Книги по МРТ КТ на английском языке / PLUM AND POSNER S DIAGNOSIS OF STUPOR AND COM-1

abnormal enhancement, but without mass effect. Lesions are frequently multiple.

The diagnosis, if suspected, can often be made by intestinal biopsy or sometimes by PCR of the spinal fluid, but may require meningeal biopsy.404 The disease is curable with antibiotics but lethal if not treated.

INFECTIOUS DISORDERS OF THE CENTRAL NERVOUS SYSTEM: VIRAL

Overview of Viral Encephalitis

Viruses, bacteria, rickettsia, protozoa, and nematodes can all invade brain parenchyma. However, only viruses, bacteria, and the rickettsial infection Rocky Mountain spotted fever405 invade the brain acutely and diffusely enough to cause altered states of consciousness and to demand immediate attention in the diagnosis of stupor or coma. Bacterial encephalitis has been considered above as a part of meningitis. Viral encephalitis is discussed in this section.

Viral encephalitis can be divided into four pathologic syndromes. These syndromes are sometimes clinically distinct as well, but the clinical signs of the first three are often so similar as to preclude specific diagnosis without biopsy, CSF PCR,406 or, sometimes, autopsy. (1) Acute viral encephalitis results from invasion of the brain by a virus that produces primarily or exclusively a CNS infection.407 (2)

Parainfectious encephalomyelitis also occurs during or after viral infections, particularly the childhood infections of measles, mumps, and varicella.407 (3) Acute toxic encephalopathy usually occurs during the course of a systemic infection with a common virus. (4) Progressive viral infections are encephalitides caused by conventional viral agents but occurring in susceptible patients, usually those who are immunosuppressed, or who develop the infection in utero or during early childhood. Such infections lead to slow or progressive destruction of the nervous system. During intrauterine development these disorders include cytomegalovirus, rubella, and herpes infections, although nonviral causes such as toxoplasma or syphilis can have a similar result. During

childhood, progressive brain damage may occur with subacute sclerosing panencephalitis, subacute measles encephalitis, or progressive rubella panencephalitis, but all of these are now rarely seen in vaccinated populations. Progressive multifocal leukoencephalopathy, a slow infection with JC virus, may occur at any time of life in an immune-compromised host. These latter disorders are subacute or gradual in onset, producing stupor or coma in their terminal stages. Hence, they do not cause problems in the differential diagnosis of stupor or coma, and are not dealt with here in detail. Progressive multifocal leukoencephalopathy is considered along with the primary neuro-

nal and glial disorders of brain (Table 5–1, heading G). Prion infections,408,409 includ-

ing Creutzfeldt-Jakob disease, GerstmannStrau¨ ssler disease, and fatal familial insomnia,410 were at one time also thought to be ‘‘slow viral’’ illnesses, but they are now known to be due to a misfolded protein. With the occasional exception of Creutzfeldt-Jakob disease, these disorders likewise are gradual in onset; they do not represent problems in differential diagnosis and are not discussed here.

In each of the pathologically defined viral encephalitides, the viruses produce neurologic signs in one of three ways: (1) they invade, reproduce in, and destroy neurons and glial cells (acute viral encephalitis). Cell dysfunction or death may occur even in the absence of any inflammatory or immune response. (2) They evoke an immune response that can cause hemorrhage, inflammation, and necrosis, or demyelination (parainfectious encephalomyelitis). (3) They provoke cerebral edema and sometimes vascular damage (toxic encephalopathy), both of which increase the ICP and, like a supratentorial mass lesion, lead to transtentorial herniation

The clinical findings in each of the viral encephalitides are sometimes sufficiently different to allow clinical diagnosis even when the illness has progressed to the stage of stupor or coma. Furthermore, within each of these categories, specific viral illnesses may have individual clinical features that strongly suggest the diagnosis. Unfortunately, all too often the first three categories, which cause acute brain dysfunction, cannot be distinguished on a clinical basis, and the generic term acute encephalitis must be used unless PCR, biopsy, or

autopsy material establishes the exact pathologic change. To compound the complexity, certain viruses can cause different pathologic changes in the brain depending on the setting. For example, acute toxic encephalopathy, parainfectious encephalomyelitis, subacute sclerosing panencephalitis, and subacute measles encephalitis were all reported to be caused by the measles virus (although now this is rarely seen). Despite these difficulties in diagnosis, an attempt should be made to separate the acute encephalitides into pathologic categories and to establish the causal agent, since the treatment and prognosis are different in the different categories. Brain biopsy is only rarely necessary, as discussed in detail on page 273.

Acute Viral Encephalitis

Although a number of viruses cause human encephalitis, only two major types are both common and produce coma in the United States: arboviruses (Eastern equine, Western equine, and St. Louis encephalitis) and herpes viruses.

Uncommon causes of stupor and coma include

West Nile virus (especially between August and October),411,412 severe acute respiratory

syndrome (SARS), and other emerging neurotropic viruses that may become more common causes of encephalitis-induced coma in the future.413 (The varicella-zoster virus, a rare cause of stupor in the normal adult population, may produce cerebral vasculitis [page 275]).

HERPES SIMPLEX ENCEPHALITIS (FIGURE 5–11)

This disease is pathologically characterized by extensive neuronal damage in the cerebral hemispheres with a remarkable predilection by the virus for the gray matter of the medial temporal lobe as well as other limbic structures, especially the insula, cingulate gyrus, and inferior frontal lobe. Neuronal destruction is accompanied by perivascular invasion with inflammatory cells and proliferation of microglia with frequent formation of glial nodules. The vascular endothelium often swells and proliferates. Areas of focal cortical necrosis are

common. Local hemorrhage into brain tissue may occur. Cowdry type A inclusion bodies in neurons and glial cells are a distinctive feature.

Clinically, herpes simplex encephalitis begins with the acute onset of a confusional state, aphasia, or behavioral changes, often accompanied by headache, fever, and seizures. The illness progresses acutely or subacutely to produce stupor or coma. In one series of 45 patients, 28 had Glasgow Coma Score of less than 10 and 13 were deeply comatose.414 This early stage may be fulminating, and in some instances may transition from full health to stupor in only a few hours. Often, behavioral disturbances or agitated delirium, particularly with olfactory or gustatory hallucinations, precedes coma by hours or days, a pattern so characteristic as to suggest the diagnosis. Focal motor signs frequently accompany the onset of coma, and tremors of the extremities, face, and even trunk commonly complement the agitated delirium of herpes encephalitis. Occasionally the neu-

rologic signs of herpes simplex encephalitis, either type 1415 or type 2,416, are limited to the

brainstem, with cranial nerve palsies predominating.

The CSF pressure is usually increased (180 to 400 mm CSF) and the white cell count is usually elevated (10 to 1000/mm3, mostly mononuclear). Both may be normal, particularly early in the course of the illness. Up to 500 red cells/mm3 are common and the CSF protein content usually is elevated (values up 870 mg/ dL having been reported). The CSF sugar is usually normal but occasionally depressed. Identification of viral DNA by PCR establishes

the diagnosis and obviates the need for a biopsy.417,418 The EEG is always abnormal.

Distinctive, periodic, high-voltage, 1-Hz sharp waves from one or both temporal lobes are highly characteristic of herpes simplex encephalitis and suggest a poor prognosis. Imaging with MRI typically identifies the lesions much earlier than CT. Abnormalities in the temporal lobes, and sometimes the frontal lobe as well, suggest the diagnosis. Functional imaging identifies hyperperfusion in the temporal lobe.417 Extratemporal involvement on MRI is found in a significant minority of patients.419 Early diagnosis of herpes simplex encephalitis is vital as treatment with acyclovir or an equivalent antiviral drug yields the best results when administered before patients become comatose.

Sometimes, as in the following cases, severe hemispheral brain swelling produces transtentorial herniation and may lead to death.

Patient 5–24

A 71-year-old woman was brought into the emergency department for a headache and confusion. Her temperature was 988F and she complained of a diffuse headache, but could not answer questions coherently. Neurologic examination showed a mild left hemiparesis and some left-sided inattention. A right hemisphere ischemic event was suspected, but the CT did not disclose any abnormality. She was admitted to the stroke service. The following day her temperature spiked to 1028F, and a lumbar puncture was done showing seven white blood cells, 19 red blood cells, a protein of 48, and a glucose of 103 with a normal opening pressure. An MRI showed T2 signal involving the medial and lateral temporal lobe, as well as the insular and cingulate cortex on the right, with less intense but similar involvement of the right cingulate cortex. By this time she had lapsed into a stuporous state, with small but reactive pupils, full roving eye movements, and symmetric increase in motor tone. She was started on acyclovir. Despite treatment she developed edema of the right temporal lobe with uncal herniation.

Comment: Because the initial presentation suggested a right hemisphere ischemic event, the patient was treated according to standard stroke protocols, which do not require lumbar puncture. By the time the MRI scan was done, revealing the typical pattern of herpes simplex encephalitis, the patient had progressed to a stuporous state and acyclovir was not able to prevent the swelling and herniation of her right temporal lobe.

The following case was seen in the era prior to CT and antiviral therapy. It is presented because it illustrates the natural history of herpes encephalitis and included a pathologic examination.

HISTORICAL VIGNETTE

Patient 5–25

A 32-year-old children’s nurse was admitted to the hospital in coma. She had felt vaguely unwell 5

days before admission and then developed occipital headache and vomiting. Two days before admission, a physician carefully examined her but found only a temperature of 398C and a normal blood count. She remained alone for the next 48 hours and was found unconscious in her room and brought to the emergency department.

Examination showed an unresponsive woman with her head and eyes deviated to the right. She had small ecchymoses over the left eye, left hip, and knee. Her neck was moderately stiff. The right pupil was slightly larger than the left, both reacted to light, and the oculocephalic reflex was intact. The corneal reflex was bilaterally sluggish and the gag reflex was intact. Her extremities were flaccid, the stretch reflexes were 3þ, and the plantar responses were flexor. In the emergency department she had a generalized convulsion associated with deviation of the head and the eyes to the left. The opening pressure on lumbar puncture was 130 mm of CSF. There were 550 mononuclear cells and 643 red blood cells/mm3. The CSF glucose was 65 and the protein was 54 mg/dL. Skull x-ray findings were normal. A right carotid arteriogram showed marked elevation of the sylvian vessels with only minimal deviation of the midline structures. Burr holes were placed; no subdural blood was found. A ventriculogram showed the third ventricle curved to the right. The EEG contained 1- to 2-Hz high-amplitude slow waves appearing regularly every 3 to 5 seconds from a background of almost complete electrical silence. Low-amplitude 10to 12-Hz sharp-wave bursts of gradually increasing voltage began over either frontal area and occurred every 1 to 2 minutes; they lasted 20 to 40 seconds and were associated with seizure activity.

Her seizures were partially controlled with anticonvulsants and she received 20 million units of penicillin and chloramphenicol for possible bacterial meningitis. Her condition gradually deteriorated, and on the eighth hospital day she developed midposition fixed pupils with absence of oculovestibular responses, and diabetes insipidus with a serum osmolality of 313 mOsm/L and urine specific gravity of 1.005. Eight days after admission, lumbar puncture yielded a serosanguineous fluid with 26,000 red blood cells and 2,200 mononuclear cells. The protein was 210 mg/dL. CSF antibody titers for herpes simplex virus were 1:4 at admission but 1:32 by day 8. She died 10 days after admission, having been maintained with artificial ventilation and pressor agents for 48 hours.

At autopsy, herpes simplex virus was cultured from the cerebral cortex. The leptomeninges were

congested, and the brain was swollen and soft with bilateral deep tentorial grooving along the hippocampal gyrus. The diencephalon was displaced an estimated 8 to 10 mm caudally through the tentorial notch. On cut section, the medial and anterior temporal lobes as well as the insula were bilaterally necrotic, hemorrhagic, and soft. Linear and oval hemorrhages were found in the thalamus bilaterally and extended down the central portion of the brainstem as far as the pons. Hemorrhages were also found in the cerebellum, and there was a small, intact arteriovenous malformation in the right sylvian fissure. There were meningeal infiltrations predominantly of lymphocytes, some plasma cells, and polymorphonuclear leukocytes. The perivascular spaces were also infiltrated in places extending to the subcortical white matter. In some areas the entire cortex was necrotic with shrunken and eosinophilic nerve cells. Numerous areas of extravasated red blood cells were present in the cortex, basal ganglia, and upper brainstem. Marked microglial proliferation and astrocytic hyperplasia were present. Cowdry type A intranuclear inclusion bodies were present primarily in the oligodendroglia, but were also seen in astroglia, small neurons, and occasional capillary endothelial cells.

Comment: This patient’s history, findings, and course in the days before imaging, PCR, or antiviral agents were available were characteristic of herpes simplex encephalitis. The pathologic examination of the brain complements the imaging available in modern cases, and was able to demonstrate the presence of viral inclusions.

Many noninfectious illnesses may mimic infections. Some present as acute meningeal reactions, others as more chronic reactions. Table 5–20 lists some of these.

Acute Toxic Encephalopathy

During Viral Encephalitis

Acute toxic encephalopathy is the term applied to a nervous system disorder, seen predominantly in children under the age of 5, which usually occurs during or after a systemic viral infection and is characterized clinically by the acute onset of increased ICP, with or without focal neurologic signs, and without CSF pleocytosis. The disorder is distinguished pathologically from acute viral encephalitis by the

absence of inflammatory change or other pathologic abnormalities of acute viral encephalitis, save for cerebral edema and its consequences. Edema is induced by inflammatory cytokines, inducible nitric oxide synthase, adhesion molecules, and miniplasmin.421 The cause of acute toxic encephalopathy is unknown and may represent several different illnesses. The best characterized of these was Reye’s syndrome (see below), which rarely is seen anymore, after the use of aspirin was abandoned in children with febrile illnesses. It often accompanies viral infection, particularly influenza,422 but also the common exanthems such as measles and mumps; it also appears without evidence of preceding systemic viral infection. In some instances, viruses have been identified in the brain at autopsy. There may be accompanying evidence of an acute systemic illness, such as liver and kidney damage in Reye’s syndrome, or the patient may be free of symptoms other than those of CNS dysfunction. Death is caused by cerebral edema with transtentorial herniation. At autopsy neither inflammation nor demyelination are encountered in the brain, only evidence of severe and widespread cerebral edema.

Clinically, the disease is characterized by an acute or subacute febrile onset associated with headache, sometimes nausea and vomiting, and often delirium or drowsiness followed by

stupor or coma. Focal neurologic signs usually are absent but may be prominent and include hemiparesis or hemiplegia, aphasia, or visual field defects. In its most fulminant form, the untreated illness progresses rapidly, with signs of transtentorial herniation leading to coma with impaired ocular movements, abnormal pupillary reflexes, abnormal posturing, and, eventually, respiratory failure and death. Status epilepticus marks the early course of a small proportion of the patients. Patient 5–26 illustrates such a case.

Patient 5–26

A 46-year-old man was in hospital 10 days following a negative inguinal lymph node dissection for the treatment of urethral cancer. He was well and ready for discharge when he complained of a sudden left temporal headache and was noted by his roommate to be confused. Neurologic examination revealed a modest temperature elevation to 38.18C in an awake but confused individual who was disoriented to time and had difficulty carrying out three-step commands. The neurologic examination was entirely intact, and laboratory evaluation for infection or metabolic abnormalities was entirely normal. The EEG was bilaterally slow,

more so on the right side than the left. The lumbar puncture pressure was 160 mm CSF. There were two red cells, one white cell, and a protein of 41 mg/dL. The glucose was 75 mg/dL. Within 48 hours he became agitated and mildly aphasic, with a right homonymous visual field defect. He then had a generalized convulsion. The day following the seizure, the lumbar puncture pressure was 230 mm CSF; there was one white cell, a protein of 90 mg/dL, and glucose of 85 mg/dL. A CT scan was normal, as were bilateral carotid arteriograms. Cultures of blood and CSF for bacteria, viruses, and viral titers were all negative, as was a coagulation profile. Within 48 hours after the convulsion, the patient lapsed into coma with evidence of transtentorial herniation leading to respiratory arrest and death despite treatment with mannitol and steroids. At autopsy, the general examination was normal except for evidence of his previous surgery. There was no evidence of residual cancer. The brain weighed 1,500 g and was grossly swollen, with evidence of both temporal lobe and tonsillar herniation and a Duret hemorrhage in the pons. Microscopic examination was consistent with severe cerebral edema and herniation, but there was no inflammation, nor were there inclusion bodies.

Comment: Except for his age and a somewhat protracted course, this patient is typical of patients with acute toxic encephalopathy.

a normal cellular content, suggests acute toxic encephalopathy. In many instances, however, neither a clinical nor laboratory diagnosis can be made immediately.

REYE’S SYNDROME

A variant of acute toxic encephalopathy is Reye’s syndrome. This disorder seemed to appear out of nowhere in the 1950s and then, except for rare reports, disappeared before 1990. In children it was believed to be precipitated by the use of aspirin to treat viral infections. Whether this is true has been questioned.423 This disorder, like other acute toxic encephalopathies, was characterized by progressive encephalopathy with persistent vomiting often following a viral illness (particularly influenza B and varicella). It differs from other forms of acute toxic encephalopathy in that it occurred in epidemics and there was usually evidence of hepatic dysfunction and often hypoglycemia. The illness was pathologically characterized by fatty degeneration of the viscera, particularly the liver but also the kidney, heart, lungs, pancreas, and skeletal muscle. The cause of death in most cases, as in acute toxic encephalopathy, was cerebral edema with transtentorial and cerebellar herniation.

A clinical distinction between acute, sporadic viral encephalitis and acute, toxic encephalopathy often cannot be made. Certain clues, when present, help to differentiate the two entities: acute encephalopathy appears with or shortly after a banal viral infection, usually occurs in children under 5 years of age, may be associated with hypoglycemia and liver function abnormalities, and usually produces only a modest degree of fever. Rapidly developing increased ICP in the absence of focal signs or neck stiffness also suggests acute toxic encephalopathy. Conversely, prominent focal signs, particularly those of temporal lobe dysfunction accompanied by an abnormal CT or MRI, indicate an acute viral encephalitis such as herpes simplex. The presence of pleocytosis (with or without additional red cells) in the CSF suggests acute viral encephalitis, whereas a spinal fluid under very high pressure, but with

Parainfectious Encephalitis (Acute

Disseminated Encephalomyelitis)

Parainfectious disseminated encephalomyelitis and acute hemorrhagic leukoencephalopathy are terms applied to distinct but related clinical and pathologic disorders, both of which are probably caused by an immunologic reaction either to the virus itself or to antigens exposed due to viral injury. Another term for this disorder is acute disseminated encephalomyelitis (ADEM). The same reaction can also be triggered by vaccination and rarely by bacterial or parasitic infection.424,425 Two pathogenetic mechanisms have been advanced. In the first, the invading organism or vaccine is molecularly similar to a brain protein (molecular mimicry), but sufficiently different for the immune system to recognize it as nonself and mount an immune attack against the brain or spinal cord. In the second, the virus invades the brain causing tissue damage and leakage of antigens into

the systemic circulation. Because the brain is a relatively immune protected site, the immune system may not have been exposed to the brain protein before and it mounts an immune attack.424 Similar clinical and pathologic disorders can be produced in experimental animals by the injection of brain extracts of myelin basic protein mixed with appropriate adjuvants (experimental allergic encephalomyelitis [EAE]) and by Theiler virus.424 Hemorrhagic changes appear to signify a hyperacute form of allergic encephalomyelitis (see encephalomyelitis, below). The disorder largely affects children, but adults and even the elderly are sometimes affected. The estimated incidence is 0.8 per 100,000 population per year.424 Fifty to 75% of patients have a febrile illness within the 30 days preceding the onset of neurologic symptomatology.

In parainfectious disseminated encephalomyelitis, the brain and spinal cord contain multiple perivascular zones of demyelination in which axis cylinders may be either spared or destroyed. There is usually striking perivascular cuffing by inflammatory cells. Clinically, the illness occasionally arises spontaneously, but usually it follows by several days a known or presumed viral infection, frequently an exanthem (e.g., rubella, varicella), but occasionally a banal upper respiratory infection or another common viral infection (e.g., mumps or herpes). The onset is usually rapid, with headache and a return of fever. In most cases, there is early evidence of behavioral impairment, and as the disorder progresses, the patient may lapse into delirium, stupor, or coma. In one series of 26 patients, five (19%) were comatose.426 Nuchal rigidity may be present. Both focal and generalized convulsions are common, as are focal motor signs such as hemiplegia or paraplegia.

Careful examination often discloses evidence for disseminated focal CNS dysfunction in the form of optic neuritis, conjugate and dysconjugate eye movement abnormalities, and sensory losses or motor impairment. In 80% of cases, the CSF white cell count is elevated, usually to less than 500 lymphocytes/mm3, but in the remainder there may be no elevation of CSF white blood count. The CSF protein may be slightly increased, but the glucose is normal. Oligoclonal bands may be present, but are commonly absent. In about one out of five patients, the CSF is normal. MRI scanning usually discloses multiple white matter lesions that are bright on T2 and FLAIR imaging, and which may show

contrast enhancement. Sometimes gray matter is involved as well as white matter, which may explain the tendency for seizures to occur. However, early in the course of the illness, the MRI scan may be normal. We observed one patient who became comatose during the first few days of a severe attack, but whose MRI scan was normal for another week, at which time it progressed rapidly to diffuse T2 signal throughout the white matter of the brain (Patient 4–4). The diagnosis of acute disseminated encephalomyelitis should be suspected when a patient becomes neurologically ill following a systemic viral infection or vaccination. Evidence of widespread or multifocal nervous system involvement and of mild lymphocytic meningitis supports the diagnosis. An MRI strongly supports the diagnosis when it is consistent with multifocal areas of demyelination.

Acute hemorrhagic leukoencephalopathy is considered a variant of encephalomyelitis.427 However, a recent report suggests that organisms may be found in the brains of patients who die of the disorder. The organisms, measured by PCR, include herpes simplex virus, herpes zoster virus, and HHV-6. Whether the virus itself or an immune reaction to it was causal was unclear.428

This disorder is marked pathologically by inflammation and demyelination similar to disseminated encephalomyelitis, plus widespread hemorrhagic lesions in the cerebral white matter. These latter vary in diameter from microscopic to several centimeters and are accompanied by focal necrosis and edema. The perivascular infiltrations frequently contain many neutrophils, and there is often perivascular fi- brinous impregnation. The clinical course is as violent as the pathologic response. The illness may follow a banal viral infection or may complicate septic shock, but often no such history isobtained.Theillnessbeginsabruptlywithheadache, fever, nausea, and vomiting. Affected patients rapidly lapse into coma with high fever but little or no nuchal rigidity. Convulsions and focal neurologic signs, especially hemiparesis, are common. Focal cerebral hemorrhages and edema may produce both the clinical and radiographic signs of a supratentorial mass lesion. The CSF is usually under increased pressure and contains from 10 to 500 mononuclear cells and up to 1,000 red blood cells/mm3. The CSF protein may be elevated to 100 to 300 mg/dL or more.

As a rule, the problem in the differential diagnosis of coma presented by disseminated and hemorrhagic encephalomyelitis is to distinguish it from viral encephalitis and acute toxic encephalopathy. At times a distinction may be impossible, either clinically or virologically. As a general rule, patients with viral encephalitis tend to be more severely ill and have higher fevers for longer periods of time than patients with disseminated encephalomyelitis, with the exception of the hemorrhagic variety. Acute toxic encephalopathy usually is more acute in onset and is associated with higher ICP and with fewer focal neurologic signs, either clinically or radiographically.

Cerebral Biopsy for Diagnosis of Encephalitis

When faced with a delirious or stuporous patient suspected of suffering acute encephalitis, the physician is often perplexed about how best to proceed. The clinical pictures of the various forms of encephalitis are often so similar that only cerebral biopsy will distinguish them, but the treatment of the various forms differs. Of the acute viral encephalitides, herpes simplex can be effectively treated by antiviral agents, and it is likely that in some immune-suppressed patients other viral infections such as varicella-zoster and cytomegalovirus also respond to antiviral treatment. Acute toxic encephalitis does not respond to antiviral treatment but, at least in Reye’s syndrome, meticulous monitoring and control of ICP is effective therapy. Acute parainfectious encephalomyelitis is not reported to respond to either antiviral treatment or control of ICP, but often does respond to steroids or immunosuppressive agents.

Weighing the pros and cons, we tentatively conclude that when noninvasive imaging (MRI, MRS, PET) and other tests (CSF PCR for organisms, cytology, oligoclonal bands, and immune globulins) are unrevealing, the risk of biopsy is often small compared to the risk of missing treatment for a specific diagnosis. If there is a

focal lesion, a stereotactic needle biopsy will often suffice.429,430 If there is no focal lesion, an

open biopsy, ensuring that one procures leptomeninges and gray and white matter,431 is required. The biopsy should be taken either from an involved area, or if the illness is diffuse, from

the right frontal or temporal lobe. Complications of either stereotactic or open biopsy are uncommon. However, nondiagnostic biopsies are common. In one series of 90 brain biopsies for evaluation of dementia, only 57% were diagnostic.431 However, in this and other studies, the biopsy sometimes identified treatable illnesses such as multiple sclerosis, Whipple’s dis-

ease, cerebral vasculitis, or paraneoplastic encephalopathy.431,432

CEREBRAL VASCULITIS AND OTHER VASCULOPATHIES

Certain inflammatory vascular disorders of the brain are either restricted to CNS vessels (e.g., granulomatous angiitis) or produce such prominent CNS symptoms as to appear to be primarily a brain disorder.433 Recent reviews classify and detail the clinical and arteriographic findings in a large number of illnesses that produce cerebral or systemic vasculitis (Table 5–21). Only those specific illnesses that may be perplexing causes of stupor or coma are considered here.

Granulomatous Central Nervous

System Angiitis

In this acute disorder of the nervous system, the pathologic changes in blood vessels may be limited to the brain or involve other systemic organs. When the disease is limited to the brain, it tends to affect small leptomeningeal and intracerebral blood vessels. When more widespread, it affects larger blood vessels. Even when the disease is extracerebral, it can affect the blood supply of the brain, producing acute neurologic symptomatology including coma.434 The cause of granulomatous angiitis restricted to the nervous system is unknown and possibly multifactorial. The disorder has been associated with herpes zoster infection, lymphomas, sarcoidosis, amyloid angiopathy, and infections by mycoplasma, rickettsia, viruses, and Borrelia burgdorferi.435 Because the inflammatory lesions can involve blood vessels of any size, the disease can cause large or small infarcts.

Clinically, the onset is usually acute or subacute with headache, mental changes, impair-

Table 5–21 Classification of Vasculitides That Affect the Nervous System

Systemic necrotizing arteritis Polyarteritis nodosa Churg-Strauss syndrome Microscopic polyangiitis

Hypersensitivity vasculitis Henoch-Scho¨nlein purpura Hypocomplementemic vasculitis Cryoglobulinemia

Systemic granulomatous vasculitis Wegener granulomatosis Lymphomatoid granulomatosa Lethal midline granuloma

Giant cell arteritis Temporal arteritis Takayasu arteritis

Granulomatous angiitis of the nervous system Connective tissue disorders associated with

vasculitis

System lupus erythematosus Scleroderma

Rheumatoid arthritis Sjo¨gren syndrome

Mixed connective tissue disease Behc¸et’s disease

Inflammatory diabetic vasculopathy

Isolated peripheral nervous system vasculitis Vasculitis associated with infection

Varicella zoster virus Spirochetes

Treponema pallidum Borrelia burgdorferi

Fungi Rickettsia

Bacterial meningitis Mycobacterium tuberculosis HIV-1

Central nervous system vasculitis associated with amphetamine abuse

Paraneoplastic vasculitis

From Younger,433 with permission.

ment of consciousness, focal or generalized seizures, and frequently focal neurologic signs including hemiparesis, visual loss, and extrapyramidal disorders. Patients who are usually alert at onset can rapidly progress to stupor or coma. Untreated, the disease may be fatal. More benign forms of the disorder also exist, including those that are chronic and progressive over months or years, those that recover

completely, and those that show a relapsing course.436,437 In those patients who recover, the

original angiographic abnormalities reverse.437

The laboratory examination is usually but not always characterized by an elevated blood erythrocyte sedimentation rate (ESR) as opposed to systemic granulomatous angiitis, in which the blood ESR is nearly always elevated. There is mild CSF pleocytosis (20 to 40 lymphocytes/mm3) with an elevated total protein and an increased gamma-globulin level. MR angiography often fails to identify signs of vascular involvement unless there are irregularities of the larger vessels. Conventional cerebral angiography is more sensitive, but still will only identify irregularity of vessels of 1 mm or larger. In addition, the pattern of irregularity does not verify the underlying pathology, but only indicates areas at which biopsy may be fruitful. The specific diagnosis can only be established by cerebral biopsy, but because the lesions are often multifocal but not diffuse, at times even that fails to demonstrate the pathology. Immunosuppression is sometimes effective, but some patients relapse while on

maintenance therapy or when therapy is withdrawn.436

Systemic Lupus Erythematosus

Systemic vasculitis occurs in 10% to 15% of patients with systemic lupus erythematosus (SLE) often early in the course of the disease, but there is no evidence of cerebral vasculitis in this condition.438 Nevertheless, acute neurologic dysfunction, including seizures, delirium, and occasionally cerebral infarcts, stupor or coma, may complicate the course of SLE.439 The pathophysiology of these disturbances is not well understood, but may reflect the effects of autoantibodies against brain or cerebral blood vessels, or perhaps the effects of cytokines induced by an immune attack on body tissues. For example, antiphospholipid antibodies are common in SLE, and may be a cause of venous thrombi or arterial emboli that produce cerebral infarcts. In addition, the deposition of fibrinplatelet thrombi on heart valves (Libman-Sachs endocarditis) suggests a hypercoagulable state. The CNS disorder may occur early in the course of the systemic disease or even preceding systemic diagnosis.440

The clinical onset of CNS lupus is abrupt, often with seizures and/or delirium and sometimes accompanied by focal neurologic signs. Most patients have fever; some have papille-

dema and elevations of CSF pressure on lumbar puncture. The spinal fluid contents are usually normal, but in about 30% of patients, the CSF is abnormal with a modest pleocytosis and/or an elevated protein concentration (lupus cerebritis). The EEG is usually abnormal, with either diffuse or multifocal slow-wave activity. The CT or MRI is usually normal, as is angiography. The diagnosis should be considered in any febrile patient, particularly a young woman with undiagnosed delirium or stupor, especially if complicated by seizures. The diagnosis is supported by systemic findings, particularly a history of arthritis and arthralgia (88%), skin rash (79%), and renal disease (48%), and is established by laboratory evaluation. Ninety percent of patients with nervous system involvement by lupus have antinuclear antibodies in their serum; lupus erythematosus cells are present in 79%, and there is hypocomplementemia in 64%. Anti-DNA antibodies and other autoantibodies are common. However, many of these findings may be absent if the lupus is restricted to the CNS. Even when the diagnosis of systemic lupus erythematosus is established, one must be careful not to attribute all neurologic abnormalities that develop directly to the lupus. In patients with lupus, neurologic disability can be caused by uremia or intercurrent CNS infection.441 A special concern is that SLE is usually treated with high doses of glucocorticoids, which themselves can produce a delirious state (steroid psychosis). It can be difficult to distinguish this condition from the underlying SLE, but even though the response is more common at doses of prednisone greater than 40 mg/day, there is little if any evidence that decreasing the steroid dose shortens this idiosyncratic response.442 Hence, the usual recommendation is to treat the SLE as medically necessary, and to give neuroleptic medication to control behavior until the delirium clears. Drugs such as lithium and valproic acid have been used as mood stabilizers, but the underlying illness appears to be self-limited, rarely lasting more than a few weeks even without specific treatment; controlled trials have not been done.

Subacute Diencephalic

Angioencephalopathy

DeGirolami and colleagues described a patient with the subacute onset of a confusional state

followed by progressive dementia, obtundation, and diffuse myoclonus.443 The CSF showed a progressive rise in the protein concentration. On postmortem examination, there were extensive destructive lesions of the thalami bilaterally associated with a focal vasculitis of small arteries and veins (20 to 80 microns in diameter). The vascular lesions were characterized by thickening of all layers of the vessel wall, with occasional scattered polymorphonuclear leukocytes in the wall and some collections of mononuclear inflammatory cells in the adventitia. Giant cells were absent. The authors were unable to find similar patients reported in the literature. The disease is so rare, and its clinical signs so nonspecific, as to make it unlikely to be diagnosed in the antemortem state. Since the original report, several other cases have been described.444 In most instances, imaging revealed patchy contrast enhancement suggesting a brain tumor. In one instance, the diagnosis was made by biopsy

prior to the patient’s death and then confirmed by autopsy.445

Varicella-Zoster Vasculitis

Herpes zoster rarely causes stupor or coma. It usually presents as a cutaneous dermatomal infection, initially with itching and pain, followed by a rash and then vesicular lesions. As many as 40% of patients with uncomplicated herpes zoster have meningitis, usually asymptomatic and characterized only by mild CSF pleocytosis, but sometimes accompanied by fever, headache, and stiff neck.

Less commonly, herpes zoster infection may cause more profound CNS problems by causing a vasculitis.446 Pathologically, this is a viral infection of the affected cerebral blood vessels, and in immunocompetent patients, this may lead to stroke. This syndrome is especially common with ophthalmic division trigeminal zoster, and typically involves the ipsilateral carotid artery. In an immunocompromised patient, the infectious vasculitis may be more widespread, leading to a diffuse encephalopathy. The diagnosis may be difficult because neurologic features are protean446 and the disease sometimes occurs months after the cutaneous lesions have cleared. Occasionally there is no history of a zoster rash. The MRI or cerebral angiography suggests a vasculitis. Examination