Catastrophic Neurologic Disorders in the Emergency Department , 2nd Edition

Chapter 17. Acute Encephalitis

Unravelling the cause in patients with acute encephalitis is a burden with a dire need for specific management in many of them. There are a bewildering number of causes of acute encephalitis. Clinical findings that are often diagnostic of acute encephalitis are fever, agitation, localizing neurologic signs, and changes in personal behavior (Chapter 7). Progression to coma is expected in fulminant variants, and attending physicians may then feel pressured because little in the presentation discriminates among the possible triggering agents.

Viral infection remains the most common cause, but other infectious agents should be considered1 (Table 17.1). In the United States, one new problem has emerged, West Nile encephalitis,2 and one may happen in the future—anthrax meningoencephalitis.3 Noninfectious causes should be considered in appropriate circumstances, and the diagnostic considerations of major importance are listed in Table 17.2. This chapter concentrates on patients with acute encephalitis with more defined management and diagnostic tests.

Herpes Simplex Encephalitis

Epidemiologic registries have demonstrated that herpes simplex encephalitis is uncommon (2 cases per 1 million population annually) and can be implicated in less than 10% of all reported encephalitides in middle-aged and elderly adults.4 Untreated, it frequently leads to further deterioration of consciousness, brain death, and, in survivors, permanent morbidity. The primary concern is to treat early and preempt further progression. Prompt treatment with acyclovir has considerably improved the neurologic outcome; but even so, there may be ravaging consequences despite early treatment.

Clinical Presentation

The clinical diagnosis of herpes simplex encephalitis should be urgently considered in patients with abrupt onset of a triad of fever (up to 39°C-40°C), change in personality, and localizing neurologic findings (e.g., aphasia, hemiparesis, and apraxia).5,6 Seizures, often focal and transient, are present in one-third of patients. As the disorder progresses, epilepsia partialis continua and temporal lobe seizures may reflect frontal or temporal lobe involvement. Auras of temporal lobe seizures may consist of hallucinations and dysgeusia. Progression to coma may take days but can be rapid, and even the interval between the development of febrile illness and the late stages of coma with extensor responses may be surprisingly short. Some patients may be healthy in the morning and fulfill the criteria for brain death at night. Unusual features are visual field defects, papilledema (only in moribund patients), and memory loss (more commonly apparent in late survivors). Autonomic dysfunction with profound instability in blood pressure, tachypnea, and sweating may occur (60% of biopsy-proven cases) and in exceptional cases may further deteriorate into a sympathetic overdrive with catatonia and extensive rigidity (Chapter 5). For unclear reasons, herpes simplex encephalitis in immunocompromised patients seems to occur more often as a brain stem encephalitis with diplopia, dysarthria, and ataxia.7,8

Table 17.1. Infectious Diseases That Can Masquerade as Viral Central Nervous System Infections

Bacteria
   Spirochetes
     Syphilis (secondary or meningovascular)
     Leptospirosis
     Borrelia burgdorferi infection (Lyme disease)
   Mycoplasma pneumoniae infection
   Cat-scratch fever
   Listeriosis
   Brucellosis (particularly due to Brucella melitensis)
   Tuberculosis
   Typhoid fever
   Parameningeal infections (epidural infection, petrositis)
   Partially treated bacterial meningitis
   Brain abscesses
   Whipple's disease
Fungi
   Cryptococcosis
   Coccidioidomycosis
   Histoplasmosis
   North American blastomycosis
   Candidiasis
Parasites
   Toxoplasmosis
   Cysticercosis
   Echinococcosis
   Trichinosis
   Trypanosomiasis
   Plasmodium falciparum infection
   Amebiasis (due to Naegleria and Acanthamoeba)

Source: Modified from Johnson RT: Acute encephalitis. Clin infect Dis 23:219, 1996. By permission of the University of Chicago.

Table 17.2. Noninfectious Diseases Mimicking Encephalitis

CNS vasculitis
Fulminant bacterial meningitis
ADEM
Thrombotic thrombocytopenic purpura
Fulminant hepatic failure, Reyes syndrome
Endocrine crisis (e.g., myxedema, Addison's disease)
Toxic encephalopathy (e.g., cyclosporine, tacrolimus, MTX, 5-FU, illicit drugs)

ADEM, allergic demyelinating encephalomyelitis; CNS, central nervous system; 5-FU, 5-fluorouracil; MTX, methotrexate.

An anterior operculum syndrome has been reported,9 and failure to recognize its distinguishing features may potentially delay therapy. Involvement of the anterior operculum (the operculum is the cortex and white matter tissue overlying the insula) results in difficulty chewing, a tendency for the mouth to be half open, bifacial palsy, dysphagia, drooling, anarthria, and trismus. Automatic facial movements, such as yawning, are preserved.9,10 Manic behavior (hallucinations, elevated mood, decreased need for sleep, increased sexual desire, flirtations) has been pointed out (patients feel “absolutely marvelous, relaxed and happy”) but is highly uncommon.11 Cerebellitis with profound swelling, a location more preferentially affected in children, has been reported in an adult.12 These complex presentations should alert the neurologist to herpes simplex encephalitis, but the very untraditional presentation may not be linked to this encephalitis.

Interpretation of Diagnostic Tests

Time is needed to document the source and nature of any infection, whether for careful preparation of cerebrospinal fluid (CSF) for cultures, priming of a polymerase chain reaction (PCR), or awaiting the results of blood cultures. Certain laboratory tests are helpful in the emergency department and can be used in early assessment of prognosis.

Cerebrospinal Fluid

Pleocytosis with lymphocytes (50–2000/mm3) and a fivefold increase in protein are common. CSF glucose may be decreased. CSF is normal only exceptionally, mostly in patients examined very early in the course of the illness. CSF PCR has a sensitivity of 98% and a specificity of 94% (Box 17.1, Table 17.3). Acyclovir may reduce PCR sensitivity, but herpes simplex DNA can still be detected in one-third of cases long after acyclovir treatment.4

Electroencephalography

In the electroencephalogram (EEG), typical but not-to-be-mistaken nonspecific abnormalities over the temporal regions are spike-and-slow-wave activity, delta waves, or triphasic waves evolving into unilateral periodic lateralized epileptiform discharges, which rapidly spread to both temporal hemispheres.19 This pattern is seen in 84% of typical cases of herpes simplex encephalitis but with a specificity of only 30%.19

Box 17.1. Polymerase Chain Reaction Technology for Fulminant Encephalitis

PCR has revolutionized the diagnosis of herpes simplex, cytomegalovirus, and toxoplasmic encephalitides. Small quantities of viral DNA or RNA in the CSF can be selectively amplified. Target sequences of DNA are amplified by DNA polymerase, and with multiple repeating of cycles, large copies can be obtained. This amplified DNA is visualized on gel stained by ethidium bromide. PCR is the method of choice for diagnosis but not useful to monitor treatment efficacy. In addition, persistent viral load DNA does not correlate with outcome.13 False-negative PCR may result from antiviral treatment or, more commonly, technical difficulty with primers.14,15,16

Computed Tomography and Magnetic Resonance Imaging

Computed tomographic (CT) scanning is generally not useful in herpes simplex encephalitis, and the findings become abnormal only after days and predominantly in advanced cases evolving into coma. Abnormal CT scan findings in the temporal and insular regions (Fig. 17.1) develop in approximately 50% of patients, but the reported radiologic series are certainly skewed toward the more severe cases. Initial unilateral involvement may occur in almost 60% of cases.20 Hypodensity and swelling in the temporal lobe may become prominent and hemorrhagic and be initially misinterpreted as a lobar hematoma or hemorrhagic infarct (Fig. 17.2). Unilateral swelling may suggest a glioma or an abscess (and sometimes it is).

Magnetic resonance imaging (MRI) is the definitive diagnostic test, with a high sensitivity and specificity for early T2 changes in the temporal lobe and, to a lesser extent, in the frontobasal or cingulate gyrus of the frontal lobe, in the insular cortex, and across the splenium (Fig. 17.3). Increased signal solely present in the cerebellar hemispheres has been noted.12 Fluid-attenuated inversion recovery is more sensitive and may clearly show abnormal images not evident on routine T2-weighted sequences.21 MRI abnormalities may appear within 1 day of herpes simplex encephalitis. Conversely, normal MRI findings in a comatose patient virtually exclude herpes simplex encephalitis.

Table 17.3. Sensitivity and Specificity of Polymerase Chain Reaction in Cerebrospinal Fluid

Agent

Sensitivity (%)

Specificity (%)

Herpes simplex15

98

94

Cytomegalovirus17

79

95

Toxoplasma18

42

100

Single-Photon Emission Computed Tomography

With single-photon emission computed tomography (SPECT), in which technetium Tc 99m hexamethyl propyleneamine oxime is the radiopharmaceutical, unilateral hyperfusion is a common finding and, as expected, the tracer preferentially lodges in the temporal lobe and adjacent frontal lobe. This phenomenon of increased uptake is not specific for herpes simplex encephalitis and indicates only inflammation and early neuronal injury.

Figure 17.1 Computed tomographic scan findings of early herpes encephalitis with subinsular hypodensity (arrows).

Figure 17.2 Computed tomographic scans showing unilateral swollen, hypodense, and partly hemorrhagic temporal lobe lesion from herpes simplex encephalitis (arrows).

Approximately half of SPECT scans performed within days of symptoms yield normal results. It may become a preferred test in patients seen in the emergency department because data are rapidly acquired and, despite moderate sensitivity, it may be more helpful than EEG or MRI in the first days after presentation.

First Priority in Management

An immediate intravenous dose of acyclovir, 10 mg/kg, is needed, followed by maintenance with 10 mg/kg every 8 hours for 10 days. Intravenous loading with fosphenytoin, 18–20 mg/kg, is needed after presentation with seizures; but its use as prophylaxis is not established. Propofol is useful to control extreme agitation. With the introduction of PCR and MRI, earlier dilemmas about the need for brain biopsy have almost been resolved.22,23 Biopsy should be considered if the PCR result is negative, if CSF pleocytosis is absent, and when, primarily to exclude a glioma, only unilateral temporal lobe swelling is present. Comatose patients with CT evidence of increased intracranial pressure (mass effect, obliteration of basal cisterns) should receive an intracranial pressure (ICP) monitor. In patients with a markedly swollen temporal lobe and shift and impending herniation despite conventional measures to reduce ICP, a craniotomy with dural grafting is indicated. Some of the necrotic tissue may need to be removed to decompress the supratentorial compartment.

Figure 17.3 Magnetic resonance images with typical hyperintensities (T2-weighted [left], T1-weighted [middle], fluid attenuated inversion recovery [right]) in temporal, frontal lobe, and insular regions from herpes simplex encephalitis (arrows).

Predictors of Outcome

Treatment with acyclovir within 5 days of onset of the first symptoms remains associated with a 25% incidence of fatal outcome. Fatal outcome is associated with brain edema but more commonly as a consequence of persistent vegetative state and terminal systemic infection. Good recovery with return to a similar productive life is possible in 50% of patients.24 Mild forms of herpes simplex encephalitis have been reported in immunosuppressed patients with mostly involvement of the nondominant temporal lobe.25 MRI abnormalities26 and bilateral EEG abnormalities predict disability, with memory deficits27 and inability to function at a normal intellectual level. A large study found a delay of more than 2 days between admission and that acyclovir was highly predictive of poor outcome. This, again, emphasizes that suspicion should be high and early treatment is needed while awaiting CSF/PCR results.20

SPECT may have some predictive value: a close association between focal hyperfusion on SPECT and poor outcome was emphasized in a large study of patients with acute encephalitis.28

Triage

·     Supportive care, monitor and manage increased ICP in the neurologic intensive care unit.

·     Consider video EEG monitoring in the intensive care unit if the patient has had seizures and impaired consciousness.

Arthropod-Borne Viral Encephalitis

Arthropod-borne (ARBO) viral encephalitides are widespread geographically and commonly endemic; sporadic cases are seasonal during the summer months, and cluster cases may signal an outbreak. Fatality depends on the type of virus and amplifying host. The virus is transmitted through ticks and mosquitoes after replication in wild animals. The most common viruses are bunyavirus (La Crosse, California), alphavirus (eastern and western equine), and flavivirus (St. Louis, West Nile).29,30

Clinical Presentation

Differences in presentation are apparent. La Crosse (California) encephalitis is most commonly reported to the Centers for Disease Control and predominates in children younger than 15 years. The hosts for the mosquito are chipmunks and squirrels, and the mosquito breeds in rainwater-filled tires and birdhouses. In California encephalitis, seizures are common (50%) and seizure disorder develops later in many patients. Within 2 weeks after prodromal fever, the patient may experience malaise, very severe headaches, confusion, drowsiness, and coma, in roughly that order.

The equine encephalitides (western and eastern) differ substantially in mortality.31 The mosquito breeds in freshwater swamps, and birds (sparrows, ducks, and pheasants) are the hosts. It is prevalent along the Atlantic and Gulf coasts, but eastern encephalitis is infrequent. Evolution to coma from massive cerebral edema is rapid, usually within 1 week, but unusual.31,32 The virus causes an acute encephalitis in horses, and it can be isolated from brain tissue specimens.32 Western equine encephalitis peaks in August and September, and outbreaks have been reported from the midwestern United States. Improved vector control has reduced the incidence of both types of encephalitis.

St. Louis encephalitis occurs commonly in the United States. Its manifestations appear to be milder in children than in adults. The susceptible populations are persons living in public housing projects and, possibly, patients infected with human immunodeficiency virus (HIV).

In the tropics, Venezuelan equine encephalitis is most common, particularly in Central and South America, and is very comparable to western equine encephalitis in prevalence, clinical presentation, morbidity, and mortality. Japanese encephalitis is endemic in Southeast Asia and India. Vaccination of children has markedly decreased its prevalence in Japan, but vaccination for travelers to endemic areas is recommended. Most cases occur in China, India, and Thailand.33 Japanese encephalitis peaks during the rainy season.

It may occur during only brief stays, such as a vacation,34 although the risk of exposure increases with a longer stay.

The clinical features of Japanese encephalitis are nonspecific, but seizures are very common,35 with elements of diffuse involvement of both hemispheres; spinal cord involvement (often leading to the incorrect diagnosis of fulminant multiple sclerosis) has been noted.33,36

Flaviviruses are transmitted by tick bites. Encephalitis develops in only 1 of 10 infected persons, usually after a flu-like illness. Tick-borne encephalitis has become a serious health problem in forested areas of Europe and Russia.37,38,39,40

West Nile encephalitis swept the western and midwestern United States in the summer of 2002, and in 2003 moved to western states such as Colorado. The outbreaks are severe, and the ravages in survivors are not yet entirely known. The flavivirus is amplified in mosquitoes in the characteristic spring to fall season and is spread through birds. The virus is commonly found in all continents, with prior outbreaks in Africa, Romania, Russia, and Israel. The risk of developing encephalitis is estimated to be 1 in 150 infected persons and increases with age and prior poor immunologic state. Parkinsonism is a common feature. Fatalities have been common. The combination of neck stiffness, pleocytosis in the CSF, hyponatremia (30%), and clinical or electrophysiologic signs of asymmetric flaccid paralysis should suggest the diagnosis. Polio-like syndromes (marked asymmetry and pure motor involvement, Fig. 17.4) involving facial, cervical, and limb muscles have been described, with early indications of poor outcome.2,41,42,43

Interpretation of Diagnostic Tests

Diagnosis of arthropod-borne viral encephalitis is often delayed, and no specific neuroimaging finding has been reported that would link it to a certain types of encephalitis.

Computed Tomography and Magnetic Resonance Imaging

CT scans are normal or may show diffuse cerebral edema (see Chapter 9). Abnormal MRI findings have been described in a large series of patients with a predilection for basal ganglionic and thalamic lesions in all types of arbovirus encephalitis. The midbrain and cortex may be involved in some. In one study, MRI findings were abnormal in 11 comatose patients, but other arboviruses can produce coma without MRI abnormalities in the earlier diagnostic phase.31 MRI abnormalities, however, can be present soon after the onset of neurologic symptoms, if any. Diffuse cerebral edema appears after several days of coma. Similar MRI findings have been reported in Japanese encephalitis44,45,46 and European tick-borne encephalitis. The sensitivity of MRI in these types of encephalitis is not known.

Cerebrospinal Fluid and Serology

As expected, pleocytosis with lymphocytosis is found along with increased protein. A CSF profile mimicking bacterial meningitis has been described in eastern equine encephalitis. The diagnosis of arbovirus encephalitis is based on determination of immunoglobulin M (IgM) antibodies by an enzyme-linked immunosorbent assay, which has a high sensitivity, but needs confirmation with a plaque reduction neutralization test. Isolation of the virus from blood or CSF is unrewarding. One study documented positive findings in 10% of tested specimens of CSF.47 PCR detection of virus-derived DNA is available but not very sensitive (±50%) and thus the diagnosis is based on detectable IgM in the CSF or a fourfold increase in IgM in serum measured in the convalescent phase of the illness.

First Priority in Management

No specific antiviral therapy is available, but acyclovir (10 mg/kg intravenously every 3 hours) should be administered until PCR results are confirmed negative. Supportive therapy consists of antiepileptic drugs, mechanical ventilation, and prevention of medical complications in the more severe cases. Corticosteroids are not effective.48 Reduction of increased intracranial pressure is not a typical feature of management in many ARBO encephalitides.

Predictors of Outcome

Mortality in La Crosse and California encephalitides is fortunately low, but neurologic sequelae with hemiparesis or aphasia are possible in 15% of patients. Eastern equine encephalitis may cause numerous deaths, and up to 70% of patients have severe neurologic disability. In western equine encephalitis, in contrast, full recovery occurs, although elderly patients may die. The death rate in St. Louis encephalitis is approximately one in four for elderly patients. Neuropsychologic sequelae seem more common than overt localizing neurologic signs in tick-borne encephalitis. Fatality is high in West Nile encephalitis,41,42 but it appears that several patients awaken from coma without residual symptoms.42

Figure 17.4 A: Patient with confirmed West Nile encephalitis. Marked pleocytosis and asymmetric pure motor weakness of arms (“man in the barrel”), able to lift only left hand. Follow-up photographs 1 month later show asymmetric eyelid closing when asked to forcefully close eyelids (B) and only partial lifting of left arm when instructed (C). Right arm remained flaccid and paralyzed.41

Triage

·     Neurologic or medical intensive care unit for supportive care.

Cytomegalovirus and Varicella-Zoster Virus Encephalitis

Cytomegalovirus (CMV) is an opportunistic infectious agent. In a review of 676 patients, 85% with CMV encephalitis were infected with the acquired immunodeficiency syndrome (AIDS) virus.17,49 CMV ventriculoencephalitis is the hallmark of the infection and the cause of death.

The patterns of varicella-zoster virus (VZV) encephalitis have been classified by Amlie-Lefond et al.13 and Kleinschmidt-DeMasters et al.50 into three major categories: (1) large- or medium-vessel vasculopathy involving large vessels at the base of the brain or convexity, which may affect large territories and cause hemorrhagic infarctions (arteritis and the virus inside the artery have been well documented); (2) small-vessel vasculopathy producing demyelinating ischemic lesions with a more subacute clinical course; and (3) ventriculitis. VZV encephalitis has been associated with hematologic-oncologic malignant disease, sarcoidosis, rheumatoid arthritis, tuberculosis, transplantation, and AIDS.

Clinical Presentation

Confusion and lethargy in a patient with a history of CMV retinitis or pneumonitis should suggest the diagnosis. The clinical features include confusion (60% of patients), coma (45%), cranial nerve palsy (40%), and seizures (25%).49 Ventriculitis and hydrocephalus may be the cause of reduced consciousness. Hyponatremia from CMV adrenalitis is common and an important laboratory indicator in patients with AIDS and rapidly developing encephalitis.

VZV encephalitis should be the first consideration in immunosuppressed (e.g., HIV-infected) patients with recent shingles.51 In most reported cases, however, a rash developed days to months before the onset but was not always remembered by the patients. In several reports, VZV encephalitis actually occurred without a skin eruption.

Progressive multifocal neurologic deficits occur, often leading to visual field defects, aphasia, apraxia, hemiparesis, and more specific neurocognitive syndromes, such as Gerstmann's syndrome (acalculia, finger agnosia, rightleft confusion, and agraphia) and Anton's syndrome (cortical blindness). Progressive mental impairment with frontal release signs and spastic paraparesis has been observed in patients with a type of small-vessel vasculopathy causing widespread white matter demyelination without cortical involvement.

Interpretation of Diagnostic Tests

Computed Tomography and Magnetic Resonance Imaging

MRI in CMV encephalitis may show nonspecific brain atrophy and enlarged ventricles with typical ependymal signal enhancement.49 Brain stem and cerebellar abnormalities after gadolinium have been reported in isolated cases.

In patients with VZV encephalitis, both neuroimaging studies show multiple T1-weighted hyperintensity and T2-weighted hyperintensity involving the white and gray matter. Subcortical enhancing, coalescing lesions followed by gray matter involvement are characteristic.52 Involvement of multiple territories is compatible with several large intracranial vasculitides representing infarction (Fig. 17.5).

Figure 17.5 Varicella-zoster virus encephalitis with multiple infarcts (white arrows) and vasculitis (black arrows) on carotid angiogram.

Cerebrospinal Fluid

The CSF formula is normal in many instances, complicating detection. PCR of CMV has significantly increased the ability to make the diagnosis (sensitivity, 79%; specificity, 95%).

In VZV encephalitis, a marked variation in inflammatory response is known, from only a few to several hundred cells, with accompanying increase in protein. Glucose concentration is normal. PCR has become available for VZV encephalitis, but the diagnostic validity is not yet known.53

First Priority in Management

Ganciclovir is the preferred agent (10 mg/kg), with maintenance of 5 mg/kg once a day for 14 days. Patients previously receiving a maintenance dose of ganciclovir need the addition of foscarnet, 180 mg/kg. The efficacy of cidofovir is not clear in these infections, although successful in retinitis.54

Predictors of Outcome

The outcome in CMV-associated encephalitis is poor because of underlying HIV infection and, commonly, concomitant opportunistic infection. The outcome in VZV encephalitis is entirely determined by associated vasculitis; without it, full recovery is possible.

Triage

·     Neurologic intensive care unit.

·     Consider ventriculostomy in patients with hydrocephalus.

Encephalitis from Rickettsiae

Rickettsial diseases are transmitted through ticks, mites, lice, and fleas. The stings are often not remembered because they are painless and may not be followed by a rash at the injection site. The most important and potentially fatal disorder is Rocky Mountain spotted fever, which causes a generalized vasculitis and meningoencephalitis. It emerges in late spring and summer, predominantly in the southeast region of the United States55 (regardless of its name, which suggests the west).

Other rickettsial infections that may involve the central nervous system are encephalitides from the typhus group. The typhus group includes Q fever, epidemic typhus, murine typhus, and scrub typhus. The epidemic can be worldwide and produce similar neurologic manifestations, with typical maculopapular rash and multifocal central nervous system manifestations.55

Clinical Presentation

Rocky Mountain spotted fever is evident in patients with fever who have a marked purpuric rash involving the palms and soles. The flexor surfaces of the hands and feet are involved first before the rash spreads over the body. The purpuric lesions are a consequence of rickettsiae invading small blood vessels and causing occlusion and necrosis. This rash (see Color Fig. 17.6 in separate color insert) may be absent early in the disease.56

Neurologic manifestations are protean, but severe headache, profound neck stiffness, and clouding of consciousness are common, with progression to stupor in more than one-fourth of affected patients.57,58

Q fever occurs as a result of exposure to farm animals, rabbits, or deer and may result in fever, pneumonia, myocarditis, endocarditis, and meningoencephalitis. The involvement of the central nervous system is less common in Q fever but may mimic herpes simplex encephalitis.59 Neurologic involvement from the responsible agent, Coxiella burnetii, is uncommon but can be dramatic. Severe headache and myalgias are common.60 Neurologic manifestations that may precede stupor are cranial nerve involvement and cerebellar signs.59 Acute confusion evolving into acute manic behavior has been reported as well. Epidemic, murine, and scrub types, which occur widely in Southeast Asia, the Pacific Islands, India, and Nepal, are not further considered here.

Interpretation of Diagnostic Tests

Computed Tomography and Magnetic Resonance Imaging

The findings in Rocky Mountain spotted fever are multiple small subcortical infarcts (often in the basal ganglia), development of cerebral edema with loss of gray-white matter differentiation, and sulci effacement.5 A survivor in one report had multiple punctate areas of increased intensity throughout the white matter in the distribution of the perivascular (Virchow-Robin) spaces, possibly representing a perivascular inflammatory response.61,62 Meningeal enhancement after gadolinium is typical.

Cerebrospinal Fluid and Serum

Increased protein occurred in only one-third of patients, with only mild pleocytosis (<50 mm3) in most cases. PCR detection in blood samples from infected patients has been successful, even in those obtained on the day of onset.63

Predictors of Outcome

These types of encephalitides are typically diagnosed at autopsy because patients deteriorate rapidly from brain edema.

No early clinical predictors are known other than brain edema, which may be difficult to control. Increased ICP (>40 mm Hg) despite aggressive mannitol therapy predicts poor outcome.

First Priority in Early Management

Early treatment of rickettsial or tick-borne encephalitis with oral tetracycline is needed (25–50 mg/kg daily in two or four divided doses). A relapse can be treated with chloramphenicol, but tetracycline remains the agent for first-line therapy.64

Triage

·     Neurologic intensive care unit for monitoring of ICP.

·     Cardiac consultation in Q fever for possible myocarditis.

Encephalitis from Anthrax

Exemplary of the potential of effective bioweaponry, anthrax may cause a fatal meningoencephalitis. The clinical presentation emerging from a cutaneous infection is dramatic and involves multiorgan failure. (An important review by Lanska is available.3) It may also cause a gastrointestinal symptom when spores are ingested from uncooked meat.

Clinical Presentation

Cutaneous or gastrointestinal symptoms are common and found in association with fever. Seizures appear in 40% of reported cases, followed by marked decline in consciousness. Pleural effusions, widened mediastinum, and soft tissue edema are additional clues.

Interpretation of Diagnostic Tests

Computed Tomography and Magnetic Resonance Imaging

Due to its nonspecific appearance, multiple diagnostic tests are needed to point in this direction. Focal hemorrhages, subarachnoid hemorrhages, diffuse edema, and meningeal enhancement have been noted; but the experience is limited.65,66 Contrast-enhanced CT scan may document, next to parenchymal hematoma, noticeable enhancement after contrast administration.66 The combination of subarachnoid hemorrhage, lobar hematoma with pulmonary infiltrates, and cutaneous lesions could suggest the diagnosis.

Cerebrospinal Fluid and Serum

Blood and tissue cultures may document the gram-positive spore-forming Bacillus anthracis. The CSF is pink or bloody, with pleocytosis varying from a few increased polymorphonuclear leukocytes to several thousand. A high yield of positive rods has been claimed on gram staining.

First Priority in Early Management

Management includes treatment of the rapid evolution of multiorgan failure, hypotension, and therapy-resistant shock, with a high probability of death. Ciprofloxacin and doxycycline are the preferred drugs. Rifampin with vancomycin has been suggested as adjuvant therapy.

Triage

·     To medical intensive care unit for management of multiorgan failure

Toxoplasmic Encephalitis

Normal host immunity contains an infection with Toxoplasma gondii. Therefore, toxoplasmic encephalitis is a leading cause of acute encephalitis in patients with AIDS or in immunosuppressed patients.67 HIV encephalitis has a more protracted course. Toxoplasmainfestation can be a defining illness in previously HIV-positive patients. It is much less common in transplant recipients, patients with Hodgkin's disease, or patients with systemic lupus erythematosus.68 Its incidence may be lower in patients with AIDS receiving trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis carinii.

Clinical Presentation

Toxoplasma infection may result in a single mass effect, multiple abscesses, or multiple hemorrhages in abscesses mimicking coagulopathy-associated hemorrhages. The total parasite burden to the brain determines the clinical manifestations, but many of these abscesses do not produce clinical signs other than headache and lethargy. Progression may be in days or protracted over months. Decreasing alertness, onset of seizures, and persisting headache should alert one to the diagnosis.69 Toxoplasma has a predilection for the basal ganglia and cerebellum, but hemichorea, hemiballismus, and ataxia are uncommon manifestations.

Interpretation of Diagnostic Tests

The diagnosis is confirmed by CSF PCR, MRI of the brain, or biopsy of the brain in selected cases.

Computed Tomography and Magnetic Resonance Imaging

CT scanning underestimates the number of abscesses, even when contrast material is administered in double doses; therefore, its use is limited to initial screening.70 Acute hydrocephalus without defined abscesses may point to the diagnosis in the proper clinical situation. Multiple intra-cerebral hemorrhages in patients with AIDS often indicate Toxoplasma (or Aspergillus) rather than a coagulopathy.71,72

MRI of toxoplasmic encephalitis, which displays multiple abscesses, is nonspecific because very similar signal abnormalities and ring enhancement can be seen with lymphoma, tuberculous abscesses, nocardiosis, cryptococcosis, and, less commonly, syphilitic gummas.

Hyperintensity on T2-weighted images is common, but after treatment, it evolves into T2-weighted isointensity comparable with that of necrotizing abscesses (Fig. 17.7).73 Marked perilesional edema is typical.

Figure 17.7 Toxoplasmic encephalitis with multiple abscesses (arrows and arrowhead). The abscesses are poorly defined by computed tomographic scan (A,B) and more evident by magnetic resonance imaging fluid-attenuated inversion recovery (C) and postcontrast T1-weighted scan (D).

Cerebrospinal Fluid

An inflammatory profile is present in the CSF, with increased protein concentration and, rarely, marked mononuclear pleocytosis (fewer than 100 cells). The sensitivity of PCR for Toxoplasma is 42%, but the specificity is 100%.18,74 The comparatively low sensitivity is determined by intra-parenchymal localization of Toxoplasma, so it is more likely that CSF does not contain Toxoplasma DNA. Its diagnostic value, therefore, is limited, but PCR technology has reduced the number of brain biopsies for confirmation.

Single-Photon Emission Computed Tomography SPECT of the brain with thallium-201 may differentiate lymphoma from toxoplasmic encephalitis. The high mitotic activity of the lymphoma increases uptake, causing a “hot” region. Its accuracy in predicting lymphoma is questionable despite impressive predictive value in a first series of patients.75,76,77

Serum Serology

Low or absent antitoxoplasmic antibody titers (IgG) are common in immunosuppressed patients, and IgM titers are negative. Variation is great, from 1:8 to titers exceeding 1:1024. A significant increase in serum titer over time has no significance because it may occur in immunocompromised patients without active Toxoplasma infection.

First Priority in Management

The standard therapeutic agents for toxoplasmic encephalitis are pyrimethamine, 50–100 mg, and sulfadiazine, 4–8 g, daily, combined with folinic acid, 10 mg/day, to reduce bone marrow depression.78

Adverse reactions are a rash and anemia, leukopenia, or thrombocytopenia, occurring in 20% of patients. Any allergic reaction should result in replacement of sulfadiazine by clindamycin (600–900 mg every 8 hours).79 When Toxoplasma is the culprit, within 3 weeks radiologic improvement (defined as less edema and isointense signals rather than hyperintense signals on MRI) or complete resolution should be expected in 70% of patients.

Predictors of Outcome

Fatal outcome occurs in patients with multiple hemorrhagic abscesses. The response to therapy determines outcome.78,80 Often, underlying central nervous system lymphoma (together with toxoplasmic encephalitis) reduces prospects of full recovery.

Triage

·     Most patients can be initially managed on wards rather than in an intensive care unit.

·     Surgical drainage of a large abscess should be considered if a mass effect is present.

·     Biopsy should be strongly considered when PCR is negative, primarily to exclude lymphoma. Immunofluorescence techniques can confirm Toxoplasma in brain tissue with the use of monoclonal antibodies in the tissue samples.

Fungal Encephalitis

Viral meningoencephalitis is the most common cause in patients with progressive headache, nuchal rigidity, confusion, and lymphocytic predominance, but a fungal cause should always be considered.81 One should be especially alert if an acute presentation is followed by an insidious course, particularly in endemic regions. Prompt diagnosis and therapy with amphotericin B result in survival and reduced morbidity.

Clinical Presentation

The lung is the port of entry of the fungus and generally the primary site of infection. Evidence of infection in organ systems outside the central nervous system, such as skin, bone, and prostate, is commonly needed to implicate fungal infection. Typical clinical features are headaches, myalgia, fever, intermittent nausea, and photophobia. Cognition may rapidly become impaired, and patients may have marked abulia and lethargy due to irreversible, devastating brain damage. The presentation often is nonspecific and atypical, making the diagnosis very difficult.

Coccidioides immitis is endemic to the south-western United States and the central valley of California. Dissemination is usually seen only in immunosuppressed patients but occurs in 1% of infected patients. Central nervous system involvement is typically severe and fatal if untreated.

Other fungal causes must be considered in the differential diagnosis. Organisms include Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Aspergillus species, and a number of uncommon pathogens, all with possibly similar presentations and CSF formulae. Meningitis is the most common manifestation of infection by C. neoformans and is generally found in immunocompromised patients. It is ubiquitous and protean in its presentation, ranging from indolent changes in cognitive function to florid meningoencephalitis.82,83 H. capsulatum is found in the Ohio and Mississippi river valleys, and most persons in endemic areas have positive skin tests for previous infection. Active disease is rare and, again, seen most commonly in immunocompromised hosts. Aspergillus is a common fungal pathogen with a predilection for the brain parenchyma over the meninges. Abscess formation is common, as is central nervous system vasculitis.

Case reports of blastomycotic meningitis are noteworthy for the frequent misdiagnosis of tuberculous meningitis (see Chapter 16).84,85 The similar clinical characteristics and the nodular appearance of meningeal enhancement on MRI in both diseases make distinction between the two difficult. Not infrequently, patients have been treated with antituberculous agents before the accurate diagnosis of blastomycotic meningitis. This can further confuse the diagnosis, because rifampin has some therapeutic benefit in treating blastomycosis and incomplete treatment with that drug may lead to reactivation of disease.

Interpretation of Diagnostic Tests

Magnetic Resonance Imaging

Prominent enhancement of the meninges can be found. A nodular appearance may suggest a fungal cause. Scattered hyperintensities in the basal ganglia may represent extension of infection along penetrating arteries (Fig. 17.8).86

Cerebrospinal Fluid

Typical findings are lymphocytic pleocytosis, borderline decreased glucose concentration, and mildly increased protein level. CSF serology for C. neoformans, C. immitis, H. capsulatum, and B. dermatitidis should be done; but the results may be negative.

Brain Biopsy

Brain biopsy should be considered early, but the poor sensitivity of microscopy in identifying the organism in biopsied specimens is often remarkable. Culture of CSF and brain tissue obtained at operation remains the prime diagnostic test.

Figure 17.8 Magnetic resonance images showing diffuse nodular enhancement of basal meninges, with abnormal T2 signal in the basal ganglia bilaterally and bitemporal lesions representing encephalitis (arrows). The fungus isolated from brain biopsy culture was Blastomyces. (From Friedman et al.86)

First Priority in Management

Ketoconazole or, more recently, itraconazole is the first-line agent for pulmonary blastomycosis.87 Amphotericin B is usually reserved for more serious clinical situations or refractory disease, but many experts believe that it is the drug of choice in patients with meningeal involvement. Most authorities recommend a total dose of amphotericin B of 2–3 g. One should also consider intrathecal (using the Ommaya reservoir) amphotericin B (test dose of 0.01–0.1 mg for 3 days followed by 0.5 mg 3 times a week). Hydrocephalus may become considerable, and ventriculostomy is needed. This provides the opportunity to culture CSF, but brain biopsy may be needed to unveil the fungus.88

Predictors of Outcome

These disorders are rare, but morbidity is substantial. Amphotericin therapy may be successful in arresting progression of neurologic manifestations. Despite early initiation of empirical treatment with amphotericin, death has been reported.

Triage

·     Brain biopsy to confirm the diagnosis, and surgery may be indicated if a single abscess has formed.

·     Ventriculostomy may be needed to relieve hydrocephalus.

·     To the ward for intravenous amphotericin B therapy.

Paraneoplastic Limbic Encephalitis

The rare disorder paraneoplastic limbic encephalitis should be considered when infectious agents seem highly unlikely. A history of depression, agitation, paranoia, and feelings of depersonalization and memory loss may be obtained.89 The pathologic substrate can be extensive, with neuronal loss, perivascular monocytic infiltrates, and microglial nodules, predominantly in the limbic and insular cortices but also located in the brain stem, spinal cord, and dorsal root ganglia.90 It is uncommon to find a neoplasm during life, but the condition can be the first manifestation or appear in a patient with a previous diagnosis of small cell (oat cell) carcinoma, Hodgkin's disease, or testicular seminoma.91,92,93,94

Clinical Presentation

Rapid onset of mood changes, usually sadness, detachment, and loss of recent memory, is the characteristic presentation, but more fulminant forms are manifested by agitation, hallucinations, and bizarre behavior preceding a decrease in alertness. (The diagnosis is often suggested when the psychiatric symptoms progress despite psychotropic drugs.) Lack of topographic orientation has been noted.95 Coma is uncommon and, if present, mostly from secondary causes, such as infections, sepsis, and acute metabolic derangements.

Neurologic examination clearly demonstrates only poor recall, clinical signs of major depression, and, if the patient is specifically asked, behavioral abnormalities and hallucinations. Subtle brain stem or cerebellar signs and symptoms may be evident in some patients.

Interpretation of Diagnostic Tests

Full evaluation for a possible malignancy workup is therefore needed and should include CT scan of the chest and lymph node biopsy in patients with lymphadenopathy because of the common association with Hodgkin's disease and lung cancer. However, diagnostic evaluation may be extended to exclude gastrointestinal, kidney, and gynecologic malignant diseases and thus should include mammogram, pelvic examination, testicular ultrasonography, serum cancer markers, and antineuronal nuclear antibodies.92,93,96,97,98

Electroencephalography

The EEG may be normal early in the course but will show progressive nonspecific slowing of the background rhythm with temporal slow waves and spike foci. Epileptiform activity is uncommon.

Computed Tomography and Magnetic Resonance Imaging

Normal findings are common and often suggest the diagnosis in the proper situation. However, T2-weighted hyperintensity changes in the medial temporal lobes may appear with contrast enhancement in the temporal lobes, amygdala, and hippocampus (Fig. 17.9).94 MR abnormalities may improve with successful treatment of underlying cancer.99

Cerebrospinal Fluid and Serum

CSF is under normal opening pressures, but an increased protein and mononuclear pleocytosis varied from 30 to 150 total nucleated cells in more than 50% of the reported cases. Normal CSF or only mildly increased protein is less common.

Anti-HU (term derived from a patient's initials) denotes an autoantibody in patients with cancer, predominantly small cell lung cancer (Chapter 2). It is found mostly in patients with subacute sensory neuropathy leading to severe ataxia but can be found in paraneoplastic limbic encephalitis.96 Anti-HU is a polyclonal IgG antibody reacting with neuron nuclei in vitro. The HU antigen has been cloned, and a cell-mediated response toward one of the HU antigens (HUD) has been documented.97 The specificity and sensitivity for the anti-HU test are not exactly known, but low titers can be found in patients with cancer and no neurologic involvement. Antibodies to voltage-gated potassium channels were detected and seem to correlate with clinical manifestation.100

Figure 17.9 Magnetic resonance images of limbic paraneoplastic encephalitis, showing symmetric T2 signal in mesial temporal lobe (arrows).

Brain Biopsy

Stereotactic brain biopsy may show perivascular infiltrates with predominantly B cells, and microglia-like cells may be observed surrounding neurons.101

Predictors of Outcome

The clinical course is progressive, but fluctuations may occur. The interval from initial psychiatric signs to death due to infections varies greatly, from 1 month to 2 years. Treatment of underlying cancer has resulted in substantial improvement in only some patients. Plasma exchange resulted in improvement in a patient with potassium channel antibodies.100

Triage

·     Supportive measures and hospital admission for full medical evaluation and a search for the underlying cancer are needed.

·     Management of respiratory complications from aspiration or sepsis and brain biopsy to exclude other treatable disorders may justify brief intensive care unit admission.

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