Disorders of Consciousness in Systemic Diseases




Keywords

consciousness, coma, metabolic encephalopathy, brain death, vegetative state, minimally conscious state

 


Consciousness is a complex and elusive concept that has been the subject of extensive thought and speculation by philosophers, theologians, and scientists since antiquity. The fact that consciousness may mean different things depending on the context (philosophy, religion, science) demonstrates the importance that understanding normal and disordered consciousness holds across a wide variety of fields of study. In medicine, disorders of consciousness are pervasive among the effects of systemic diseases on the nervous system. Because alterations in consciousness may have important diagnostic, therapeutic, and prognostic implications, a pragmatic approach using the neurologic principle of localization and the medical approach of differential diagnosis is useful. The spectrum of consciousness, from wakefulness to coma to brain death, has an anatomic and biologic substrate.




Consciousness


Historical Perspective


Ever since the Greek physician Galen (130 to 200 a . d .) recognized that a wound of the brain could affect the mind, the roles of consciousness and thought as manifestations of brain injury and impairment have held a special role. During the Renaissance, the philosopher Descartes (1596 to 1650) focused on the “mind–brain problem.” He thought that the pineal gland was the seat of the soul, and this structure therefore played a special role in his concept of consciousness, although contemporaries granted this honor to the corpus callosum. Late nineteenth and early twentieth century efforts such as William James’s “stream of consciousness” focused on psychologic, not anatomic, mechanisms. Although the effect of systemic diseases on consciousness has been recognized since Hippocrates in the fifth century b . c . described “madness on account of bile,” the ability to ascribe testable anatomic and biologic correlates to consciousness is distinctly modern. The two main advances that have made this possible are (1) development of an operational definition of consciousness that has practical applicability and (2) understanding of the anatomic substrate of consciousness.


Definition of Consciousness


In medicine, consciousness can be defined as awareness of self and the environment. Thus, decreased consciousness involves impairment of this state of awareness, with coma being its absence. Consciousness and conscious behavior have two basic components: arousal and content. Arousal is behaviorally related to the level of alertness or wakefulness. Content describes the complex range of cognitive functions, including thought, memory, and language. As described later, a simplified anatomic model of consciousness gives arousal and content distinct anatomic localizations. Arousal and content may be independent but are frequently interdependent. For content to be present or at least to be assessed clinically, some degree of arousal must be present. Conversely, if decreased arousal (e.g., from sedative drug intoxication) is overcome by a noxious stimulus, content may be seen to be largely normal until arousal fades again. A description of the state of consciousness of an individual must take into account both level of arousal and quality of content. Different diseases and neuroanatomic sites may be implicated, depending on the specifics of the state of consciousness. The term level of consciousness usually refers to level of arousal ( Table 60-1 ).



Table 60-1

Spectrum and Components of Consciousness





























Spectrum of Arousal
Alert
Confused
Lethargic
Obtunded
Stuporous
Comatose
Components of Content
Cognition (thought)
Awareness of environment
Memory
Language
Visuospatial integration


Anatomy of Consciousness


Although somewhat of an oversimplification, the two different components of consciousness are mediated by two distinct neuroanatomic systems ( Fig. 60-1 ). Arousal is mediated by the ascending reticular activating system (RAS). The RAS is located in the brainstem and is a loosely arranged column of neurons extending from the upper third of the pons to the diencephalic structures of the thalamus and hypothalamus. Projections via subcortical relay nuclei, primarily in the thalamus, integrate RAS-mediated arousal with more diffuse cerebral cortical functions. Experimental studies have demonstrated that stimulation of the RAS in a sleeping animal results in immediate behavioral arousal, but when the RAS is destroyed, no amount of sensory stimulation reverses coma, even with subcortical and cortical structures intact.




Figure 60-1


Neuroanatomy of consciousness. The reticular formation (also known as the reticular activating system [RAS]) is a loosely arranged column of neurons located in the brainstem. Arousal is largely mediated by the RAS through projections to the cerebral cortex through the thalamus. The content of consciousness is localized more diffusely throughout the cerebral cortex. The reticular formation is distinguished from other brain structures associated with induction of sleep.

(Netter illustration from www.netterimages.com . © Elsevier Inc. All rights reserved.)


The content of consciousness is localized more broadly throughout the cerebral cortex. Certain cognitive functions are diffusely localized throughout both cerebral hemispheres, whereas other functions may have more narrow localization. Receptive language and expressive language are principally localized to the superior temporal lobe or posterior frontal lobe, respectively, of the dominant hemisphere. Although various aspects of memory may be stored diffusely, the mesial temporal lobes and mamillary bodies are important for storage of new short-term memory. Conversely, processes such as thought, orientation, attention, and planning are localized diffusely, especially among both frontal lobes. Because a severe impairment of receptive language is likely to alter the state of awareness of self or environment (as far as can be deduced by examination), some may consider it an altered state of consciousness. Others place more emphasis on impairment of bihemispheric dysfunction, evidenced by decreased attention, concentration, and coherent thought, as defining altered content of consciousness. The important lesson is that different aspects of the content of consciousness may have different anatomical localizations and that global impairment of cognitive function implies bilateral cerebral hemispheric dysfunction or disease.


Implications for Systemic Diseases


Coma, or unconsciousness, is a state of unresponsiveness in which the subject has closed eyes and cannot be aroused appropriately with stimuli. For coma to be present, one of two general anatomic conditions must be satisfied: there must be significant impairment of either the RAS or both cerebral hemispheres ( Table 60-2 ). Structural lesions usually cause coma through direct brainstem involvement or through brainstem displacement or compression with subsequent RAS involvement. The underlying pathologic processes are often primary neurologic disorders such as intracerebral hemorrhage, traumatic brain injury, subdural hematoma, brain tumors or abscesses, or large cerebral infarctions with mass effect. Transtentorial herniation because of a supratentorial mass, direct brainstem impingement from an infratentorial lesion, or direct parenchymal brainstem involvement from hemorrhagic or ischemic stroke are common examples. Less commonly, subfalcine herniation or bihemispheric mass lesions may lead to coma with an intact brainstem due to diencephalic injury. Metabolic disturbances, by contrast, usually cause coma from diffuse bihemispheric involvement, which presumably results in disconnection between the RAS (and subcortical thalamic relay nuclei) and the hemispheres. The neurologic examination of the comatose patient is an important key in distinguishing the cause and anatomic basis of coma, specifically the presence or absence of other brainstem and cranial nerve abnormalities such as pupillary or extraocular movement dysfunction. The cause of lesser degrees of impaired level of consciousness can also be assessed by determining whether bihemispheric or brainstem dysfunction is responsible.



Table 60-2

Neuroanatomic Localization of Coma

































































Brainstem (RAS)
Brainstem compression
Transtentorial herniation from supratentorial mass lesion
Subdural hematoma
Intracerebral hemorrhage
Post-traumatic cerebral edema
Large hemispheric infarction with mass effect
Brain tumor or abscess
Acute hydrocephalus
Infratentorial mass lesion
Cerebellar hematoma
Cerebellar infarct
Cerebellar tumor
Intrinsic brainstem involvement
Pontine hemorrhage
Basilar artery occlusion
Metabolic brainstem involvement
Severe hypoxic-ischemic injury
Anesthetic agents (?)
Severe organ failure (?)
Bilateral Cerebral Hemispheres
Subfalcine (cingulate) herniation
Brain tumor or abscess (with edema)
Large hemispheric infarction with mass effect
Bilateral structural hemispheric involvement
Widely metastatic cancer
Primary brain tumor (crossing corpus callosum)
Metabolic encephalopathy
Organ failure
Medications (drugs)
Hypoxic-ischemic injury

RAS, reticular activating system.


Sleep should be considered as a separate and distinct entity. Externally, patients in coma initially appear asleep, but sleeping individuals can be roused and then respond to the environment. Normal sleep has several stages that have distinct electroencephalographic (EEG) patterns as discussed in Chapter 51 . The EEG findings in coma may vary, depending on the cause, but, in general, do not resemble those of sleep. Altered consciousness in systemic disease is a pathologic state in contrast to sleep, which is a necessary and normal function.




Mechanisms of Impaired Consciousness in Specific Diseases


A practical approach to determining the cause of impaired consciousness in systemic disease requires an understanding of the mechanisms by which primary neurologic disorders as well as systemic diseases may affect the central nervous system (CNS). The neuroanatomic localization of consciousness implies that both focal and global, or diffuse, processes may alter the level or content of consciousness. Structural causes are intuitively easier to understand than many metabolic or diffuse causes. Compression, distortion, or infarction of the brainstem and RAS are processes for which urgent interventions, such as neurosurgical evacuation of a mass lesion or thrombolysis of an occluded artery, may be indicated. In contrast, metabolic encephalopathies cause impaired consciousness (either content or arousal) by interfering diffusely with the functions of the brain on a biochemical level; however, some metabolic encephalopathies can be considered “structural” on a microscopic level when they result in direct cellular brain injury. Although the mechanisms by which systemic diseases cause alteration in consciousness are diverse, they can be divided into three broad categories: metabolic encephalopathies, focal neurologic manifestations of systemic disorders, and primary neurologic disorders caused by systemic disease.


Metabolic Encephalopathies


Metabolic encephalopathy is the most frequent cause of disordered consciousness in systemic diseases, and is defined as an alteration in consciousness caused by diffuse or global brain dysfunction from impaired cerebral metabolism. The list of metabolic encephalopathies is extensive and includes such disparate conditions as hypoxic-ischemic encephalopathy, hepatic encephalopathy, drug overdose, bacterial meningitis, and the postseizure state. The principal reason for grouping together this wide variety of disorders is that the neurologic examination may appear quite similar regardless of the underlying etiology. Nevertheless, the cause of the metabolic encephalopathy is the fundamental determinant of treatment and prognosis. Thus, considering the biochemistry of metabolic encephalopathies is of prime importance in their differentiation.


Two common themes emerge with regard to presumptive etiologies of metabolic encephalopathies in systemic disease: impaired substrate delivery (glucose or oxygen) to the brain or release by a systemic disease of a circulating substance that crosses the blood–brain barrier (or enters through a broken blood–brain barrier) and causes neuronal and cellular dysfunction ( Table 60-3 ). The former, implicated in hypoxic-ischemic encephalopathy and hypoglycemia, may result in irreversible brain injury. The latter, implicated in most metabolic encephalopathies associated with organ system dysfunction (e.g., hepatic, renal) or with systemic infection, may be largely reversible if the underlying disorder is treated. Although there are exceptions, this mechanistic differentiation can be of great importance in determining treatment and prognosis.



Table 60-3

Mechanisms of Metabolic Encephalopathies























































Impaired Substrate Delivery
Hypoxia-ischemia
Hypoglycemia
Organ Failure
Hepatic encephalopathy
Renal failure
Pancreatic encephalopathy
Carbon dioxide narcosis
Circulating Cytokines (Putative)
Sepsis
Multisystem organ failure
Meningitis
Electrolyte Abnormalities
Hyponatremia
Hypernatremia
Hypercalcemia
Diffuse Brain Infection
HIV infection
Syphilis
Lyme disease
Autoantibodies
Paraneoplastic syndromes
Collagen vascular diseases
Diffusely Decreased Cerebral Metabolism
Medications/anesthesia/sedative drugs
Hypothermia

HIV, human immunodeficiency virus.


When substrate delivery to the brain is globally reduced, encephalopathy and eventually coma may result. Hypoxia, and especially hypoxia-ischemia, may result in permanent cerebral damage diffusely or in selectively vulnerable areas such as the hippocampus, cerebellum, and thalamus. The degree and duration of hypoxia or decreased cerebral blood flow determine the severity and irreversibility of damage. Hypoxic-ischemic encephalopathy most commonly results from severe hypotension or cardiac arrest and is mediated by the neuronal ischemic injury cascade, which includes release of excitatory amino acids, intracellular calcium influx, lipid peroxidation, and cell breakdown. Two clinical trials have demonstrated a beneficial effect of immediate treatment of comatose survivors of cardiac arrest with mild hypothermia (33°C for 12 to 24 hours after out-of-hospital cardiac arrest from ventricular fibrillation or pulseless ventricular tachycardia), and this treatment is part of standard resuscitation guidelines as discussed in Chapter 9 . Hypoglycemic encephalopathy is potentially reversible, but permanent damage may occur if it is not treated early. Hypertensive encephalopathy may be due to disordered cerebral autoregulation, elevated cerebral vascular resistance, and subsequent globally decreased cerebral blood flow. These substrate-delivery encephalopathies have altered cerebral oxygen and glucose delivery as a common pathway, regardless of cause, and may result in severe permanent neurologic damage if not treated urgently.


In contrast, systemic organ failure is a common cause of metabolic encephalopathy and carries a different prognosis than the substrate-delivery encephalopathies. Kidney (uremia) and liver failure are common causes. Carbon dioxide narcosis from pulmonary failure and, rarely, pancreatic failure can also cause encephalopathy. The biochemical mechanism of uremic encephalopathy is not known precisely, but decreased ability to utilize adenosine triphosphate by the uremic brain and elevated calcium content in the cerebral cortex and hypothalamus have been suggested. In hepatic encephalopathy, endogenous benzodiazepine-like substances may play a role, as suggested by animal studies and from experience in humans with improvement after administration of flumazenil. In hepatic failure, elevated levels of α-ketoglutaramate in the cerebrospinal fluid (CSF) correlate with systemic elevations in ammonia as well as depth of coma. Patients with fulminant hepatic failure may also have severe diffuse cerebral edema, and the acutely increased intracranial pressure provides a structural basis for the coma in this situation. Abnormal function of endocrine organs may cause encephalopathy through primary mechanisms (e.g., myxedema coma, thyrotoxicosis, hypocortisolemia) or through changes in electrolytes or the cerebral acid-base environment (e.g., hypercalcemia in hyperparathyroidism).


Encephalopathy frequently accompanies sepsis, especially when associated with multisystem organ failure. Critically ill patients may have multiple reasons for encephalopathy including primary organ failure (especially of kidneys and liver), electrolyte abnormalities, and concurrent use of sedative agents to facilitate interventions such as mechanical ventilation. However, sepsis itself is associated with a metabolic encephalopathy. Although proposed mechanisms of septic encephalopathy range from multiple microabscesses throughout the brain to alterations in cerebral blood flow mediated by nitric oxide, circulating cytokines that cross the blood–brain barrier and are released during sepsis or the systemic inflammatory response syndrome are likely to be implicated. In contrast to substrate-delivery metabolic encephalopathies, these alterations in consciousness are generally thought to be reversible if the underlying organ pathologic process or sepsis is reversed.


Electrolyte and acid-base disturbances are a common cause of encephalopathy. Among these, hyponatremia, hypernatremia, and hypercalcemia are most commonly associated with a decreased level of consciousness. In most circumstances, these encephalopathies are reversible, although rapid correction of hyponatremia should be avoided to decrease the potential of osmotic demyelination (central pontine myelinolysis).


A global decrease in the cerebral metabolic rate of oxygen consumption may occur during profound hypothermia and following sedative drug overdose. This is reversible if substrate delivery is maintained. Thus, general anesthesia itself can be viewed as a cause of reversible metabolic encephalopathy or coma. Metabolic encephalopathy, often without a markedly decreased level of consciousness, may be caused by numerous prescription medications and may be mistaken for dementia in the elderly. Encephalopathy may also be a manifestation of collagen vascular disease (e.g., systemic lupus erythematosus, SLE), or systemic cancer. Although the latter may be mediated by electrolyte disturbances in the setting of the syndrome of inappropriate secretion of antidiuretic hormone or through paraneoplastic antibodies or circulating cytokines, these disorders may also cause alterations in consciousness from focal processes related specifically to the underlying cancer or collagen vascular disease.


The term delirium refers to a state of globally disturbed consciousness in which a subject has decreased attention and an altered sensorium, usually developing over hours to days and often with fluctuating symptoms. Agitation and hallucinations may be present but are not required for the diagnosis. Delirium has historically been a general descriptive term akin to metabolic encephalopathy and distinguished from dementia by its fairly abrupt onset, altered sensorium, and association with other medical conditions. However, within the past decade, delirium has been used specifically to describe a state of fluctuating confusion in hospitalized patients, often in those who are critically ill. The presence of delirium has been associated with worsened clinical outcome in these patients, and some studies have suggested that delirium is itself an independent condition with a pathophysiology and treatment distinct from the many other systemic diseases known to cause metabolic encephalopathy. The neurotransmitter acetylcholine is particularly implicated in delirium. Predisposing factors include older age, dementia, sensory impairment, sleep deprivation, and the use of sedative medications. Inflammatory serum markers and genetic polymorphisms of the apolipoprotein E gene have also been suggested as predictors of presence or duration of delirium. In the intensive care unit, the use of the sedative medication dexmedetomidine has been associated with less delirium than benzodiazepine infusions. Long-term cognitive impairment has been associated with delirium in acutely hospitalized patients, especially those with preexisting cognitive impairment. It is distinctly uncommon, however, for delirium to lead to a chronic vegetative or minimally conscious state. It remains controversial whether delirium is principally an indicator of the need for aggressive treatment of underlying medical problems and minimization of sedative usage in the hospital.


Systemic Disorders with Focal Neurologic Manifestations


A variety of systemic disorders may cause alteration of consciousness through either infiltration of the CNS or the presence of discrete lesions. Occasionally, patients may appear clinically to have a diffuse encephalopathy, but close examination reveals focal neurologic signs. In this setting, the distinction between metabolic encephalopathy and diffuse multifocal cerebral disease may be clinically difficult and appear to be only a matter of semantics. Pathologically, however, the processes are quite different, with the latter representing more than just an alteration in substrate delivery or a global process related to circulating systemic factors. The three categories of systemic disease that most often manifest in this manner are collagen vascular diseases, systemic malignancies, and diffuse infections.


Neuropsychiatric complications are frequent clinical manifestations of SLE. Neuropathologic findings in these patients vary from normal to the presence of diffuse microinfarcts. Lupus cerebritis commonly manifests as a focal process with pathologic findings of a bland, and occasionally necrotizing, vasculopathy with perivascular inflammatory infiltrates. There is debate whether this represents a “true” vasculitis or a more infiltrative process surrounding, rather than invading, the vessels. Particular neurologic manifestations depend on lesion location, and aphasia due to focal lesions in the language regions or abulia due to bifrontal lesions are common. Neurosarcoidosis most often manifests as meningeal inflammation or focal cranial neuropathies but can occur as a large cerebral or brainstem mass lesion that affects consciousness.


Systemic cancer affects consciousness in a variety of ways. Cancer may cause metabolic problems related to electrolyte disturbances and primary organ dysfunction. Focal neurologic manifestations in patients with cancer more likely suggest metastatic disease to the CNS, as discussed in Chapter 26 . Metastatic brain tumors are much more common than primary brain tumors. Most commonly occurring supratentorially, mass effect from metastases may cause cerebral herniation with brainstem compression or bihemispheric dysfunction. Meningeal carcinomatosis often spares consciousness, except when so extensive that intracranial vessels at the base of the brain are affected, leading to stroke. Cancer treatments themselves may have effects on consciousness. Metabolic encephalopathy may be caused by certain chemotherapeutic agents, and cranial irradiation may result in focal necrosis that is initially difficult to differentiate from recurrent tumor.


Infection may also cause focal or global neurologic disturbances of consciousness. Brain abscess, meningitis, or encephalitis may occur in otherwise normal individuals or in those with compromised immune systems due to a variety of systemic diseases. Several systemic infections are particularly associated with focal processes or infiltration of the nervous system including human immunodeficiency virus (HIV) infection, syphilis, and Lyme disease. Direct infection of neurons by HIV may result in HIV encephalopathy. Although described as a diffuse encephalopathy, it is probably a “microscopic structural” process related to global infection and infiltration. Progressive multifocal leukoencephalopathy (PML) occurs from infection with the JC papovavirus and manifests principally as cerebral white matter lesions that may involve altered consciousness. Patients immunocompromised from HIV infection are also at risk of a myriad of CNS problems, including primary CNS lymphoma, toxoplasmosis, and other opportunistic infections, discussed further in Chapter 44 . Syphilis may have a variety of CNS manifestations; consciousness may be affected by strokes in meningovascular syphilis, and dementia occurs in tertiary syphilis. Lyme neuroborreliosis may cause generalized confusion that has been mistaken for psychiatric disease. Like a number of other systemic disorders including SLE, sarcoidosis, PML, and syphilis, Lyme disease may have the neuroimaging appearance of diffuse cerebral white matter (or demyelinating) lesions, and therefore, may mimic multiple sclerosis.


Systemic Diseases Presenting as Primary Neurologic Disorders


Seizures, stroke, and acute mass lesions are primary neurologic disorders that may occur secondary to systemic diseases. Generalized seizures, by definition, result in alteration or loss of consciousness. Stroke and acute mass lesions may cause alterations in consciousness depending on their location. Although systemic diseases such as hypertension and diabetes are implicated in the genesis of stroke, cancer is implicated in metastatic CNS disease, and many systemic disorders cause seizures, certain conditions have primary neurologic diagnoses as their principal manifestation.


Large-vessel ischemic strokes may occur from either embolic or thrombotic causes. Infective endocarditis or marantic endocarditis (as in SLE or cancer) may result in embolic infarction that may alter consciousness depending on stroke location and size, as discussed in Chapter 6 . Hypercoagulable states may occur in cancer or autoimmune disorders and cause thrombotic large-vessel occlusion of the cerebral arterial circulation. Hypercoagulability may also lead to thrombosis of the cerebral venous sinuses; alterations in factors V and VIII as well as proteins C and S during an ulcerative colitis flare are a potentially underrecognized cause. Leukemia with white blood cell counts in excess of 100,000/µl, polycythemia vera with hematocrit greater than 55 percent, and essential thrombocythemia with a platelet count above 1,000,000/µl may each increase blood viscosity leading to thrombotic occlusion. Small-vessel or lacunar infarcts rarely result in alterations in consciousness. Cerebral vasculitis, however, is often associated with confusion and alteration in behavior and the content of consciousness due either to large-vessel stroke or, more commonly, to widespread mid-size and small-vessel infarction. Although cerebral vasculitis may occur in isolation (e.g., granulomatous angiitis of the nervous system), numerous connective tissue disorders, including polyarteritis nodosa and Churg–Strauss syndrome, may be implicated (see Chapter 50 ).


Cerebral mass lesions that lead to a decrease in the level of consciousness usually develop rapidly. Primary and secondary brain tumors may manifest in this manner, but acute intracranial hemorrhage is the most common responsible lesion. Hypertension is the most common cause of intracerebral hemorrhage. Coagulopathy in the setting of liver failure, disseminated intravascular coagulation, or thrombotic thrombocytopenic purpura may precipitate a spontaneous intracerebral, subdural, or epidural hematoma. Mild head trauma, which would otherwise be well tolerated, may lead to severe intracranial bleeding with subdural or intraparenchymal hematoma formation if a concomitant coagulopathy is present.




Approach to Patients with Disordered Consciousness


The fundamental goal of evaluation of patients with disorders of consciousness is to distinguish processes that may cause ongoing brain injury from those that are reversible if concurrent systemic diseases are treated adequately. The manifestations of systemic diseases in the CNS are protean, and “benign” and “malignant” causes of altered consciousness may appear clinically similar. Thus, an orderly approach to the evaluation of patients is essential for timely and accurate diagnosis, which can direct focused treatment. The approach should combine clinical neurologic assessment with judicious use of other diagnostic studies including neuroimaging, electrophysiologic evaluation, CSF analysis, and other laboratory tests.


Neurologic History and Examination


The neurologic findings in patients with altered consciousness and the time course of onset are the principal components of patient assessment. All supporting studies, regardless of their nature, must be interpreted within the context of the neurologic examination. The neuroanatomy of consciousness forms the underpinning for neurologic assessment, and it is this localization that allows the formation of a differential diagnosis. The first step is to define whether the primary disturbance is of content or arousal.


When content of consciousness is impaired in patients who are alert and without marked decrease in the level of consciousness, neurologic assessment focuses on higher cortical function. Abnormalities of language, visuospatial orientation, and visual fields suggest a focal cerebral cortical lesion. Disordered attention, concentration, and short-term memory usually suggest a more global process involving both cerebral hemispheres. In the former case, stroke, tumor, a demyelinating process, or focal abscess should be considered, and neuroimaging may be diagnostic. In disorders of global cerebral content, a diffuse process is implicated; depending on the history and associated medical and neurologic findings, a primary neurologic process such as Alzheimer disease or a global metabolic encephalopathy from organ dysfunction, medications, or postictal state may be responsible.


The more urgent circumstance occurs in patients with decreased level of arousal, especially coma. Processes, either structural or metabolic, that develop acutely tend to involve a disproportionately decreased level of consciousness compared with those that develop over much longer periods of time. The initial focus of the neurologic examination of the stuporous or comatose patient should be in defining the anatomic localization of the process, distinguishing between brainstem (RAS) and bihemispheric disease. This is also often the distinction between structural (usually RAS) and metabolic (usually bihemispheric) causes of coma. A notable exception is the locked-in state, in which a structural lesion, usually a stroke, involves the brainstem but spares the RAS. Patients who are “locked in” are not comatose and may have intact consciousness; motor function in the form of eye opening and blinking is usually retained, whereas ocular movements and appendicular motor function are typically absent. Thus, the first step in clinical evaluation of the apparently comatose patient is to exclude the possibility of the locked-in syndrome, which is suggested by the observation that the patient can open their eyes and blink to command.


Once coma is established, assessment of brainstem and motor function can proceed. Abnormalities of pupillary function, ocular motility, corneal and gag reflexes, and respiratory function help distinguish an intact from an impaired brainstem. Preserved pupillary function is a hallmark for distinguishing between metabolic and structural causes of coma. Reflexive ocular movements (oculocephalic reflexes tested with “doll’s eyes” or “cold caloric” maneuvers) are typically preserved in metabolic coma. Occasionally, however, odd conjugate downgaze, skew deviation, and loss of ocular reflexes are found in deep coma caused by metabolic disorders, especially liver failure or sedative drug overdose. Unilateral absence of the corneal or gag reflex suggests structural brainstem impairment. Motor function is symmetric in coma of metabolic origin. Depth of coma, regardless of cause, may determine whether purposeful response to pain is present. Gross asymmetry of purposeful or reflex motor response to pain suggests a structural process. Patients in deep coma of metabolic cause, especially from sedative drug overdose, may exhibit symmetric flexor or extensor posturing, with retained brisk pupillary reflexes and intact brainstem reflexes.


Neuroimaging


Findings on clinical examination direct the need for, and type of, neuroimaging required. Most patients without a history of head trauma who are somnolent with a global alteration in cognitive function and intact brainstem reflexes have a metabolic encephalopathy. When a known systemic cause of metabolic encephalopathy, such as uremia, liver failure, or sedative or other drug use, is present, neuroimaging may not be necessary. Conversely, all patients with coma of unknown etiology require urgent head imaging.


The principal value of early neuroimaging is to evaluate for structural processes. Computerized tomography (CT) is particularly effective at demonstrating acute intracranial hemorrhage and in most centers is more easily obtained in neurologically impaired patients than magnetic resonance imaging (MRI); therefore noncontrast CT is the best first option for neuroimaging in patients with acute alteration or loss of consciousness. CT in acute stroke (within the first 12 hours) may be normal or show only subtle abnormalities such as loss of gray-white differentiation or mild edema. CT is greater than 91 percent sensitive for subarachnoid hemorrhage following aneurysm rupture, and nearly always shows acute intraparenchymal or extra-axial processes such as hemorrhage and mass lesions that are causing cerebral herniation. By contrast, head CT in metabolic encephalopathy is usually negative or nondiagnostic.


MRI is much better than CT at delineating specific anatomic structures, especially in the posterior fossa. It is usually not necessary in the emergency setting when CT has been performed. An important exception is when cerebral venous sinus thrombosis is suspected; CT with contrast demonstrates a sign known as the “empty delta” in approximately 30 percent of cases; this represents clot in the torcula, where the superior sagittal sinus meets the paired transverse sinuses. However, MRI with contrast, especially when done with magnetic resonance venography, is highly sensitive and specific for thrombosis of the sagittal sinus or other intracranial venous sinus that might be the cause of coma. For patients in whom altered consciousness or coma is not acute, MRI may be preferable to CT because it is more likely to reveal cerebral metastases, subtle signs of infection or cerebral swelling, or changes that are sometimes seen in certain metabolic conditions, such as basal ganglia abnormalities in liver disease or posterior white matter changes in hypertensive encephalopathy or eclampsia. Newer tools such as magnetic resonance spectroscopy can provide a more direct measure of cerebral metabolism in regions of interest, but its role in routine evaluation remains unclear.


Electrophysiologic Studies


EEG and evoked potentials are the major electrophysiologic modalities of diagnostic use in patients with altered consciousness. They are used mainly to exclude seizures (especially nonconvulsive status epilepticus), to confirm the diagnosis of certain metabolic encephalopathies that may have characteristic EEG patterns, and to provide a guide to prognosis in irreversible cerebral injuries, especially hypoxic-ischemic encephalopathy. EEG is indicated in patients with coma of unknown etiology, especially those who have nondiagnostic head imaging studies.


Nonconvulsive status epilepticus is a disorder in which generalized seizures continue without gross motor manifestations of convulsions. This may occur in patients who present with clinically apparent seizures and then continue to seize even after clinical evidence of convulsions ceases. It includes patients with frequent complex partial seizures or absence status (spike-wave stupor). Subclinical electrographic seizures may be identified in up to 20 percent of patients with significant primary neurologic injuries (such as stroke or traumatic brain injury) who undergo continuous EEG monitoring in the neurologic intensive care unit. In two studies of inpatients with primarily medical illness outside the intensive care unit, electrographic seizures were found in 7 to10 percent of those monitored with EEG. Although this form of status epilepticus as the sole reason for decreased level of consciousness is uncommon, the diagnosis cannot be made without an EEG. Overt status epilepticus, especially myoclonus or nonconvulsive status, after a hypoxic-ischemic cerebral insult carries a poor prognosis.


Metabolic encephalopathies have a relatively uniform pattern on EEG, with diffuse bilateral slowing of the background rhythm. As metabolic coma deepens, amplitude may decrease. Triphasic waves may be found in hepatic encephalopathy but are nonspecific and present in other metabolic encephalopathies, including uremic and septic encephalopathies. In patients with hepatic encephalopathy who are receiving flumazenil as a diagnostic or therapeutic maneuver, EEG monitoring can demonstrate return of more normal background rhythms concurrent with improvement in level of consciousness.


Evoked potential monitoring is usually reserved for the evaluation of comatose patients. Short-latency somatosensory evoked potentials are typically preserved in reversible metabolic encephalopathies. However, in conditions that cause neuronal death, they may be abnormal and of prognostic value. In hypoxic-ischemic encephalopathy, bilateral absence of the N20 component of the somatosensory evoked potential (SSEP) to median nerve stimulation is strongly predictive of a very poor neurologic outcome (see Chapter 9 ). However, timely availability and variable expertise in interpretation remain shortcomings to widespread implementation.


Cerebrospinal Fluid and Other Laboratory Studies


Prior to the development of CT and MRI, lumbar puncture was a standard part of the investigation of patients with alterations in consciousness. Lumbar puncture is currently performed selectively when meningitis and encephalitis are diagnostic possibilities or when the etiology of coma remains elusive despite clinical evaluation, laboratory testing, and neuroimaging. In comatose patients, neuroimaging should be performed before lumbar puncture because of the rare but potential risk of precipitating transtentorial herniation.


Lumbar puncture may be of particular diagnostic utility in patients with an altered level of consciousness related to unsuspected cerebral venous sinus thrombosis from a hypercoagulable state, in which an elevated opening pressure may be the first diagnostic clue of increased intracranial pressure due to venous outflow obstruction. Analysis of the CSF may also be helpful for evaluation for suspected neurosyphilis, Lyme disease, and neurosarcoidosis. In other conditions such as HIV encephalopathy, CSF cell counts may be mildly elevated. A CSF pleocytosis may rarely be present after seizures, even when no apparent CNS infection is present, but this is uncommon and remains a diagnosis of exclusion.


Laboratory testing of serum electrolytes and of renal and liver function is a fundamental part of the evaluation of all patients with alterations in consciousness. It is important that metabolic derangements found on laboratory testing match the neuroanatomic localization of the patient’s syndrome; otherwise, further laboratory, neuroimaging, electrophysiologic, and CSF testing may be required. For example, a patient with liver failure, unilateral impairment of ocular reflexes, and a hemiparesis requires urgent neuroimaging to rule out an intracranial mass lesion such as an acute hematoma, especially because patients with liver failure often have concurrent coagulopathy. Also, when the degree of electrolyte abnormality does not correlate with the depth of alteration in consciousness (e.g., deep coma with a mildly depressed serum sodium concentration), more extensive neurodiagnostic testing should occur.


Diagnosis and Treatment: Coordinated Clinical Approach


The major concern in the management of patients with altered consciousness is preservation or restoration of brain function. The resuscitation principles of maintaining the airway, breathing, and circulation should always be attended to first. By ensuring oxygenation, ventilation, and adequate brain and tissue perfusion, impaired substrate delivery to the brain may be restored and secondary brain injury limited. Neurologic examination should then proceed. Urgent hematologic and biochemical screening tests, including renal and possibly hepatic function studies, should be performed concurrently with neuroimaging, usually CT scanning. Based on these results, EEG and lumbar puncture can be considered. If alteration in consciousness is mild or of relatively long standing, investigation can proceed less urgently.

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Aug 12, 2019 | Posted by in NEUROLOGY | Comments Off on Disorders of Consciousness in Systemic Diseases
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