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Table 9–10 Grading System for Subarachnoid Hemorrhage

World Federation of Neurological Surgeons score is indexed by Glasgow Coma Scale (GCS) and evidence of identifiable motor deficits.

From the World Federation of Neurological Surgeons,51 with permission

However, as many as one-half of the patients presenting with grades I or II deteriorate from vasospasm, rebleeding, hydrocephalus, or brain edema. About 10% (range 3% to 17%) of patients die before reaching medical attention and another 10% prior to hospital evaluation. The overall mortality is 40% to 50%.53

GCS is a good predictor of outcome from SAH if the patient’s age, the amount of blood on CT scan, the location of the aneurysm (worse for posterior circulation sites compared with anterior circulation),53 and secondary complications following the initial rupture are also factored in. A high percentage of patients with grades IV and V die from secondary complications if they remain in coma for 2 weeks or more.

Rebleeding of an aneurysm causing coma and depression or loss of brainstem reflexes carries a mortality rate of 50%. In one study, bilateral loss of pupillary responses carried a 95% mortality rate. Electrophysiologic measurements have also shown some utility in the prognosis of SAH; loss of BAERs and SSEPs correlate with poor grades on examination.54,55

Central Nervous System Infection

Coma was present on admission in 14% of 696 patients with bacterial meningitis56 (see also page 262). Obtundation on admission was a significant risk factor for death or a GOS less than 4, as were age older than 60 years, hypotension, seizures within 24 hours (often associated with a low serum sodium), and cere-

brospinal fluid (CSF) abnormalities including decreased glucose concentration or elevation of the CSF protein (greater than or equal to 250 mg/dL). In most cases, death was a result of herniation, occasionally following an illadvised lumbar puncture. Some investigators have suggested that the presence of coma is the best predictor of morbidity from acute meningitis.57 Coma is often the result of increased ICP resulting from alteration of the blood-barrier by toxins (vasogenic edema), impaired resorption of CSF (interstitial edema), or venous or arterial occlusions (infarction with cytotoxic edema).58 A brain abscess causing coma also has a poor prognosis (GOS less than 4)59; herniation is the principal cause of coma with a 60% mortality rate.60

Acute Disseminated

Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) (see also page 366) is a monophasic autoimmune demyelinating disease most commonly affecting children and young adults that follows viral or bacterial illnesses or may arise postvaccination.61 Although prognosis for ADEM has historically been considered poor, current experience reflects that most patients (range 55% to 90% across studies) will recover fully or with minor neurologic disabilities. The improved prognosis may reflect either the increased frequency of diagnosis of relatively mild cases, which often can be demonstrated on magnetic resonance imaging (MRI), or perhaps the tendency to treat patients with corticosteroids. Most patients with ADEM improve within 6 months, although many documented cases showed longer recovery times.

Hepatic Coma

Hepatic coma develops either as an inexorable stage in progressive hepatic failure or as a more reversible process in patients with portal systemic shunts when increased loads of nitrogenous substances are suddenly presented into the circulation (see Chapter 5). Prognosis in hepatic coma depends on the cause, the acuteness and severity of the liver failure, and the presence or absence of dysfunction of other organs. The prognosis is far worse in fulminant

hepatic failure than in coma associated with chronic cirrhosis or portacaval shunting. Among patients with nontraumatic coma, those with hepatic encephalopathy demonstrated the best chance for recovery (33%).4

Survival also correlates with age in patients with infectious and serum hepatitis. Patients with chronic hepatocellular disease often drift in and out of encephalopathy, a situation that can be managed by correction of intercurrent processes such as infection or reduction of circulating nitrogenous load. If no exogenous factor can be identified, the presence of encephalopathy is far more ominous and correlates with high mortality; approximately 50% of patients with cirrhosis die within 1 year of demonstrating encephalopathy.62

Depressant Drug Poisoning

Most fatal intentional depressant drug poisonings occur outside the hospital. Once such patients reach treatment, experienced centers worldwide generally report an overall mortality among patients with altered consciousness of less than 1% (Table 9–7). The death rate climbs to approximately 5% in those with grade 3 to 4 coma. The mortality can be substantially higher when institutions treat only small numbers of patients or lack experience or proper facilities. Adverse prognostic factors in depressant drug coma include an advanced age, the presence of complicating medical illnesses (especially systemic infections, hepatic insufficiency, and heart failure), and lengthy coma. Alkaline diuresis (for phenobarbital), hemodialysis, and charcoal hemoperfusion all have been reported to shorten coma and improve prognosis for patients with severe poisoning, especially from phenobarbital. Barring unexpected complications, patients recovering from depressant drug poisoning suffer no residual brain damage even after prolonged coma lasting 5 days or more. Rare exceptions to this rule occur in overdose patients who suffer aspiration pneumonia or cardiac arrest (e.g., during tracheal or gastric intubation). A small number of patients develop cutaneous pressure sores or pressure neuropathies from prolonged periods of immobility during the period of immobile coma before the victim is found and brought to hospital; this may be particularly common with barbiturate overdoses.

VEGETATIVE STATE

The vegetative state (also called coma vigil or apallic state) denotes the recovery of a crude cycling of arousal states heralded by the appearance of ‘‘eyes-open’’ periods in an unresponsive patient.63 Very few patients remain in eyes-closed coma for more than 10 to 14 days; vegetative behavior usually replaces coma by that time. Patients in VS, like comatose patients, show no evidence of awareness of self or their environment, but do retain brainstem regulation of cardiopulmonary function and visceral autonomic regulation. The term persistent vegetative state is now commonly reserved for patients remaining in that state for at least 30 days (see ANA Committee on Ethical Affairs 1993). As indicated in the paragraphs below, there are no clear criteria for determining when PVS becomes permanent.

One reason for the inability to predict permanence early in the course of PVS is that patients usually have badly damaged cerebral hemispheres combined with a relatively intact brainstem. Such a combination during the early days of illness causes coma with relatively good brainstem function, a picture similar to patients with reversible cerebral injury.

Since the publication of the third edition of Stupor and Coma, guidelines to aid construction of prognosis in VS have advanced greatly.64–66 The Multisociety Task Force on PVS,64,65 a joint commission composed of neurologists, neurosurgeons, and other specialists, organized a comprehensive review of outcomes of patients with prolonged VS using GOS criteria. Outcomes of 434 adult and 106 pediatric patients with TBI and 169 adult and 45 pediatric patients with nontraumatic etiologies were assessed. Figure 9–4 displays data from the TBI group for adults. For patients in VS for at least 1 month, 52% had recovered consciousness at 1 year postinjury (some 33% of the patients had recovered earlier than 3 months from the time of injury). If adult TBI patients remained in VS at 3 months, the percentage recovering consciousness at 1 year dropped to 35%, and to 16% for VS lasting at least 6 months. For pediatric patients with a TBIinduced VS for 1 month, 62% recovered consciousness at 1 year; if VS persisted for 3 months, this percentage dropped only to 56%, and to 32% for patients in VS for at least 6

Traumatic Injury (N = 106)

Months after Injury

months. The outcome of ‘‘conscious’’ per se does not reflect level of disability. However, the Task Force review indicated that for adults, within the 52% of patients recovering consciousness after 1 month in VS, only 24% became independent by GOS criteria. This figure dropped to 16% for VS lasting 3 months and to only 4% if taken out to at least 6 months.

Not surprisingly, nontraumatic VS carries a far less optimistic prognosis. Figure 9–4 shows comparison percentages for adult and pediatric patients with nontraumatic VS. For adult VS patients remaining in VS at 1 month, only 15% regained consciousness (with only 4% independent by GOS). These percentages worsened to 8% and 0% for patients remaining in a nontraumatic VS for 3 and 6 months, respectively.

Based on these data, the Task Force paper suggested that VS after 12 months following TBI, or 3 months following an anoxic injury, should be considered essentially permanent. However, it is important to recognize that a small number of patients may recover from VS beyond these time points.67–69 Such late recovery past the cutoffs for permanent VS from both anoxic and traumatic etiologies has generally been to levels of severe disability, including the minimally conscious state.66 Nevertheless, application of these statistics to individual cases can be risky, unless independent evidence of the mechanism of brain injury is available, as rare cases of late recovery continue to be reported. The uncertainty in prognosis in such cases highlights the need for better methods, such as direct measurements of cerebral function, to help identify cases where recovery is likely.

Mortality is very high within the first year; approximately one-third of patients die.64,65 If

patients remain alive after a year, mortality per year is low and some patients may continue to live for many years.66 Plum and Schiff studied one patient who had remained in PVS for 25 years (see Figure 9–8). Most patients in VS die from infection of the pulmonary system or urinary tract.

Clinical, Imaging, and

Electrodiagnostic Correlates of

Prognosis in the Vegetative State

A few clinical signs or confirmatory tests, including those negative predictors for coma in

general (as reviewed previously), help predict the prognosis of VS. As noted, abnormal SSEPs reliably indicate cortical damage and a high probability of remaining in VS following anoxic and traumatic brain injuries. However, normal evoked responses do not predict recovery. In a study of 124 patients in VS or MCS following TBI, three variables predicted recovery of ability to follow commands: (1) initial score on the Disability Rating Scale (DRS), (2) rate of change on the DRS measure in the first 2 weeks of observation, and (3) the time of admission to a rehabilitation program following injury.70

Several structural and functional correlates of VS have been examined. A prospective study of MRI imaging correlates of 80 patients remaining in VS following TBI at 6 to 8 weeks (with MRI and clinical follow-up at 2, 3, 6, 9, and 12 months) found that 42 patients who remained in VS at 1 year showed that structural injuries within the corpus callosum and dorsolateral brainstem significantly predicted nonrecovery (214-fold and sevenfold higher probability of nonrecovery from VS, respectively, based on adjusted odds ratios accounting for age, GCS, pupillary dysfunction, and number of brain lesions).71 Overall, this model achieved a classification rate of 87.5% for identifying patients who would not recover past VS.

Quantitative fluorodeoxyglucose-positron emission tomography (FDG-PET) studies measuring resting cerebral metabolism have consistently demonstrated that global cerebral metabolism is markedly reduced to 40% to 50% of normal metabolic rates in most VS patients (see page 365). Unfortunately, early identification of low metabolic activity is not a clear predictor of outcome and some patients have recovered consciousness despite significant remaining abnormalities in resting metabolic level.72 The N- acetylaspartate (NAA)-to-creatine (Cr) ratio on magnetic resonance spectroscopy (MRS) of the thalamus is low in all patients in VS, but lower in those who do not recover73; however, only a few patients have been studied.

Efforts to predict outcome or characterize VS using EEG have been disappointing. EEG studies may remain abnormal as patients improve or, conversely, improve when patients do not.74 Event-related potentials (ERPs) may hold more promise. These potentials require cortical processing of stimuli that can be passively presented to subjects in VS. The responses are long latency with peak activation

usually several hundred milliseconds after stimulation and are not strictly time locked to the stimulus onset. Long-latency auditory cortical potentials (N100, P150), the P300 response, and the mismatch negativity (MMN) ERPs have each shown some potential for providing evidence of recovery. The P300 response can be elicited by inclusion of an ‘‘oddball’’ tone in an otherwise monotonous presentation of repeated identical tones. The MMN is an early component of the auditory response to the oddball stimulus that is attention independent and reliably induced following the N100 auditory cortex potential, an early primary auditory evoked response. In a study of 346 patients in coma for 12 months with outcomes divided into VS versus all categories better than VS (including MCS), N100 and MMN were strong predictors of recovery past VS; no patient with MMN in this cohort remained in VS. If the electrophysiologic variables were combined with information about the pupillary light reflex, the probability of recovery past VS reached 89.9%.40 However, other studies have raised questions about the specificity of preserved ERP responses75 in VS.

MINIMALLY CONSCIOUS STATE

The minimally conscious state76 identifies a condition of severely impaired consciousness with minimal but definite behavioral evidence of self or environmental awareness. Table 9–12 provides the criteria for the diagnosis of MCS. Like VS, MCS often exists as a transitional state arising during recovery from coma or during the worsening of progressive neurologic disease. In some patients, however, it may be a permanent condition. A few studies have examined differences in outcome between VS and MCS. Giacino and Kalmar reported retrospective findings in 55 VS patients and 49 MCS patients evaluated at 1, 3, 6, and 12 months following either traumatic or nontraumatic injuries.77 Both presented with similar levels of disability at 1 month postinjury. The MCS patients, however, had significantly better outcomes as measured by the Disability Rating Scale compared with outcomes for VS patients at 1 year, particularly in the TBI patients. Strauss and colleagues78 retrospectively studied life expectancy of a large number of children (ages 3 to 15) in VS (N ¼ 564) and

Table 9–12 Aspen Working Group Criteria for the Clinical Diagnosis of the Minimally Conscious State

Evidence of limited but clearly discernible self or environmental awareness on a reproducible or sustained basis, as demonstrated by one or more of the following behaviors:

1.Simple command following

2.Gestural or verbal ‘‘yes/no’’ responses (independent of accuracy)

3.Intelligible verbalization

4.Purposeful behavior including movements or affective behaviors in contingent relation to relevant stimuli. Examples include:

a.Appropriate smiling or crying to relevant visual or linguistic stimuli

b.Response to linguistic content of questions by vocalization or gesture

c.Reaching for objects in appropriate direction and location

d.Touching or holding objects by accommodating to size and shape

e.Sustained visual fixation or tracking as response to moving stimuli

From Giacino et al.,76 with permission.

MCS, dividing the latter into two groups: immobile MCS (N ¼ 705) and mobile MCS (3,806). A significant increase in the percentage of patients still alive at 8 years was noted for the mobile MCS group (81%) compared to theimmobileMCS(65%)ortheVS(63%)group; the latter two were statistically indistinguishable. Lammi and associates79 examined 18 MCS patients 2 to 5 years after injury and found a marked heterogeneity of outcome despite prolonged duration of MCS after TBI. Most of their patients regained functional independence, but there was a poor correlation between duration of MCS and outcome. In general, clinical and electrodiagnostic tests have not yet been developed for use in the diagnosis and prognosis of MCS outside of a research context (see below for discussion).

MCS also includes some forms of the clinical syndrome of akinetic mutism (Box 9–1) and other less well-characterized disorders of consciousness. At least two different identifiable groups of patients are considered exemplars of akinetic mutism. Although occasionally confused with VS, classical akinetic mutism resembles a state of constant hypervigilance. The patients appear attentive and vigilant but