Chapter 53. Encephalomyelitis

• Herpes simplex virus (HSV) is the most common cause of fatal sporadic encephalitis. Early recognition and early treatment with acyclovir significantly improve outcome.
• A diagnosis of encephalomyelitis should be suspected in patients with fever, headache, behavioral changes, unexplained focal neurologic signs, seizures, or altered mental status without an obvious alternative explanation.
• Focal neurologic abnormalities are demonstrable either clinically or with neurodiagnostic evaluation in 90% of cases of HSV encephalitis (HSVE).
• If focal neurologic signs are present, computed tomography or magnetic resonance imaging should be performed before lumbar puncture. Diagnostic imaging is helpful in ruling out other treatable causes of altered mental status and also may identify patients with increased intracranial pressure in whom lumbar puncture may be dangerous.
• Unless contraindicated, an early lumbar puncture should be performed. This measure is especially important to rule out bacterial meningitis.
• The cerebrospinal fluid (CSF) is almost always abnormal in encephalomyelitis, usually demonstrating increased leukocytes, generally between 10 and 500 cells per microliter. The CSF glucose value is usually normal, and the protein content is usually normal or slightly elevated.
• Although a completely normal CSF does not rule out encephalomyelitis, it should heighten suspicion for a toxic or metabolic encephalopathy.
• Treatment with acyclovir must be commenced early when HSVE is suspected clinically. Polymerase chain reaction detection of HSV in CSF is the gold standard for the diagnosis of HSVE. However, a negative result on polymerase chain reaction does not always exclude HSVE and does not, by itself, provide justification for the termination of acyclovir treatment.
• Arboviruses are the most common cause of encephalitis worldwide. Their frequency varies dramatically, depending mainly on the season and geographic locale. West Nile virus has recently emerged as an important cause of encephalitis in North America.
• Although viruses are the most common cause of encephalomyelitis, nonviral causes should be carefully ruled out because they are often readily treatable.
• The threat of bioterrorism has increased the likelihood that unusual organisms may be etiologic agents.
• Intensive supportive care is indicated in patients with encephalitis because these patients may make remarkable recoveries even after prolonged unconsciousness.

Encephalitis and myelitis refer to inflammation of the brain and spinal cord, respectively. These processes may occur together, often with meningeal involvement; hence, the terms meningoencephalitis and meningoencephalomyelitis. Encephalomyelitis may result from direct invasion of a microorganism into the central nervous system (CNS) or from an autoimmune process that results in demyelination; the latter process is often triggered by a recent vaccination or infection. Up to 20% of all encephalitides result from autoimmune reactions; they have been variously termed postinfectious,parainfectious (when they occur simultaneously with an infection), and postvaccinial (when they occur after a vaccination). Regardless of the pathogenesis, the clinical manifestations and differential diagnosis of these processes overlap to such a degree that they may be considered together.

There are a multiplicity of etiologies for encephalomyelitis1 (Table 53-1). Unfortunately, most patients do not present with symptoms and signs pathognomonic of a certain cause, but rather with nonspecific problems of fever, headache, and behavioral changes or altered mental status. Therefore, one must have a clear approach in the workup of such patients. This should begin with a careful history and physical examination. The clinical features alone are not generally sufficient to establish an etiologic diagnosis, but they do influence the likelihood of some diagnoses. For instance, age can be a factor because neonates are the group at highest risk for meningoencephalitis from herpes simplex virus type 2 (HSV-2). Enteroviruses and bacterial infections, including infections with group B streptococcus and Listeria monocytogenes, should also be considered in the differential diagnosis of progressive encephalopathy in neonates. At the other end of the age spectrum, Varicella zoster virus (VZV) is a leading cause of encephalitis in the elderly.

The setting of disease may provide helpful clues. Arbovirus encephalitis depends more or less on the season, locale, degree of insect exposure, and current prevalence of disease in a given community. Most outbreaks of eastern equine encephalitis are preceded by enzootics of disease in local horses and pheasants. West Nile virus infections are heralded by outbreaks and deaths among birds. Epidemics of St. Louis encephalitis are often preceded by serologic changes in chickens. Tick exposure in specific geographic areas should heighten the suspicion for Lyme disease, Rocky Mountain spotted fever, or ehrlichiosis. Similarly, exposure to certain animals may be suggestive of rabies or leptospirosis.

The progression of disease often suggests certain causes. Encephalitis developing 1 to 2 weeks after immunization or a viral syndrome is more likely postinfectious, whereas an acute fulminant course is more in keeping with herpes simplex virus encephalitis (HSVE) or eastern equine encephalitis. A slowly progressive neurologic disease is more characteristic of Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, subacute sclerosing panencephalitis (SSPE), or encephalopathy due to acquired immunodeficiency syndrome (AIDS). A chronic or fluctuating course suggests mycobacterial or fungal infections, although mucormycosis may progress very rapidly. The diagnosis of CNS tuberculosis is difficult and requires a high index of suspicion. A subacute neurologic process with certain associated systemic symptoms may suggest immunologic disorders (e.g., systemic lupus erythematosus or sarcoidosis) or a neoplastic disease such as lymphoma, leukemia, and breast or lung carcinoma.

The immune status of the patient is also important when considering the various etiologic possibilities. Patients who are immunocompromised frequently develop unusual forms of encephalitis. Hypogammaglobulinemic patients may develop chronic encephalitis with enteroviruses. Rhinocerebral mucormycosis most often occurs in diabetics with ketoacidosis and in neutropenic leukemics who have been on broad-spectrum antibiotics. Toxoplasmosis is the most common cause of encephalitis in AIDS patients. Other causes of encephalitis in AIDS include cytomegalovirus (CMV) and other herpesviruses, fungi (especially Cryptococcus), Mycobacterium, and uncommon pathogens such as Nocardia, Listeria, Acanthamoeba, and papovavirus.

Physical examination lends little to the diagnostic approach except in cases in which a characteristic rash is present, as in varicella, measles, Lyme disease, or Rocky Mountain spotted fever. A cutaneous eschar may aid in the diagnosis of anthrax. Evidence of disease outside the CNS can suggest certain causes. For example, most patients with CNS disease associated with Mycoplasma pneumoniae have antecedent or concurrent respiratory tract infection. Pulmonary symptoms may accompany lymphocytic choriomeningitis or legionella infections. A thorough neurologic examination is important because the presence of focal neurologic signs heightens the likelihood of treatable infectious causes and mandates the commencement of empirical antimicrobial therapy. Although it is noteworthy that encephalitis caused by HSV is associated with focal neurologic findings in the vast majority of patients, these findings are nonspecific. Even when present in patients with fever, they could represent other CNS diseases, such as parameningeal infection, subdural empyema, brain abscess, cerebral malaria, hemorrhage, vascular disease, or tumor.

The presence of focal neurologic abnormalities clearly mandates urgent diagnostic imaging with computed tomography (CT) or magnetic resonance imaging (MRI). Although the sensitivity of these techniques is limited in diagnosing encephalitis, they are essential and invaluable in ruling out other CNS processes that could be confused clinically with encephalitis and that require a different specific therapy. In addition, CT or MRI can identify patients with increased intracranial pressure (ICP) in whom lumbar puncture is contraindicated.

A lumbar puncture is an important step in the diagnostic evaluation of encephalitis and should be performed early unless there is a specific contraindication. It is especially important to rule out bacterial meningitis. If there is concern about increased ICP and possible herniation, a cisternal puncture should be considered. Cerebrospinal fluid (CSF) should be sent for cell count, chemistry, viral studies (including polymerase chain reaction [PCR] for HSV and other viruses), and stains and culture for fungi and bacteria (including mycobacteria). Completely normal findings on lumbar puncture significantly decrease the likelihood of encephalitis and raise the possibility of toxic or metabolic encephalopathy. Reye syndrome must be distinguished from encephalitis. This syndrome has been associated with several viral infections, especially influenza and VZV, together with salicylate use. It occurs most often in children who are usually afebrile but have altered mental status and hepatomegaly. CSF protein and cell counts are normal, but the blood ammonia level is almost always elevated. Other clues to the diagnosis of Reye syndrome include elevated liver enzyme levels in serum and hypoglycemia. Patients with normal CSF examinations should be monitored carefully; if the index of suspicion for encephalitis remains high, further neurodiagnostic evaluation, including a second lumbar puncture, should be considered. Further evaluation of patients with encephalitis includes an electroencephalogram (EEG) and CT or MRI. Ancillary studies, such as serology, should be performed depending on the specific characteristics of each case. If no specific diagnosis is established, then brain biopsy should be considered. In patients with suspected HSVE, it is important to commence empirical treatment early with acyclovir. Ongoing surveillance for alternative diagnoses must be maintained.

AIDS patients are unique. The approach to management in these patients requires a complete neurodiagnostic assessment and serologic testing for Toxoplasma. If the encephalitis is compatible with toxoplasmosis, then empirical treatment with pyrimethamine and sulfadiazine is begun. Clinical and radiographic improvements are expected to occur within 10 days of the start of therapy. However, if there is evidence of disease progression, then brain biopsy for definitive diagnosis should be performed. At least one pathogen is occasionally isolated in AIDS patients with CNS disease. There are other possibilities to consider in the patient who is infected with human immunodeficiency virus (HIV) and presents with CNS mass lesions, including CNS lymphoma and progressive multifocal leukoencephalopathy (see Chap. 48).

The diagnostic and therapeutic approach to myelitis without encephalitis is somewhat different. Polio should be suspected in cases in which there is a history of recent immunization or contact with a recently immunized individual. The pattern of myelitis caused by poliovirus and other enteroviruses is primarily lower motor neuron disease; characteristically, there is an asymmetric flaccid paralysis with preserved sensation and bladder function. The diagnosis is established by isolation of virus from stools, the throat, or the CSF, in addition to serologic confirmation. It is noteworthy that Japanese virus encephalitis and West Nile virus infection can also produce a polio-like myelitis.

Patients with transverse myelitis usually present with limb weakness and a sensory level with loss of bowel and bladder control. This syndrome may result from a variety of infectious diseases; however, in most cases, there is no identifiable cause. It is important to exclude the potentially treatable causes, such as tuberculosis, syphilis, herpes zoster, schistosomiasis, and HIV infection. The numerous parainfectious etiologies of transverse myelitis include measles, mumps, rubella, influenza, and M. pneumoniae infection, and the management of these causes is strictly supportive. Regardless of the exact etiology, early neurodiagnostic evaluation with myelography and CT or MRI is important to rule out spinal cord compression, epidural abscess, or hemorrhage.

A syndrome known as tropical spastic paraparesis is associated with human T-lymphotropic virus type I infection. Tropical spastic paraparesis is characterized by spastic paraparesis or paraplegia with pyramidal signs, occasional mild distal sensory loss, and occasional sphincter incontinence. Human T-lymphotropic virus type I is endemic in certain geographic regions, including Africa, southern Japan, and the Caribbean basin.

Epidemiology and Pathogenesis

HSVE is the most common fatal nonepidemic encephalitis. It accounts for 5% to 10% of all reported cases of encephalitis.2 The exact incidence is unknown, but the disease has been estimated to have an incidence of 1 in 250,000 population per year.3 It is seen in all age groups, in both sexes, and in all seasons.4 The patient is seldom immunocompromised, and one cannot predict who is at risk for HSVE. HSVE is particularly important because it has a very high mortality rate if untreated, whereas early therapy with acyclovir significantly improves the outcome.5

A temporal lobe syndrome is the most common clinical presentation for HSVE, but atypical presentations may occur, with involvement of parietal or frontal lobes. The predilection of the disease for the frontal or temporal lobes has led to the speculation that HSVE results from the retrograde spread of infection from the nasopharynx along the olfactory pathway to the basal portion of the frontal and temporal lobes. Alternatively, latent virus in the trigeminal ganglia may become activated and may reach the CNS along a neurotropic route.6 Either of these pathogenetic mechanisms may explain why HSV-1 more commonly causes adult encephalitis than HSV-2. Serologic evaluation indicates that approximately 70% of HSVE is due to reactivation of latent HSV, whereas approximately 30% is due to primary infection. The median age for patients developing primary HSVE is 15 years, whereas the median age for recurrent infection is 50 years.5

Clinical and Laboratory Features

There are no pathognomonic clinical symptoms or signs of HSVE that distinguish it from encephalitis of other etiologies. The clinical presentation may be abrupt or insidious. There may be an influenza-like prodrome. Clinical findings include fever (90%), headache (81%), alteration of consciousness (97%), personality changes (85%), dysphasia (76%), autonomic dysfunction (60%), ataxia (40%), hemiparesis (38%), seizures (38%), cranial nerve defects (32%), visual field loss (14%), and papilledema (14%). Eighty-five percent of patients have clinical findings indicative of focal neurologic disease.4

Adult HSVE may occur in the presence or absence of mucocutaneous HSV lesions. Although a history of recurrent HSV lesions was obtained in 22% of patients with HSVE, this history was also found with equal frequency in patients with encephalitis of other etiologies.4

Examination of the CSF shows an abnormality in 90% to 97% of cases.4,7 Usually there is a lymphocytic predominance with 10 to 500 leukocytes per microliter, although early in the course of illness, polymorphonuclear cells (PMNs) may predominate. Red blood cells are present in 75% to 80% of samples, indicating the hemorrhagic nature of this encephalitis. The glucose level is generally normal, and the protein content is only moderately elevated. Viral cultures are almost always negative. PCR analysis to detect HSV DNA in CSF is the gold standard for the diagnosis of HSVE,8 especially in the early phase of the disease. It has a sensitivity of 96% and a specificity of 99%.9 Later in the course of the disease, intrathecal antibody detection may be used to confirm the diagnosis, although this is seldom used in practice.10 When the index of suspicion remains high for HSVE even though PCR has not produced a positive result, a full course of acyclovir is recommended.11

Neurodiagnostic tests, such as EEG, brain scan, CT, and MRI, are useful in confirming and localizing the CNS lesion. EEG has been shown to be more sensitive than brain scan or CT early in the course of HSVE.4 In 80% to 90% of cases, the initial EEG is abnormal, with predominantly spiked and slow wave patterns localized to the area of the brain involved. Paroxysmal lateral epileptiform discharges are characteristic of HSVE but are neither pathognomonic nor common.12 Sodium pertechnetate 99Tc brain scans are abnormal in only about 50% of cases of HSVE and demonstrate radionuclide uptake in the involved area of the brain. Similarly, CT scans are abnormal early in the course of illness in only about 50% of cases of HSVE. Abnormalities include localized edema, low-density lesions, mass effect, contrast enhancement, and hemorrhage (Fig. 53-1).4 MRI may be the most sensitive neurodiagnostic test and has excellent delineation of the temporobasal lobe of the brain13 (Fig. 53-2). MRI is more specific than the EEG and has been advocated by some as the preferred imaging test in the evaluation of suspected HSVE,14–16 although single-photon emission CT has shown abnormalities in the temporo occipital area of two HSVE patients with normal MRI.17

Diagnosis and Management

For optimal patient care, acyclovir treatment must be commenced early when HSVE is clinically suspected. The diagnosis can be confirmed subsequently by PCR detection of HSV DNA in the CSF. Although PCR detection is an extremely useful technique, false-positive and false-negative results have been reported.10,18,19 Brain biopsy should be considered in very select circumstances, when the diagnosis remains uncertain despite all available investigations, and particularly when the patient is deteriorating clinically despite empirical therapy. When the diagnosis is not established, it is important to continue diagnostic investigations to rule out other disorders that mimic HSVE, such as bacterial abscess, tuberculosis, cryptococcosis, toxoplasmosis, rickettsial infections, anthrax, and neoplastic or vascular diseases. If a brain biopsy specimen is taken, the pathology and microbiology laboratories should be notified. Specimens should be submitted for the detection and culture of bacteria (including mycobacteria), viruses, and fungi and for histopathology.20,21

The recommended treatment of HSVE is acyclovir at a dose of 10 mg/kg every 8 hours for 10 to 14 days.22 Relapse of HSVE has been described after successful treatment and may necessitate a second course of therapy.23,24 In most cases, the relapses occurred within 2 weeks of completing antiviral therapy. The precise etiology and the frequency of relapses remain unclear, although it appears to be more common in children than in adults.

The toxicity of acyclovir is minimal. Uncommonly, precipitation of crystals in renal tubules can occur in poorly hydrated patients. This is manifested by a rise in serum creatinine and blood urea levels, which can be reversed by increased hydration, dosage adjustment, or discontinuation of therapy. Patients at a higher risk of nephrotoxicity include those with pre-existing renal disease and those concurrently receiving nephrotoxic drugs. The dosage of acyclovir should be adjusted in patients with renal failure25 (Table 53-2).

Patients who receive acyclovir for suspected HSVE should also receive broad-spectrum antibiotics, such as cloxacillin, cefotaxime, and metronidazole, for the first 48 to 72 hours until CSF and other cultures for bacteria are reported negative.

The precise factors that determine the therapeutic response are unknown. Patients who are younger than 30 years and present with a Glasgow coma score higher than 10 have the best outcome.5 Patients who present with a Glasgow coma score below 6, irrespective of age, have a very poor prognosis. Other markers of poor outcome include bilateral abnormalities on the EEG and the presence of identifiable lesions on the original CT scan.

Long-term complications of HSVE infection are common and include residual dysphasias, paresis, paresthesias, behavioral changes, and a Korsakoff-like amnesia. Even with acyclovir treatment, the mortality rate is 28%, and only 38% of patients recover with little or no residuum.5,26

HSV-2 as a cause of encephalitis is seen primarily, although not exclusively, in neonates. In adults it is more frequently seen as a cause of aseptic meningitis concurrent with primary genital infection.

Neonatal infection occurs with the frequency of 26 per 100,000 deliveries, and, although infection may be localized to the skin, it is more often disseminated.27 Infection is acquired by passage of infants through the birth canal of infected mothers, especially mothers with primary infection. It is recommended that all women in labor be examined for genital HSV-like lesions and, if lesions are present (and if the membranes are intact), that a cesarean section be performed.28 Unfortunately, most neonatal exposure to HSV results from excretion of virus by asymptomatic mothers at delivery. Asymptomatic shedding in pregnant women has been documented to be not infrequent. One can neither predict nor prevent these exposures. Because HSV-2 causes 90% of primary genital herpes and 99% of recurrent infections, neonatal HSV infections are usually caused by HSV-2. HSV-2 causes more morbidity than HSV-1 in neonatal encephalitis.29 Approximately 50% of neonates with encephalitis are premature, and clinical illness typically begins 1 to 3 weeks after birth. Although CNS disease can occur in isolation, more commonly there is evidence of diffuse disease with accompanying skin lesions, hepatitis, pneumonitis, or disseminated intravascular coagulation.6

The diagnosis should be suspected in any infant who becomes encephalopathic during the first weeks of life. Skin vesicles are, if present, the easiest source of viral isolation and confirmation of diagnosis, but up to 20% of newborns with HSV infection never have skin involvement.30 These infants often excrete virus from peripheral sites in the absence of skin lesions; hence, conjunctival, throat, and CSF specimens should be submitted for viral studies. As with HSV-1, PCR testing for HSV-2 DNA in CSF is important to confirm the diagnosis. Further diagnostic evaluation may include EEG, brain scan, CT, ultrasonography, and MRI, alone or in combination, depending on the circumstances. Early empirical treatment with acyclovir is important in decreasing mortality and morbidity rates. Without treatment, the mortality rate is 50% to 85% and the morbidity rate is 100%. A new larger-dose regimen of acyclovir at 20 mg/kg every 8 hours for 21 days is the current recommended dose for neonatal HSVE.31 With this larger-dose treatment, the mortality rate has decreased to 5% in neonates and about 40% of survivors develop normally.

Primary VZV infection (chickenpox) is only rarely complicated by encephalitis, aseptic meningitis, transverse myelitis, or Guillain-Barré syndrome. There are two forms of encephalitis with primary VZV.32,33 The cerebellar form is seen in children and occurs with a frequency of 1 per 1000 cases of chickenpox. It is characterized by ataxia, nystagmus, headache, nausea, vomiting, and nuchal rigidity. This illness is usually self-limited, lasting 2 to 4 weeks, and most children have a complete recovery. The mortality rate is only 0.5%.34 A more severe form of encephalitis occurs mostly in adults and infants, with an incidence of one to two episodes per 10,000 cases of VZV. It most often begins about 1 week after the varicella rash and is manifested by altered sensorium, seizures, and focal neurologic signs; it has a mortality rate of 5% to 10%.33

After chickenpox ends, the virus becomes latent, but it may reactivate later in the form of shingles (herpes zoster). Viral invasion of the CNS is not uncommon with zoster, occurring in 35% of patients in one study.35 However, CNS complications of zoster such as meningoencephalitis or myelitis are rare. Zoster encephalitis may take the form of a stroke. This is more commonly observed in the elderly and can occur weeks to months after an episode of herpes zoster, typically involving the first division of the trigeminal nerve. It is thought that VZV directly invades cerebral arteries by extension along intracranial branches of the trigeminal nerve. Diagnosis is usually supported by angiography. The mortality rate is 20% to 25%, and there is a strong probability of permanent neurologic sequelae.33

Chronic zoster encephalitis is seen almost exclusively in immunocompromised patients, especially those with AIDS. The presentation is subacute, with headache, fever, mental status changes, seizures, and focal neurologic signs. The onset may occur months after the zoster rash, making the diagnosis more difficult. The clinical course is often progressive deterioration and death.33

A fulminant necrotizing zoster encephalitis with concomitant lymphoma related to Epstein-Barr virus (EBV) and CMV ventriculitis in an AIDS patient has been reported.36 This highlights the potential for simultaneous infection with multiple pathogens in immunodeficient patients.

The diagnosis of VZV encephalitis may be suspected on the basis of the characteristic lesions of varicella or zoster. The virus may be identified from vesicular scrapings on immunofluorescence, electron microscopy, or culture.27 The virus grows slowly, usually requiring 2 to 3 weeks for a positive culture. Serologic recognition of the presence of specific immunoglobulin M (IgM) may be useful for diagnosing primary chickenpox. It has been noted that primary varicella encephalitis and zoster encephalitis can occur in the absence of any rash.37,38 As with HSVE, PCR analysis of CSF VZV DNA and VZV antibody may be used to confirm the diagnosis.39 Intravenous acyclovir is the drug of choice for VZV encephalitis, at doses of 10 mg/kg every 8 hours. In one study, foscarnet was added and a favorable outcome was reported in one patient with zoster encephalitis who was not responding to acyclovir alone.40

CMV encephalitis (CMVE) is not uncommon in immunocompromised patients.41,42 The presentation is typically subacute, with lethargy, confusion, cranial nerve palsies, and coma being prominent clinical features. A large majority of these patients has AIDS, and most have a history of another CMV disease, especially retinitis. CSF viral cultures are typically negative. PCR detection for the presence of CMV DNA in CSF has a sensitivity of 79% and a specificity of 95%.42 Unfortunately, it does not always correlate with histologic evidence of encephalitis in immunocompromised patients.43 A high level of CMV DNA in the CSF may be an indicator of significant CMV encephalitis. MRI is more sensitive than CT and characteristically demonstrates periventricular enhancement. The diagnosis is especially challenging in AIDS patients because the clinical presentation is widely variable and because there may be coexisting processes including HIV encephalopathy, toxoplasmic encephalitis, CNS lymphoma, or coinfection with HSV or VZV.41,42

CMVE is rare in immunocompetent individuals but has been reported.42,44 Patients tend to be relatively young, 20 to 64 years. The pathogenesis is unclear. The typical clinical picture is similar to that of HSVE, with severe headache, fever, and focal neurologic signs. CSF examination shows a mild pleocytosis, and the EEG may be markedly abnormal. Differentiation from HSVE requires specific virologic studies. In contrast to AIDS patients, in whom progressive deterioration is the rule, immunocompetent patients with CMVE usually recover but may have long-term sequelae.

Ganciclovir, a nucleoside analogue, is the accepted antiviral agent of choice for CMV.25,42 The standard dose is 5.0 mg/kg intravenously every 12 hours, given for 2 to 3 weeks. Dosage must be adjusted in patients with renal dysfunction. Possible adverse effects include granulocytopenia, thrombocytopenia, anemia, and elevated serum concentrations of bilirubin, alkaline phosphatase, and creatinine. In AIDS patients adding foscarnet to ganciclovir may be more efficacious.45

Neurologic complications occur in fewer than 1% of cases of mononucleosis but are the leading cause of death in infections with EBV.6 CNS manifestations can include aseptic meningitis, Guillain-Barré syndrome, Bell palsy, transverse myelitis, or encephalitis.27

EBV encephalitis typically is acute in onset and may be diffuse or focal, with abnormalities localized usually to the cerebellum or temporal lobe. The diagnosis may be readily evident if the encephalitis occurs in the setting of fever, pharyngitis, lymphadenopathy, and positive EBV serology. CSF changes usually demonstrate a mononuclear pleocytosis with fewer than 200 cells per microliter. Atypical lymphocytes may be seen in the CSF. The protein content may be normal or mildly elevated, and the glucose level is usually normal.27 PCR detection of EBV DNA is a reliable method of diagnosing EBV encephalitis or myelitis.46 Although EBV encephalitis may be severe, it is usually self-limited, and almost all survivors recover without sequelae. Successful treatment with intravenous ganciclovir has been reported in immunocompromised patients with EBV encephalitis.47,48

Arboviruses are a group of enveloped RNA viruses that are transmitted by insects. There are numerous viruses in this group that are known to cause encephalitis; together, they are the most common cause of encephalitis worldwide.6 The relative predominance of the different arboviruses depends on the geographic locale, season, and weather conditions (Table 53-3). In temperate climates, infections tend to be seasonal, occurring mainly in the summer when arthropod populations are high. Human beings are incidental hosts and do not play a part in the natural history of the arboviruses that cause encephalitis. Asymptomatic and mild infections are most common. Serologic evidence indicates that the proportion of infections manifested as disease depends on the specific virus and on the age of the host. In eastern equine encephalitis, 1 in 10 to 40 infections results in encephalitis, whereas in Murray Valley encephalitis, only 1 in 1000 infections results in encephalitis. For West Nile virus, approximately 1 in 150 infections result in meningoencephalitis.49,50 Historically, California serogroup encephalitis was the most frequently reported arbovirus infection in the United States; the number of cases reported has remained relatively constant since the 1970s. In 1994 a case of Powassan encephalitis was reported in Massachusetts. This tick-borne flavivirus illness occurs infrequently, with only 24 confirmed cases having been reported in North America between 1958 and 1994.51 More recently, West Nile virus has arrived on the North American continent, and annual cases of West Nile virus meningoencephalitis may surpass those of California serogroup encephalitis.

The pathogenesis of arbovirus encephalitis is believed to begin with an initial viremia followed by localization in the CNS. The virus likely crosses the blood-brain barrier by infected cells that migrate through the blood vessels of the brain. Once within the CNS, the virus may replicate in neurons or glial elements.

The clinical features of the different arbovirus encephalitides are presented in Table 53-4. In general, arbovirus encephalitides follow the typical pattern of acute onset of fever, headache, and meningismus, with progression to an alteration in mental status. Examination of the CSF usually shows fewer than 500 leukocytes per microliter; most leukocytes are mononuclear, although early on there may be a PMN predominance. The protein content is usually normal or slightly elevated. The glucose level is characteristically normal. Virus isolation is rare; hence, distinguishing among the different viruses requires careful consideration of epidemiologic and clinical variables in addition to serology.52–56 There is an enzyme immunoassay that detects virus-specific IgM antibodies in blood or CSF of patients with suspected Japanese B encephalitis.57 Similarly, the diagnosis of West Nile virus encephalitis can be established by the presence of IgM antibody in blood or CSF.50 Molecular assays are also rapidly becoming more available.

At present, there is no proven antiviral therapy for arboviral encephalitis. In vitro activity of interferon α against West Nile virus and other flaviviruses has been demonstrated. Open clinical trials using interferon α for patients with St. Louis encephalitis and Japanese encephalitis have produced promising results. During an Israeli outbreak of West Nile virus infection in 2000, large-dose ribavirin was given without detectable benefit. Immunoglobulin from patients previously infected with West Nile virus has been given to some patients and is being considered for clinical trials.50 The mortality and morbidity rates depend on the specific arbovirus and the age and health of the patient.

Enteroviruses are very common causes of meningitis but cause only a small proportion of cases of encephalitis. They rank behind arboviruses, HSV, and lymphocytic choriomeningitis virus as causes of encephalitis that proved to be viral in the United States. Enteroviruses are distributed worldwide, and infections are most prevalent in the summer and autumn months in the temperate climates. At least 50% to 80% of nonpolio enteroviral infections are completely asymptomatic.58 When encephalitis develops, the signs and symptoms may vary, from lethargy, drowsiness, and personality changes to seizures, paresis, and coma. The clinical findings suggest generalized involvement in most cases, but focal abnormalities, including partial motor seizures, hemichorea, and acute cerebellar ataxia, have been reported. Enteroviral encephalitis can mimic HSVE, and distinguishing CNS enteroviral infection from other bacterial and viral causes of encephalitis can be clinically difficult.

CSF examination typically shows 10 to 500 leukocytes per microliter, with a lymphocytic predominance, although neutrophils may predominate early in infection. The CSF protein content is normal or slightly elevated, and the glucose level is normal. In the past, the diagnosis was established by culture of virus from the CSF. However, CSF viral cultures were often negative, and the diagnosis had to be inferred from isolation of virus from non-neurologic sites, such as throat washings or feces. More recently, PCR detection of enterovirus RNA in CSF has become the optimal method for confirming the diagnosis.59

The course of illness is generally benign, and treatment is supportive. However, neonates may develop a severe illness culminating in death, and infants younger than 1 year often have persistent neurologic sequelae. In addition, patients with antibody deficiencies may have severe infection. A syndrome of chronic enteroviral meningoencephalitis occurs in agammaglobulinemia.60 Most of these patients present with a dermatomyositis-like syndrome and many have hepatitis. The course is prolonged, and clinical manifestations may vary and fluctuate. Neurologic manifestations include headaches, seizures, lethargy or coma, weakness, and ataxia. In this syndrome the mortality rate is high. The administration of specific neutralizing antibody has been shown to be effective.60,61 A case of chronic enteroviral meningoencephalitis also has been reported associated with HIV.62 Pleconaril may be used to treat patients with serious enteroviral infections. Pleconaril is given orally at a dose of 200 to 400 mg three times daily, although the appropriate dosing has not been clearly established.62,63 A recent report on two cases of chronic enteroviral meningoencephalitis suggested that perfusion single-photon emission tomographic scans are useful for clinically monitoring treatment.62

Poliovirus is a neurotropic enterovirus, but owing to the widespread use of polio vaccines, the incidence of poliovirus infection has dramatically declined. Poliomyelitis still occurs in patients who have not received the vaccine and in underdeveloped countries. Rarely, paralytic polio develops in association with the use of the live vaccine. Currently, this is a very rare event, given that inactivated poliovirus vaccine has largely replaced oral poliovirus vaccine. Paralysis occurs in 0.1% of all poliovirus infections. In adults, poliomyelitis often begins with muscle pain, particularly involving the neck or lumbar region. This pain may be relieved by motion. Subsequently, there is progression to weakness and paralysis, usually over 2 to 3 days. A characteristic feature of the paralysis of poliomyelitis is its asymmetric distribution. Another key point to note in the clinical diagnosis of poliomyelitis is that sensation is usually preserved. If sensory loss is present, then an alternate diagnosis should be considered. Poliomyelitis very rarely takes the form of encephalitis.64 When poliovirus encephalitis does occur, it is seen principally in infants. It is manifested primarily by disturbances in consciousness. In addition, seizures and spastic paralysis may be seen. The illness is not distinguishable clinically from encephalitis due to many other viruses. The diagnosis is established when virus is isolated from the CSF. Unfortunately, it is rare to isolate poliovirus from these patients. Most often, throat and stool cultures should be taken, in addition to acute and convalescent sera. PCR technology promises to aid in the confirmation of the diagnosis.59

Enterovirus 71 is a picornavirus that can cause an epidemic paralytic disease indistinguishable from poliomyelitis. Like other enteroviruses, it may cause hand-foot-mouth disease. Paralysis may be accompanied by encephalitis or cranial nerve involvement. The diagnosis is established when enterovirus 71 is isolated from vesicle fluid, feces, oropharyngeal sections, urine, or CSF. The treatment is supportive. The mortality rate is 29.5% in patients with paralytic disease but increases to as high as 65% in patients with bulbar disease.65

Lymphocytic choriomeningitis virus is an arenavirus that is endemic in mice and can be transmitted to human beings.66 Lymphocytic choriomeningitis virus infection may occur worldwide but has been demonstrated only in Europe and the Americas. Human infection is most commonly seen in young adults, although persons of all ages may be affected. Most cases occur in the autumn. The exact mode of transmission is not known but may be related to aerosols, direct contact with rodents, or rodent bites. The incubation period is usually from 5 to 10 days. The illness typically has an influenza-like prodrome followed later by a severe headache. A few patients develop a clinical picture of encephalomyelitis, with confusion, psychosis, paraplegia, or disturbances of cranial, sensory, or autonomic nerve function. Other occasional complications include orchitis, myopericarditis, arthritis, and alopecia. Laboratory findings show a leukopenia and thrombocytopenia. The CSF typically shows several hundred lymphocytes per microliter, with a normal to elevated protein level and a normal to reduced glucose content. Infection is usually diagnosed by a fourfold rise in antibodies or isolation of virus.27 The treatment is supportive, and rarely is the illness fatal.

Rabies virus is usually transmitted to human beings by the bite of an infected mammal, although infection by the respiratory route can occur. In countries where domestic anima rabies is well controlled, most disease is associated with infection from wild animals. Human disease is rare in the United States, with only 36 cases being reported to the Centers for Disease Control and Prevention from 1980 to 1996.67 In countries where domestic animal rabies has not been controlled, human rabies remains a significant problem. In 1996, 33,209 cases of human rabies were reported to the World Health Organization, but, because this reporting is voluntary, it underestimates the actual number of cases.68 The incubation period is usually 20 to 90 days, although in reported cases it has varied from 4 days to 19 years. During the incubation period, the patient is well. A prodrome of 2 to 10 days, which may include paresthesia at the bite site, is followed by evidence of CNS infection, which may include agitation, hydrophobia, bizarre behavior, or delirium. About 20% of patients present with a paralytic form. The mental status gradually deteriorates, with disorientation, stupor, and coma.68,69 The case fatality rate is virtually 100%. No tests are currently available to diagnose rabies infection before the onset of clinical disease. A diagnosis of rabies should be suspected even in the absence of a definitive history of an animal bite because this may be missing in some cases. Diagnosis can be established rapidly by using immunofluorescent procedures to detect viral antigens on biopsy of the skin of the posterior neck. Other methods for diagnosis before death include detecting antibodies to rabies virus in serum or CSF from patients with a long clinical course and virus isolation or nucleic acid detection in saliva.70 Rabies is a disease that is much easier to prevent than cure. However, cases have occurred even in patients receiving optimal prophylaxis. Patients should be isolated because rabies virus may be present in saliva, tears, urine, CSF, and other body fluids or tissues.

Treatment is supportive, but the outcome is dismal. High-dose passive rabies immunoglobulin has been used in some cases, with no clear benefit.71 Although no single therapeutic agent is effective, a combination of therapies such as rabies vaccine, rabies immunoglobulin, monoclonal antibodies, ribavirin, interferon α, and ketamine may be considered.72

Two survivors in a review of 38 human rabies cases in the United States received rabies vaccine before the onset of their illness and intensive supportive care after the onset of illness.69

HIV is a neurotropic pathogen that may cause CNS disease varying from aseptic meningitis to encephalitis resulting in dementia and death (see Chap. 48 for more details). Postmortem studies of patients dying of HIV-related complications have suggested that CNS infection is always present, even when it is not clinically apparent. The diagnosis should be suspected in patients with encephalitis who have risk factors for or clinical evidence of HIV infection. Serology is used to confirm HIV infection, but there are no good means at present of antemortem diagnosis of CNS disease. Measurement of CSF levels of HIV RNA might prove to be a useful monitor of CNS infection.73

Measles is an acute infection caused by a paramyxovirus. This virus is highly contagious and causes infections with a worldwide distribution. It remains a significant problem, especially in unimmunized children and adults. Acute postinfectious measles encephalomyelitis is the most common neurologic complication of measles. Although it is rare in children younger than 2 years, it complicates approximately 1 of 1000 measles infections in older children.74 It probably has an autoimmune pathogenesis.75 The illness is of abrupt onset and typically begins 1 week after the onset of the rash. However, it has been reported to have occurred before the onset of the rash or weeks after. The illness is manifest by recurrence of fever, seizures, motor abnormalities, and a depressed level of consciousness. The abrupt onset of the encephalomyelitis in the setting of the typical exanthem is a characteristic feature that helps to differentiate postinfectious encephalomyelitis from other forms of viral encephalitis that have a more gradual onset. The CSF is normal in approximately 33% of patients. Neither viral RNA nor measles-specific antibody is present in the CSF. However, antibodies to myelin basic protein are present in the CSF. Up to 50% of patients with measles have detectable EEG abnormalities.76 MRI is a sensitive modality.77 Treatment is supportive; the mortality rate is 10% to 20%, and most survivors have neurologic sequelae.74

A less common complication of measles infection is SSPE, which occurs in about 1 in 300,000 cases. SSPE occurs months to years after measles, most often in children. Although the exact pathogenesis is unknown, it appears that persistent infection results from defective viral production of membrane or envelope proteins, which allow the virus to escape immunosurveillance.78 The onset is insidious, with subtle personality changes and declining intellectual performance. The disease is progressive, with mental deterioration followed by convulsive and motor signs and invariably coma and death.79 The most useful laboratory findings in SSPE include an abnormal EEG with the typical pattern consisting of well-defined periodic bursts of high-voltage activity with an interval of 3 to 5 seconds between bursts and increased levels of γ globulin and measles antibody in CSF or detection of viral RNA.80–82 Biopsy is not considered necessary for the diagnosis because the clinical findings combined with the finding of measles antibody or viral RNA in the CSF are sufficient to establish the diagnosis in almost all cases. There is no well-established effective treatment for this condition; however, isoprinosine (inosiplex) has been reported to produce remission for longer than 2 years in 5 of 15 patients in one study.83 Other reports have described mixed benefits.84–86 Combination therapy with interferon α, ribavirin, and inosiplex has been described in one case report.87

Subacute measle encephalitis (SME) is a third form of measles encephalitis. SME occurs mainly in immunosuppressed children in whom it acts like an opportunistic infection. Measles virus RNA can be detected in the brain of SME patients, and it follows a rapidly progressive course. More recently, one case report documented SME in an immunocompetent adult.88

Meningitis occurs in 15% of mumps cases, although CSF abnormalities may occur in up to 50%. Meningitis is a common benign condition, to be distinguished from encephalitis, which is rare and more serious. Encephalitis occurs in approximately 1 in 6000 cases of mumps.89 There is bimodal distribution of illness: an early-onset illness that coincides with parotitis and represents damage to neurons directly due to viral invasion, and a more common late-onset illness that develops 7 to 10 days after the onset of parotitis and is a postinfectious demyelinating process.

The clinical features are diffuse encephalitis with fever, marked change in level of consciousness, seizures, paresis, aphasia, and involuntary movements. The CSF examination shows the typical picture of viral meningoencephalitis, with a lymphocytic pleocytosis and a normal or slightly elevated CSF protein level. However, there may be a PMN cell predominance and hypoglycorrhachia. No rapid procedures are available for diagnosing mumps.24,65 Virus may be isolated from CSF on tissue culture. Serology may be used to confirm the diagnosis. Encephalitis may occur secondary to mumps in the absence of parotitis. The treatment is supportive, and sequelae of psychomotor retardation and convulsive disorders have been reported. The mortality rate is 1.4%.66 Other neurologic syndromes rarely associated with mumps include deafness, cerebellar ataxia, facial palsy, transverse myelitis, ascending polyradiculitis, and a poliomyelitis-like syndrome.

A paramyxovirus, Nipah virus, was identified as the etiologic agent of an outbreak of severe encephalitis in Malaysia and Singapore that occurred among people who had close contact exposure to pigs.90 Nipah virus is closely related to another zoonotic paramyxovirus, Hendra virus, which infects horses and rarely humans. Both viruses have the ability to infect a broad range of species. After an incubation period of 10 days, patients present with nonspecific symptoms such as fever, headache, myalgia, sore throat, and altered mental state.91,92 Other clinical features may include segmental myoclonus, areflexia, hypertension, and tachycardia. The mortality rate reported from the outbreak in Malaysia was 41%.92 An open-label trial of ribavirin for treatment has suggested some benefit.93

Encephalitis is a rare postinfectious complication of rubella. It occurs with a frequency of approximately 1 in 3000 to 1 in 24,000 rubella patients.94 It occurs more frequently in adults than in children.95 The symptoms are similar to but milder than those seen with measles. Diagnosis maybe established on the basis of serology or on the detection of anti–rubella virus IgM in the CSF. The treatment is supportive. The case fatality rate has been found to vary between 0% and 30%.94 A rubella SSPE-like syndrome occurs mainly in young adults, as opposed to measles-associated SSPE, which tends to occur in children.

Mycoplasma pneumoniae is a frequent cause of upper and lower respiratory tract infections in otherwise healthy people. Approximately 1 in 1000 patients with M. pneumoniae respiratory disease develop complicating CNS disease.96 The pathogenesis of the CNS disease is unclear; however, it has been postulated that the disease may result from direct invasion by the organism, a neurotoxin elaborated by the organism, or an autoimmune reaction precipitated by the Mycoplasma infection.96,97 Multiple patterns of CNS involvement associated with M. pneumoniae have been reported. These include meningitis, encephalitis, psychosis, cerebellar ataxia, hemiplegia, transverse myelitis, and polyradiculitis.98 The encephalitis may be focal, mimicking HSVE, or nonfocal. Most patients have antecedent respiratory symptoms. In encephalitis, the CSF usually shows a lymphocytic predominance combined with a moderate elevation of the protein content and a normal glucose level. Mycoplasma pneumoniae genomic material has been identified in cases of encephalitis related to mycoplasmal disease by using PCR techniques after CSF was collected early in the disease process.99Mycoplasma pneumoniae has rarely been identified histologically or recovered from biopsy specimens. In the absence of PCR, the diagnosis can be established by serology. The treatment is mainly supportive, and no controlled prospective trials have evaluated the role of antibiotics. However, intravenous tetracycline would seem to be an appropriate agent. The mortality rate was 5% in one series and 23% had severe sequelae.96

Encephalitis may occur as a complication of Rocky Mountain spotted fever. This disease is caused by Rickettsia rickettsii and is transmitted by the bite of an infected tick. It is seen most frequently in the eastern United States, especially in younger people. The illness is characterized by the sudden onset of fever, malaise, headache, chills, and conjunctival injection. This is followed 2 to 3 days later by a maculopapular rash that appears first on the wrist and ankles and then rapidly spreads to the rest of the body, including the palms and soles. The rash is often petechial or may become confluent and hemorrhagic. Routine laboratory tests for rapid diagnosis early in the illness are not readily available. A fourfold rise in antibody titer between acute- and convalescent-phase sera is considered diagnostic. PCR detection has been reported, but its clinical usefulness has not been established.100Doxycycline or other tetracycline is considered by many to be the agent of choice, but chloramphenicol is preferred in pregnant patients.101 Unfortunately, neurologic involvement with this disease is associated with a bad prognosis. Of 37 patients followed for 1 to 8 years after acute Rocky Mountain spotted fever, 21 had residual neurologic abnormalities.102

Since the events of September 11, 2001 and the months following in the United States, anthrax meningoencephalitis (AME) has moved up the differential diagnostic list of meningoencephalitis because of the possibility of a bioterrorist act. Patients with AME present with fever, headache, nausea, vomiting, meningeal signs, and altered mentation associated with symptoms and signs related to the source of infection.103 The three main sources of infection are cutaneous, inhalational, and gastrointestinal. The CSF studies typically show findings of hemorrhagic meningitis. Gram-stained smears of CSF may show large gram-positive bacilli suggestive of Bacillus anthracis. The organism will subsequently grow on CSF culture. PCR testing may be used to rapidly detect anthrax DNA in CSF.104 Blood cultures are positive in approximately 70% of cases. Chest radiographs are usually abnormal in those with inhalational anthrax, with findings including pleural effusion, hilar adenopathy, widened mediastinum, infiltrates, and soft tissue edema. CT or MRI of the head in these patients may show focal intracerebral hemorrhage, subarachnoid hemorrhage, intraventricular hemorrhage, diffuse cerebral edema, or prominent leptomeningeal enhancement.

The prognosis for AME is not good, with 75% of patients dead within 24 hours of presentation. Survival rate is at most 15%, but there have been no reported cases in the world literature of survival after AME associated with inhalational anthrax. The Centers for Disease Control and Prevention have indicated that ciprofloxacin or doxycycline should be included as essential components of initial treatment for anthrax from any portal of entry. Rifampin plus vancomycin would be reasonable to add given the concern of possible antibiotic resistance in bioengineered strains.103 Antianthrax serum and/or steroids have been recommended for consideration as adjunct agents in AME.

Brucella, like anthrax, is a potential bioterrorism threat. Symptoms of brucella are nonspecific and include fever, sweats, malaise, anorexia, headache, and back pain. Brucellosis may involve any organ or system. Invasion of the CNS occurs in fewer than 5% of cases. Complications in the nervous system include meningitis most frequently, and encephalitis, myelitis-radiculoneuronitis, brain abscess, epidural abscess, demyelinating syndromes, and meningovascular syndromes. CSF shows a lymphocytic pleocytosis, elevated protein, and low to normal glucose levels. The diagnosis of brucellosis is generally made by recovering brucella from blood culture. CNS disease can be confirmed by culturing brucella from CSF, but cultures are positive in only about 25%. The diagnosis also can be established by detecting antibodies in the CSF. Doxycycline with trimethoprim-sulfamethoxazole and rifampin has been used to successfully treat neurobrucellosis. When the CNS is involved with brucella, therapy is often continued for 6 to 9 months.105

Bartonella (formerly Rochalimaea) henselae has been shown to be the cause of cat scratch disease. Case reports of a variety of CNS manifestations have been reported in cases of cat scratch disease, including encephalitis, myelitis, radiculitis, and cerebellar ataxia.106 PCR has been used in a number of reports to identify B. henselae in tissue; however, such testing currently is not widely available.107 The initial therapy of choice for these infections is doxycycline or erythromycin.108

Lyme disease is the most common vector-borne infection in North America and Europe. It is a multisystem disease that results from infection with the spirochete Borrelia burgdorferi transmitted by a tick bite.109 Neurologic involvement occurs in 15% to 25% of patients, usually occurring weeks to months after infection. The typical pattern is fluctuating symptoms of meningitis with superimposed cranial or peripheral radiculoneuropathies. Acute or chronic encephalomyelitis may also occur. In patients with CNS involvement, the CSF may show a lymphocytic pleocytosis with elevated protein levels. Unfortunately, a test that uniformly indicates active infection in the CNS is lacking. The diagnosis has traditionally been made when patients with a clinically compatible illness are demonstrated to have positive serology. With the advent of PCR techniques, the difficult diagnosis of Lyme neuroborreliosis may be more firmly established in suspected cases.110 In patients who have Lyme disease with neurologic abnormalities, the recommended treatment is ceftriaxone 2 g daily for 2 to 4 weeks.

Leptospirosis is a multisystem disease that may involve the CNS.111 It is caused by spirochetes of the genus Leptospira and is a zoonosis of worldwide distribution. Humans become infected by direct or indirect contact with infected animals or by recreational exposure, especially in South Atlantic, Gulf, and Pacific coastal states in the United States (especially, in Hawaii). Subclinical infection occurs commonly. Clinical infection is commonly mild and anicteric; however, there is a severe icteric form. Leptospirosis is typically a biphasic illness, beginning with a septicemic phase characterized by an abrupt onset of fever, headache, myalgias, and nausea and vomiting. This persists for 4 to 7 days and is followed by a second or immune phase when fever is usually low grade or absent. The headache during this stage is characteristically intense and may be accompanied by mild delirium. Common physical findings include muscle tenderness, conjunctival suffusion, adenopathy, hepatosplenomegaly, and rashes. Examination of the CSF demonstrates a mild mononuclear pleocytosis with a normal or slightly elevated protein level. In this milder form of leptospirosis, focal neurologic signs and evidence of encephalitis are uncommon.

In icteric leptospirosis, the illness is more severe and is characterized by impaired renal and hepatic function, hemorrhage, myocarditis, and severe alterations in consciousness. The definitive diagnosis requires isolation of the organism or seroconversion. With the use of specialized media, the organisms may be isolated from the blood or CSF during the first 10 days of the illness or from the urine during the second week. PCR, where available, may be helpful in the detection of Leptospira.112 Treatment consists of intravenous penicillin and general supportive therapy to manage the life-threatening complications of renal failure, hypotension, and hemorrhage. The mortality rate in the more severe cases is between 5% and 10%.111

Cryptococcosis is a systemic infection caused by the ubiquitous yeast-like fungus Cryptococcus neoformans. Infection most frequently occurs in patients who are immunocompromised, especially those with AIDS. Infection tends to localize to the CNS. Onset may be abrupt in patients receiving corticosteroid therapy or those receiving treatment for lymphoreticular malignancies, but most frequently it is insidious, with mild and nonspecific complaints such as headache, irritability, somnolence, and clumsiness. Often there are behavioral changes. On physical examination, the patient is frequently afebrile with minimal or no nuchal rigidity. Papilledema is noted in about 33% of cases, and cranial nerve palsies are seen in about 20%.113 CSF examination may show an elevated opening pressure with elevated protein content, decreased glucose level, and small numbers of leukocytes. It should be emphasized that in AIDS patients there are minimal or no abnormalities of the CSF, but cryptococci grow in culture. In 50% of patients with cryptococcal meningoencephalitis, the organism may be identified in India ink smears of CSF. Latex agglutination detects antigen in CSF, but positive tests must be confirmed by cultures before a definite diagnosis of cryptococcosis can be made. The recommended treatment is amphotericin B at a dose of 0.7 mg/kg body weight daily intravenously for 2 weeks followed by fluconazole 400 mg daily for at least 10 weeks.114 Eradication of infection seldom, if ever, occurs in AIDS patients. Even after a 6-week course of amphotericin, the relapse rate was 50% to 60%.115 It is therefore currently recommended that AIDS patients receive fluconazole, 200 to 400 mg daily, indefinitely after initial therapy with amphotericin.113,116 The benefits of larger doses of fluconazole have yet to be determined. Even in immunocompetent hosts, the mortality rate in treated cryptococcal meningoencephalitis is approximately 25% to 30%.113,117

Toxoplasma gondii is the causative agent in toxoplasmosis. It is an obligate intracellular protozoan parasite that infects virtually all mammalian species and has a worldwide distribution. Toxoplasmic encephalitis historically was a relatively rare disease seen sporadically in immunocompromised patients, in particular those with malignancies of the reticuloendothelial system and organ transplant recipients. However, this disease has risen to prominence in association with AIDS. It is now recognized as the most common cause of intracerebral mass lesions in AIDS patients.118 It is believed that toxoplasmic encephalitis results from reactivation of chronic latent infection. Clinically, the CNS manifestations of toxoplasmosis are nonspecific and highly variable. They may take the form of cerebral mass lesions, meningoencephalitis, or diffuse encephalitis. Focal abnormalities are common and include focal seizures, hemiparesis, hemiplegia, cerebellar tremor, cranial nerve palsies personality changes and severe headache. Generalized abnormalities may also occur, including weakness, myoclonus, confusion, lethargy, and coma. Immunocompromised patients with toxoplasmosis have predominantly CNS manifestations; however, extraneural manifestations of the disease include chorioretinitis, pneumonitis, myocarditis, orchitis, and peritonitis.108

CSF examination of patients with toxoplasmic encephalitis generally shows an elevated protein content with a mononuclear pleocytosis of up to several hundred cells per microliter. The glucose level is normal or slightly depressed. However, results of CSF analysis may be completely normal. CT of the brain in AIDS patients with cerebral toxoplasmosis visualizes abnormalities in more than 90% of patients.119,120 Most commonly, the lesions are in the region of the basal ganglia, midbrain, or brain stem and are rounded and hypodense with peripheral “ring” enhancement, but they may show diffuse or no contrast enhancement. Lesions may be single or multiple, with multiple lesions being more specific for toxoplasmosis. MRI is reportedly more sensitive than CT.121

The diagnostic serologic changes associated with toxoplasmosis infection in immunocompetent individuals are seldom seen in AIDS patients with toxoplasmic encephalitis. Moreover, although negative toxoplasmosis serology in AIDS patients reduces the likelihood of toxoplasmosis infection, there are several reports of false-negative tests.122,123 Local antibody production to T. gondii in the CSF is specific but lacks sensitivity and therefore is of limited diagnostic usefulness. PCR has been used to amplify parts of the T. gondii genome and appears promising for diagnosis.124 Larger studies are required to characterize the role of PCR, especially in light of the current recommendations for empirical therapy.

In AIDS patients with suspected toxoplasmic encephalitis, it is desirable to have a confirmed diagnosis because similar lesions may be due to tuberculosis, other bacteria, fungi, or lymphoma. Hence, AIDS patients who have encephalitis that is clinically and radiographically compatible with toxoplasmosis are usually given a therapeutic trial with pyrimethamine and sulfadiazine. Biopsy is reserved for patients who fail to respond to therapy or whose neurologic status is rapidly deteriorating. Clinical and radiographic responses to therapy should be seen within 10 days of starting therapy. The standard treatment regimen is pyrimethamine (a 200-mg oral loading dose followed by 50 to 75 mg/day orally), folinic acid (10 to 20 mg/day orally or intravenously), and sulfadiazine (1 to 1.5 g orally every 6 hours).125 This therapy is continued for at least 6 weeks. In AIDS patients, discontinuation of therapy has been associated frequently with relapse of toxoplasmic encephalitis, and maintenance therapy should be continued indefinitely. Toxoplasmosis occasionally progresses to death even with appropriate therapy.

Granulomatous amebic encephalitis (GAE) is caused by Acanthamoeba castellani, Acanthamoeba culbertsoni,Acanthamoeba astronyxis, Acanthamoeba palestinensis, and Balamuthia mandrillaris. These are free-living amebae that have been isolated from soil, water, and air from diverse geographic locations. GAE is a subacute opportunistic infection that spreads hematogenously from pulmonary or skin lesions to the CNS. It occurs predominantly in debilitated or immunosuppressed individuals. Typically these patients present with mental status abnormalities, seizures, fever, headache, and hemiparesis. They may also demonstrate meningismus, visual disturbances, or ataxia. The diagnosis is frequently made postmortem. Brain biopsy is the only way to make the diagnosis antemortem. Little is known about the treatment of GAE; however, it has been recognized that the diamidine derivatives (pentamidine) have the greatest activity against Acanthamoeba.126

Naegleria fowleri is another free-living ameba that causes primary amebic meningoencephalitis (PAM). This ameba has been isolated from soil, river, and lake water and is especially prominent in warmer thermally polluted freshwater lakes. PAM appears primarily in healthy children and young adults who have a history of recent swimming in warm fresh water. The illness is characterized by abrupt onset of fever, nausea and vomiting, headache, and meningismus. The encephalitis is fulminant and in most patients progresses to coma and death. CSF examination typically shows a neutrophilic pleocytosis, elevated protein level, and normal or reduced glucose value. Gram stain shows pus cells but no bacteria. However, if a wet mount is made of the CSF, motile trophozoites of N. fowleri may be seen. Molecular methods to rapidly and specifically diagnose Naegleria infections are a recent development. Only six patients are known to have survived PAM. Their treatment included large-dose systemic and intrathecal amphotericin B. Passive immunotherapy with anti-Naegleria immune serum or an anti-Naegleria monoclonal antibody may in the future prove to be useful adjunctive therapy.126

Intensive supportive care is indicated in patients with encephalitis because these patients may make remarkable recoveries even after prolonged periods of unconsciousness.

The usual first principles of establishing and maintaining airway patency, oxygenation, and adequate ventilation in patients with disordered CNS function should be applied. A poor gag reflex and ineffective cough are markers of the need for airway protection. Special care must be taken in the intubation of patients with suspected encephalomyelitis to prevent potentially catastrophic increases in ICP. Intubation should be performed early in an elective fashion by an experienced person. Hypotension is also dangerous for patients with increased ICP and, if present, should be treated with intravenous fluids and appropriate inotropic support.

Strict monitoring of fluid, electrolyte, and glucose balance is necessary because of the possibility of hypothalamic involvement in the encephalitic process. Moreover, depending on the specific etiologic agent of encephalitis, there may be concurrent dysfunction of other organ systems compromising the patient's normal mechanisms of autoregulation and homeostasis. Nutrition must be maintained, preferably with enteral alimentation, but parenteral nutritional support may be necessary. Routine skin and eye care should not be neglected.

Although controversial, ICP monitoring is advocated by some for adults with severe encephalitis. Treatment of increased ICP has been required in up to 75% of patients in some series.5 Major rises in ICP may lead to further neurologic compromise or death. Elevated ICP has been associated with a poor prognosis.127 Therapy for raised ICP includes optimizing head position, hyperventilation to maintain a partial pressure of CO2 of 25 or 30 mm Hg, osmotic agents such as mannitol (100 g in 500 mL of 5% dextrose in water) infused intravenously over 10 to 20 minutes every 4 to 6 hours, as needed, in an effort to keep the ICP below 20 mm Hg (see Chap. 65).

Seizures are also a recognized complication of encephalitis and are best managed by phenytoin at a loading dose of 15 to 18 mg/kg. This should be infused at a rate not exceeding 50 mg/min in a glucose-free solution to prevent precipitation. Transient hypotension and heart block can occur during intravenous phenytoin administration, so blood pressure and electrocardiographic monitoring are required. A therapeutic plasma level of 10 to 20 mg/mL is usually achieved with a daily maintenance dose of phenytoin of 300 to 500 mg (4 to 8 mg/kg). This dose may be given intravenously or orally. The half-life of phenytoin is long (36 hours); therefore, a steady state is not achieved until 5 to 7 days have elapsed.

If seizures persist despite loading with phenytoin, then phenobarbital may need to be added (see Chap. 64). One should not assume that the seizures are secondary to the encephalitis until other treatable precipitating causes, such as structural or metabolic abnormalities, have been ruled out. Complications of prolonged seizures may include cerebral edema, aspiration, rhabdomyolysis, myoglobinuria, hyperthermia, and hypoxia. These should be treated as they arise. Extreme hyperthermia may develop secondary to the encephalitis itself and be an aggravating cause of seizures. It should be controlled by appropriate cooling measures. Medical and nursing staffs frequently ask questions about contagiousness. Except for a very few causes of encephalomyelitis, there is very little risk of disease transmission. Enteric precautions should be exercised when caring for patients with suspected enteroviral (including polio viral) infection. Isolation precautions against respiratory secretions should be taken in patients with suspected tuberculosis, rabies, measles, mumps, or lymphocytic choriomeningitis virus infection. Viral hemorrhagic fevers require strict isolation. Secretions from lesions of patients with VZV are potentially infectious, and appropriate precautions should be used. Standard precautions, including masks, gowns, gloves, and eye protection, should be worn by all personnel participating in acute resuscitation, especially those involved in endotracheal intubation.