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Harrison’s Manual of Medicine



Viral Meningitis
Viral Encephalitis
Herpes Zoster (Shingles)
Neurologic Complications of HIV Infection
Progressive Multifocal Leukoencephalopathy (PML)
Prion Diseases

The syndrome of viral meningitis consists of fever, headache, and meningeal irritation associated with a CSF lymphocytic pleocytosis, slightly elevated protein, and normal glucose. Associated symptoms can include malaise, anorexia, nausea and vomiting, abdominal pain, and diarrhea. The presence of significant impairment in consciousness, seizures, or focal neurologic findings suggests parenchymal involvement and is not typical of uncomplicated viral meningitis.
ETIOLOGY   (See Table 185-1, Table 185-2) Most cases of viral meningitis are due to enteroviruses (coxsackie-, polio-, echo-, enterovirus), including the majority of culture-negative cases. Other common causes of viral meningitis include herpes simplex virus (HSV) type 2, arboviruses, and HIV. The incidence of enteroviral and arboviral infections is greatly increased during the summer.

Table 185-1 Viruses Causing Aseptic Meningitis

Table 185-2 Seasonal Prevalence of Viruses Commonly Causing Meningitis

DIAGNOSIS   CSF polymerase chain reaction (PCR) tests have greatly facilitated diagnosis of viral meningitis and encephalitis. PCR testing is the procedure of choice for rapid, sensitive, and specific identification of viral infections caused by enteroviruses, HSV, EBV, varicella zoster virus (VZV), and CMV. Attempts should also be made to culture virus from CSF and other sites and body fluids including blood, throat swabs, feces, and urine. Serologic studies, including those utilizing paired CSF and serum specimens, may be helpful for retrospective diagnosis.
DIFFERENTIAL DIAGNOSIS   Consider bacterial, fungal, tuberculous, spirochetal, and other infectious causes of meningitis; parameningeal infections; partially treated bacterial meningitis; neoplastic meningitis; noninfectious inflammatory diseases including sarcoid and Behçet’s disease.

For the majority of cases of viral meningitis, supportive or symptomatic therapy is sufficient and hospitalization is not generally required. Neonates, the elderly, and immunocompromised pts should be hospitalized, as should individuals in whom the diagnosis is uncertain or when bacterial or other nonviral causes of meningitis cannot be excluded. The course and severity of meningitis due to HSV, EBV, and VZV may be shortened or ameliorated by antiviral treatment, specifically IV acyclovir (10 mg/kg q8h for 7 d); in mildly affected pts, a 1-week course of oral acyclovir (800 mg five times daily), famciclovir (500 mg q8h) or valacyclovir (1000 mg q8h) may be adequate. HIV meningitis should be treated with highly active antiretroviral therapy. Additional supportive or symptomatic therapy can include analgesics and antipyretics. In adults, the prognosis for full recovery from viral meningitis is excellent.

Viral encephalitis is an infection of the brain parenchyma commonly associated with meningitis (“meningoencephalitis”). Clinical features are those of viral meningitis plus symptoms and signs indicative of brain tissue involvement. These commonly include altered consciousness, seizures, and focal neurologic findings such as aphasia, hemiparesis, involuntary movements, and cranial nerve deficits.
ETIOLOGY   (See Table 185-3) The most common cause of acute sporadic encephalitis is HSV type 1. Arboviruses are responsible for both sporadic and epidemic cases of encephalitis (Table 185-4). Other common viral causes of encephalitis include enteroviruses, mumps, EBV, and VZV.

Table 185-3 Viruses Causing Encephalitis

Table 185-4 Features of Selected Arbovirus Encephalitides

DIAGNOSIS   (See Fig. 185-1)   CSF should be examined in all cases of suspected viral encephalitis. The typical CSF profile is similar to that for viral meningitis. The use of CSF PCR tests has dramatically improved the diagnosis of viral encephalitis; it allows for rapid and reliable diagnosis of infections due to HSV, EBV, VZV, CMV, and enteroviruses. CSF should be sent for culture, although this is often negative. Cultures of blood, throat swab, feces, urine, and skin lesions should also be obtained. Serologic studies, including paired CSF and serum samples, are useful for retrospective diagnosis. MRI is the neuroimaging procedure of choice and will frequently show areas of increased T2 signal. Bitemporal and orbitofrontal areas of increased signal are seen in HSV encephalitis but are not diagnostic. Multiple areas of increased T2 signal associated with decreased T1 signal and gadolinium enhancement suggest postinfectious immune-mediated demyelination. The EEG may suggest seizures and may show temporally predominant periodic spikes on a slow, low-amplitude background suggestive of HSV encephalitis.

FIGURE 185-1. Approach to the patient with suspected encephalitis. HSV, herpes simplex virus.

DIFFERENTIAL DIAGNOSIS   Includes both infectious and noninfectious causes of encephalitis, including vascular diseases; abscess and empyema; fungal (Cryptococcus and Mucor), spirochetal (Leptospira), rickettsial, bacterial (Listeria), tuberculous, and mycoplasma infections; tumors; Reye’s syndrome; toxic encephalopathy; SLE; and acute disseminated encephalomyelitis.

All pts with suspected HSV encephalitis should be treated with IV acyclovir (10 mg/kg q8h). Pts with a PCR-confirmed diagnosis of HSV encephalitis should receive a 14-day course of therapy. CSF PCR testing for HSV, performed by an experienced and reliable laboratory, is sufficiently sensitive that with rare exceptions a negative result excludes the diagnosis of HSV encephalitis and allows acyclovir therapy to be discontinued. Acyclovir treatment may also benefit pts with encephalitis due to EBV and VZV, although clinical studies are limited. No specific therapy is currently available for enteroviral encephalitis or encephalitis caused by mumps or measles. Intravenous ribovarin [15–25 (mg/kg)/d given in 3 divided doses] has been reported to be of benefit in isolated cases of severe arbovirus encephalitis due to California encephalitis (LaCrosse) virus. Encephalitis due to HIV infection should be treated with appropriate antiretroviral therapy. CMV encephalitis, which occurs almost exclusively in immunocompromised pts, should be treated with ganciclovir, foscarnet, or a combination of the two drugs; cidofovir may provide an alternative for nonresponders. Additional treatment should be directed at reducing or controlling fever, elevations in intracranial pressure, and seizures. Appropriate measures should be taken to reduce the risk of aspiration pneumonia, decubitus ulcers, thrombophlebitis, pulmonary emboli, and gastritis.

PROGNOSIS   There is considerable variation in the incidence of sequelae following infection with different agents. In patients with HSV encephalitis treated with acyclovir, data indicates 81% survival; neurologic sequelae were mild or absent in 46%, moderate in 12%, and severe in 42%.
Paresthesia or dysesthesia in a dermatomal distribution, followed by a localized cutaneous eruption of clear vesicles on an erythematous base, most commonly involving the lower thoracic (T5-10) dermatomes.

Oral acyclovir (800 mg 5 times a day), famciclovir (500 mg tid), or valacyclovir (1 g tid) for 7 days if instituted within 72 h of rash onset will diminish the duration and severity of viral shedding, new lesion formation, and acute pain. These effects are modest, and supportive therapy alone is sufficient for immunocompetent pts <50 years of age whose lesions do not involve the trigeminal dermatome. A role for antiviral drugs in reducing the incidence of postherpetic neuralgia (PHN), defined as pain persisting for >4–6 weeks after zoster rash, has been suggested but not established. PHN rarely occurs in patients <50 years of age. Treatment of PHN can include nonnarcotic analgesics, tricyclic antidepressants (amitriptyline), anticonvulsants (carbamazepine, gabapentin, phenytoin, sodium valproate), and topical capsaicin ointment. Additional complications of VZV infection can include meningoencephalitis, cerebellitis, myelitis, and granulomatous arteritis.

Direct neurologic manifestations of HIV infection are myriad. They can involve any part of the nervous system and can occur at any stage of HIV infection (Fig. 185-2). Aseptic meningitis may occur at the time of initial infection with HIV. HIV dementia typically occurs late in illness. Pts present with psychomotor slowing, apathy, difficulty with memory and concentration, and gait abnormalities. Vacuolar myelopathy also occurs in advanced HIV infection and may mimic the myelopathy of vitamin B12 deficiency. Peripheral neuropathies can occur at any stage of illness and may be either axonal or demyelinating, with predominant sensory or sensorimotor involvement.

FIGURE 185-2. Relative frequency and timing of major neurologic complications of direct HIV infection. Diseases that affect the CNS are given light shading; those that affect the peripheral nervous system are shown with darker shading. Height of the boxes is a relative indicator of the frequency of each type of disease.

Secondary neurologic complications of HIV infection result from opportunistic infections and neoplasia and typically occur in immunocompromised patients. Common causes of CNS lesions include toxoplasmosis, progressive multifocal leukoencephalopathy (PML), and primary CNS lymphoma (PCNSL). Infection with CMV can result in retinitis, meningoencephalitis, myelitis, or radiculopathy. VZV infection can produce shingles, disseminated zoster, meningoencephalitis, CNS vasculitis, or myelitis.

Direct neurologic complications of HIV infection may stabilize or improve with optimization of antiretroviral therapy. The incidence of opportunistic infections appears to be lower in pts in whom antiretroviral therapy results in improvement of immunologic function. Specific therapy is available for toxoplasmosis, CMV, and VZV. No therapy is currently available for PML. Radiation plus chemotherapy may produce modest increases in survival of PCNSL.

A progressive multifocal demyelinating disease of the CNS resulting from infection of oligodendrocytes by JC virus. Clinical manifestations reflect the location, extent, and number of lesions and can include mental status impairment, visual field abnormalities, and focal weakness. Almost all pts have an underlying immunosuppressive disorder, most commonly HIV infection.
DIAGNOSIS   MRI typically shows multifocal white matter lesions that do not enhance with contrast and are without mass effect. The CSF cell counts and chemistries are typically normal. Amplification of JC virus DNA from CSF using PCR techniques, in association with the typical clinical and neuroimaging findings, is diagnostic. A negative CSF PCR decreases the likelihood but does not exclude the diagnosis of PML. Definitive diagnosis may require brain biopsy.

No effective therapy for PML is currently available. Improvement of immune status (e.g., by optimization of antiretroviral therapy in HIV-infected individuals) has been reported to result in stabilization or remission of disease.

Prion diseases of the CNS may present as sporadic, rapidly progressive dementia associated with myoclonus (Creutzfeldt-Jakob disease, CJD), or less commonly as familial forms of rapidly progressive dementia (familial CJD); cerebellar degeneration (Gerstmann-Straussler-Scheinker disease, GSS); or complex syndromes of insomnia, hallucinations, motor abnormalities, and autonomic and endocrine disturbances (fatal familial insomnia, FFI). Iatrogenic prion diseases can result from use of contaminated corneal or dura grafts, neurosurgical instruments, or cadaveric-derived pituitary hormones. Approximately 70 cases of an atypical form of CJD (new variant CJD) characterized by early age of onset and prominent initial neuropsychiatric and behavioral abnormalities followed by ataxia and progressive dementia have been reported, initially from England and France. It has been suggested, but not definitively established, that these cases may be the result of human exposure to food or other products derived from cattle infected with bovine spongiform encephalopathy (“mad cow disease”).
DIAGNOSIS   CT and MRI are often normal but may show rapidly progressive atrophy or increased T2 signal in the basal ganglia (MRI). CSF cell counts and chemistries are normal. Both CSF and neuroimaging studies may help exclude other diagnoses. It has been reported that the presence in CSF of a specific protein (14-3-3) is suggestive but not diagnostic of CJD. EEG may show periodic sharp wave complexes in CJD, but these are absent or occur only rarely in GSS, FFI, and new variant CJD. Definitive diagnosis of sporadic forms of prion disease requires brain biopsy; findings include neuronal loss, astrogliosis, spongiform changes, absence of inflammatory response, and the presence, in GSS and new variant CJD, of typical plaques containing protease-resistant prion protein. The detection of protease-resistant prion proteins by immunoblotting or immunocytochemistry establishes the diagnosis. If the pt has a family history suggestive of inherited CJD, sequencing the prion protein gene may facilitate the diagnosis.

CNS prion diseases are all inexorably progressive and invariably fatal. No effective treatment is currently available.


For a more detailed discussion, see Tyler KL: Viral Meningitis and Encephalitis, Chap. 373, p. 2471, in HPIM-15; Prusiner SB, Bosque P: Prion Diseases, Chap. 375, p. 2486 in HPIM-15; and HPIM-15 chapters covering specific organisms or infections.

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