periventricular lesions surround the third ventricle, aqueduct, and fourth ventricle, with petechial hemorrhages in occasional acute cases and atrophy of the mammillary bodies in most chronic cases. There is frequently endothelial proliferation, demyelination, and some neuronal loss. These changes may be detected by MRI scanning (Fig. 33-6). The amnestic defect is related to lesions in the dorsal medial nuclei of the thalamus.

Pathogenesis

Thiamine is a cofactor of several enzymes, including transketolase, pyruvate dehydrogenase, and α-ketoglutarate dehydrogenase. Thiamine deficiency produces a diffuse decrease in cerebral glucose utilization and results in mitochondrial damage. Glutamate accumulates due to impairment of α-ketoglutarate dehydrogenase activity and, in combination with the energy deficiency, may result in excitotoxic cell damage.

TREATMENT

Critical illness with disorders of the peripheral nervous system (PNS) arises in two contexts: (1) primary neurologic diseases that require critical care interventions such as intubation and mechanical ventilation, and (2) secondary PNS manifestations of systemic critical illness, often involving multisystem organ failure. The former include acute polyneuropathies such as Guillain-Barré syndrome (Chap. 54), neuromuscular junction disorders including myasthenia gravis (Chap. 55) and botulism, and primary muscle disorders such as polymyositis (Chap. 56). The latter result either from the systemic disease itself or as a consequence of interventions.

General principles of respiratory evaluation in patients with PNS involvement, regardless of cause, include assessment of pulmonary mechanics, such as maximal inspiratory force (MIF) and vital capacity (VC), and evaluation of strength of bulbar muscles. Regardless of the cause of weakness, endotracheal intubation should be considered when the MIF falls to <−25 cmH₂O or the VC is <1 L. Also, patients with severe palatal weakness may require endotracheal intubation in order to prevent acute upper airway obstruction or recurrent aspiration. Arterial blood gases and oxygen saturation from pulse oximetry are used to follow patients with potential respiratory compromise from PNS dysfunction. However, intubation and mechanical ventilation should be undertaken based on clinical assessment rather than waiting until oxygen saturation drops or CO₂ retention develops from hypoventilation. Noninvasive mechanical ventilation may be considered initially in lieu of endotracheal intubation but is generally insufficient in patients with severe bulbar weakness or ventilatory failure with hypercarbia.

NEUROPATHY

Although encephalopathy may be the most obvious neurologic dysfunction in critically ill patients, dysfunction of the PNS is also quite common. It is typically present in patients with prolonged critical illnesses lasting several weeks and involving sepsis; clinical suspicion is aroused when there is failure to wean from mechanical ventilation despite improvement of the underlying sepsis and critical illness. Critical illness polyneuropathy refers to the most common PNS complication related to critical illness; it is seen in the setting of prolonged critical illness, sepsis, and multisystem organ failure. Neurologic findings include diffuse weakness, decreased reflexes, and distal sensory loss. Electrophysiologic studies demonstrate a diffuse, symmetric, distal axonal sensorimotor neuropathy, and pathologic studies have confirmed axonal degeneration. The precise mechanism of critical illness polyneuropathy remains unclear, but circulating factors such as cytokines, which are associated with sepsis and SIRS, are thought to play a role. It has been reported that up to 70% of patients with the sepsis syndrome have some degree of neuropathy, although far fewer have a clinical syndrome profound enough to cause severe respiratory muscle weakness requiring prolonged mechanical ventilation or resulting in failure to wean. Aggressive glycemic control with insulin infusions appears to decrease the risk of critical illness polyneuropathy. Treatment is otherwise supportive, with specific intervention directed at treating the underlying illness. Although spontaneous recovery is usually seen, the time course may extend over weeks to months and necessitate long-term ventilatory support and care even after the underlying critical illness has resolved.

DISORDERS OF NEUROMUSCULAR TRANSMISSION

A defect in neuromuscular transmission may be a source of weakness in critically ill patients. Botulism may be acquired by ingesting botulinum toxin from improperly stored food or may arise from an anaerobic abscess from Clostridium botulinum (wound botulism). Infants can present with generalized weakness from gut-derived Clostridium infection, especially if they are fed honey. Diplopia and dysphagia are early signs of foodborne botulism. Treatment is mostly supportive, although use of antitoxin early in the course may limit the duration of the neuromuscular blockade. General ICU care is similar to patients with Guillain-Barré syndrome or myasthenia gravis with focused care to avoid ulcer formation at pressure points, deep venous thromboprophylaxis, and infection prevention. Public health officers should be rapidly informed when the diagnosis is made to prevent further exposure to others from the tainted food or source of wound botulism (such as injection drug use).

Undiagnosed myasthenia gravis (Chap. 55) may be a consideration in weak ICU patients; however, persistent weakness secondary to impaired neuromuscular junction transmission is almost always due to administration of drugs. A number of medications impair neuromuscular transmission; these include antibiotics, especially aminoglycosides, and beta-blocking agents. In the ICU, the nondepolarizing neuromuscular blocking agents (nd-NMBAs), also known as muscle relaxants, are most commonly responsible. Included in this group of drugs are such agents as pancuronium, vecuronium, rocuronium, and cisatracurium. They are often used to facilitate mechanical ventilation or other critical care procedures, but with prolonged use persistent neuromuscular blockade may result in weakness even after discontinuation of these agents hours or days earlier. Risk factors for this prolonged action of neuromuscular blocking agents include female sex, metabolic acidosis, and renal failure.

Prolonged neuromuscular blockade does not appear to produce permanent damage to the PNS. Once the offending medications are discontinued, full strength is restored, although this may take days. In general, the lowest dose of neuromuscular blocking agent should be used to achieve the desired result and, when these agents are used in the ICU, a peripheral nerve stimulator should be used to monitor neuromuscular junction function.

MYOPATHY

Critically ill patients, especially those with sepsis, frequently develop muscle weakness and wasting, often in the face of seemingly adequate nutritional support. Critical illness myopathy is an overall term that describes several different discrete muscle disorders that may occur in critically ill patients. The assumption has been that a catabolic myopathy may develop as a result of multiple factors, including elevated cortisol and catecholamine release and other circulating factors induced by the SIRS. In this syndrome, known as cachectic myopathy, serum creatine kinase levels and electromyography (EMG) are normal. Muscle biopsy shows type II fiber atrophy. Panfascicular muscle fiber necrosis may also occur in the setting of profound sepsis. This less common acute necrotizing intensive care myopathy is characterized clinically by weakness progressing to a profound level over just a few days. There may be associated elevations in serum creatine kinase and urine myoglobin. Both EMG and muscle biopsy may be normal initially but eventually show abnormal spontaneous activity and panfascicular necrosis with an accompanying inflammatory reaction. Acute rhabdomyolysis can occur from alcohol ingestion or from compartment syndromes.

A thick-filament myopathy may occur in the setting of glucocorticoid and nd-NMBA use. The most frequent scenario in which this is encountered is the asthmatic patient who requires high-dose glucocorticoids and nd-NMBA to facilitate mechanical ventilation. This muscle disorder is not due to prolonged action of nd-NMBAs at the neuromuscular junction but, rather, is an actual myopathy with muscle damage; it has occasionally been described with high-dose glucocorticoid use or sepsis alone. Clinically this syndrome is most often recognized when a patient fails to wean from mechanical ventilation despite resolution of the primary pulmonary process. Pathologically, there may be loss of thick (myosin) filaments. Thick-filament critical illness myopathy has a good prognosis. If patients survive their underlying critical illness, the myopathy invariably improves and most patients return to normal. However, because this syndrome is a result of true muscle damage, not just prolonged blockade at the neuromuscular junction, this process may take weeks or months, and tracheotomy with prolonged ventilatory support may be necessary. Some patients do have residual long-term weakness, with atrophy and fatigue limiting ambulation. At present, it is unclear how to prevent this myopathic complication, except by avoiding use of nd-NMBAs, a strategy not always possible. Monitoring with a peripheral nerve stimulator can help to avoid the overuse of these agents. However, this is more likely to prevent the complication of prolonged neuromuscular junction blockade than it is to prevent this myopathy.

Subarachnoid hemorrhage (SAH) renders the brain critically ill from both primary and secondary brain insults. Excluding head trauma, the most common cause of SAH is rupture of a saccular aneurysm. Other causes include bleeding from a vascular malformation (arteriovenous malformation or dural arteriovenous fistula) and extension into the subarachnoid space from a primary intracerebral hemorrhage. Some idiopathic SAHs are localized to the perimesencephalic cisterns and are benign; they probably have a venous or capillary source, and angiography is unrevealing.

SACCULAR (“BERRY”) ANEURYSM

Autopsy and angiography studies have found that about 2% of adults harbor intracranial aneurysms, for a prevalence of 4 million persons in the United States; the aneurysm will rupture, producing SAH, in 25,000–30,000 cases per year. For patients who arrive alive at hospital, the mortality rate over the next month is about 45%. Of those who survive, more than half are left with major neurologic deficits as a result of the initial hemorrhage, cerebral vasospasm with infarction, or hydrocephalus. If the patient survives but the aneurysm is not obliterated, the rate of rebleeding is about 20% in the first 2 weeks, 30% in the first month, and about 3% per year afterward. Given these alarming figures, the major therapeutic emphasis is on preventing the predictable early complications of the SAH.

Unruptured, asymptomatic aneurysms are much less dangerous than a recently ruptured aneurysm. The annual risk of rupture for aneurysms <10 mm in size is ~0.1%, and for aneurysms ≥10 mm in size is ~0.5–1%; the surgical morbidity rate far exceeds these percentages. Because of the longer length of exposure to risk of rupture, younger patients with aneurysms >10 mm in size may benefit from prophylactic treatment. As with the treatment of asymptomatic carotid stenosis, this risk-benefit ratio strongly depends on the complication rate of treatment.

Giant aneurysms, those >2.5 cm in diameter, occur at the same sites (see below) as small aneurysms and account for 5% of cases. The three most common locations are the terminal internal carotid artery, middle cerebral artery (MCA) bifurcation, and top of the basilar artery. Their risk of rupture is ~6% in the first year after identification and may remain high indefinitely. They often cause symptoms by compressing the adjacent brain or cranial nerves.

Mycotic aneurysms are usually located distal to the first bifurcation of major arteries of the circle of Willis. Most result from infected emboli due to bacterial endocarditis causing septic degeneration of arteries and subsequent dilation and rupture. Whether these lesions should be sought and repaired prior to rupture or left to heal spontaneously with antibiotic treatment is controversial.

Pathophysiology

Saccular aneurysms occur at the bifurcations of the large- to medium-sized intracranial arteries; rupture is into the subarachnoid space in the basal cisterns and often into the parenchyma of the adjacent brain. Approximately 85% of aneurysms occur in the anterior circulation, mostly on the circle of Willis. About 20% of patients have multiple aneurysms, many at mirror sites bilaterally. As an aneurysm develops, it typically forms a neck with a dome. The length of the neck and the size of the dome vary greatly and are important factors in planning neurosurgical obliteration or endovascular embolization. The arterial internal elastic lamina disappears at the base of the neck. The media thins, and connective tissue replaces smooth-muscle cells. At the site of rupture (most often the dome), the wall thins, and the tear that allows bleeding is often ≤0.5 mm long. Aneurysm size and site are important in predicting risk of rupture. Those >7 mm in diameter and those at the top of the basilar artery and at the origin of the posterior communicating artery are at greater risk of rupture.

Clinical manifestations

Most unruptured intracranial aneurysms are completely asymptomatic. Symptoms are usually due to rupture and resultant SAH, although some unruptured aneurysms present with mass effect on cranial nerves or brain parenchyma. At the moment of aneurysmal rupture with major SAH, the ICP suddenly rises. This may account for the sudden transient loss of consciousness that occurs in nearly half of patients. Sudden loss of consciousness may be preceded by a brief moment of excruciating headache, but most patients first complain of headache upon regaining consciousness. In 10% of cases, aneurysmal bleeding is severe enough to cause loss of consciousness for several days. In ~45% of cases, severe headache associated with exertion is the presenting complaint. The patient often calls the headache “the worst headache of my life”; however, the most important characteristic is sudden onset. Occasionally, these ruptures may present as headache of only moderate intensity or as a change in the patient’s usual headache pattern. The headache is usually generalized, often with neck stiffness, and vomiting is common.

Although sudden headache in the absence of focal neurologic symptoms is the hallmark of aneurysmal rupture, focal neurologic deficits may occur. Anterior communicating artery or MCA bifurcation aneurysms may rupture into the adjacent brain or subdural space and form a hematoma large enough to produce mass effect. The deficits that result can include hemiparesis, aphasia, and abulia.

Occasionally, prodromal symptoms suggest the location of a progressively enlarging unruptured aneurysm. A third cranial nerve palsy, particularly when associated with pupillary dilation, loss of ipsilateral (but retained contralateral) light reflex, and focal pain above or behind the eye, may occur with an expanding aneurysm at the junction of the posterior communicating artery and the internal carotid artery. A sixth nerve palsy may indicate an aneurysm in the cavernous sinus, and visual field defects can occur with an expanding supraclinoid carotid or anterior cerebral artery aneurysm. Occipital and posterior cervical pain may signal a posterior inferior cerebellar artery or anterior inferior cerebellar artery aneurysm (Chap. 32). Pain in or behind the eye and in the low temple can occur with an expanding MCA aneurysm. Thunderclap headache is a variant of migraine that simulates an SAH. Before concluding that a patient with sudden, severe headache has thunderclap migraine, a definitive workup for aneurysm or other intracranial pathology is required.

Aneurysms can undergo small ruptures and leaks of blood into the subarachnoid space, so-called sentinel bleeds. Sudden unexplained headache at any location should raise suspicion of SAH and be investigated, because a major hemorrhage may be imminent.

The initial clinical manifestations of SAH can be graded using the Hunt-Hess or World Federation of Neurosurgical Societies classification schemes (Table 33-3). For ruptured aneurysms, prognosis for good outcomes falls as the grade increases. For example, it is unusual for a Hunt-Hess grade 1 patient to die if the aneurysm is treated, but the mortality rate for grade 4 and 5 patients may be as high as 80%.

Delayed neurologic deficits

There are four major causes of delayed neurologic deficits: rerupture, hydrocephalus, vasospasm, and hyponatremia.

1. Rerupture. The incidence of rerupture of an untreated aneurysm in the first month following SAH is ~30%, with the peak in the first 7 days. Rerupture is associated with a 60% mortality rate and poor outcome. Early treatment eliminates this risk.

2. Hydrocephalus. Acute hydrocephalus can cause stupor and coma and can be mitigated by placement of an external ventricular drain. More often, subacute hydrocephalus may develop over a few days or weeks and causes progressive drowsiness or slowed mentation (abulia) with incontinence. Hydrocephalus is differentiated from cerebral vasospasm with a CT scan, CT angiogram, transcranial Doppler (TCD) ultrasound, or conventional x-ray angiography. Hydrocephalus may clear spontaneously or require temporary ventricular drainage. Chronic hydrocephalus may develop weeks to months after SAH and manifest as gait difficulty, incontinence, or impaired mentation. Subtle signs may be a lack of initiative in conversation or a failure to recover independence.

3. Vasospasm. Narrowing of the arteries at the base of the brain following SAH causes symptomatic ischemia and infarction in ~30% of patients and is the major cause of delayed morbidity and death. Signs of ischemia appear 4–14 days after the hemorrhage, most often at 7 days. The severity and distribution of vasospasm determine whether infarction will occur.

   Delayed vasospasm is believed to result from direct effects of clotted blood and its breakdown products on the arteries within the subarachnoid space. In general, the more blood that surrounds the arteries, the greater the chance of symptomatic vasospasm. Spasm of major arteries produces symptoms referable to the appropriate vascular territory (Chap. 32). All of these focal symptoms may present abruptly, fluctuate, or develop over a few days. In most cases, focal spasm is preceded by a decline in mental status.

   Vasospasm can be detected reliably with conventional x-ray angiography, but this invasive procedure is expensive and carries the risk of stroke and other complications. TCD ultrasound is based on the principle that the velocity of blood flow within an artery will rise as the lumen diameter is narrowed. By directing the probe along the MCA and proximal anterior cerebral artery (ACA), carotid terminus, and vertebral and basilar arteries on a daily or every-other-day basis, vasospasm can be reliably detected and treatments initiated to prevent cerebral ischemia (see below). CT angiography is another method that can detect vasospasm.

   Severe cerebral edema in patients with infarction from vasospasm may increase the ICP enough to reduce cerebral perfusion pressure. Treatment may include mannitol, hyperventilation, and hemicraniectomy; moderate hypothermia may have a role as well.

4. Hyponatremia. Hyponatremia may be profound and can develop quickly in the first 2 weeks following SAH. There is both natriuresis and volume depletion with SAH, so that patients become both hyponatremic and hypovolemic. Both atrial natriuretic peptide and brain natriuretic peptide have a role in producing this “cerebral salt-wasting syndrome.” Typically, it clears over the course of 1–2 weeks and, in the setting of SAH, should not be treated with free-water restriction as this may increase the risk of stroke (see below).

Laboratory evaluation and imaging

(Fig. 33-7) The hallmark of aneurysmal rupture is blood in the CSF. More than 95% of cases have enough blood to be visualized on a high-quality noncontrast CT scan obtained within 72 h. If the scan fails to establish the diagnosis of SAH and no mass lesion or obstructive hydrocephalus is found, a lumbar puncture should be performed to establish the presence of subarachnoid blood. Lysis of the red blood cells and subsequent conversion of hemoglobin to bilirubin stains the spinal fluid yellow within 6–12 h. This xanthochromic spinal fluid peaks in intensity at 48 h and lasts for 1–4 weeks, depending on the amount of subarachnoid blood.

The extent and location of subarachnoid blood on a noncontrast CT scan help locate the underlying aneurysm, identify the cause of any neurologic deficit, and predict delayed vasospasm. A high incidence of symptomatic vasospasm in the MCA and ACA has been found when early CT scans show subarachnoid clots >5 × 3 mm in the basal cisterns, or layers of blood >1 mm thick in the cerebral fissures. CT scans less reliably predict vasospasm in the vertebral, basilar, or posterior cerebral arteries.

Lumbar puncture prior to an imaging procedure is indicated only if a CT scan is not available at the time of the suspected SAH. Once the diagnosis of hemorrhage from a ruptured saccular aneurysm is suspected, four-vessel conventional x-ray angiography (both carotids and both vertebrals) is generally performed to localize and define the anatomic details of the aneurysm and to determine if other unruptured aneurysms exist (Fig. 33-7C). At some centers, the ruptured aneurysm can be treated using endovascular techniques at the time of the initial angiogram as a way to expedite treatment and minimize the number of invasive procedures. CT angiography is an alternative method for locating the aneurysm and may be sufficient to plan definitive therapy.

Close monitoring (daily or twice daily) of electrolytes is important because hyponatremia can occur precipitously during the first 2 weeks following SAH (see above).

The electrocardiogram (ECG) frequently shows ST-segment and T-wave changes similar to those associated with cardiac ischemia. A prolonged QRS complex, increased QT interval, and prominent “peaked” or deeply inverted symmetric T waves are usually secondary to the intracranial hemorrhage. There is evidence that structural myocardial lesions produced by circulating catecholamines and excessive discharge of sympathetic neurons may occur after SAH, causing these ECG changes and a reversible cardiomyopathy sufficient to cause shock or congestive heart failure. Echocardiography reveals a pattern of regional wall motion abnormalities that follow the distribution of sympathetic nerves rather than the major coronary arteries, with relative sparing of the ventricular wall apex. The sympathetic nerves themselves appear to be injured by direct toxicity from the excessive catecholamine release. An asymptomatic troponin elevation is common. Serious ventricular dysrhythmias occurring in-hospital are unusual.

TREATMENT