Infections of the Nervous System: Viral Encephalitis and Meningitis

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Chapter 53B Infections of the Nervous System

Viral Encephalitis and Meningitis

Hundreds of viruses exhibit tropism for the central (CNS) and/or peripheral (PNS) nervous systems. In the case of some viruses, involvement of the CNS or PNS is the predominant feature of illness, whereas in others, involvement of the nervous system is a rare complication of a more generalized illness. Viral infection of the nervous system can result in a myriad of clinical presentations occurring separately or in combinations including acute or chronic meningitis, encephalitis, myelitis, ganglionitis, and polyradiculitis. Viruses may also incite para- or postinfectious CNS inflammatory or autoimmune syndromes such as acute disseminated encephalomyelitis (ADEM) (see Chapter 54). The neurological complications of human immunodeficiency virus (HIV) and human T-cell lymphotropic virus (HTLV) infections are discussed separately (see Chapter 53A).

Table 53B.1 lists the most common viral causes of nervous system disease in North America and the relative propensity of each virus to cause meningitis, encephalitis, postinfectious encephalomyelitis, or myelitis. Infections that occur in residents or travelers to areas outside the United States are listed in Table 53B.2. In the United States, the most common viruses causing meningitis are enteroviruses, herpes simplex virus type 2 (HSV-2), and arboviruses. The most common identified viral causes of encephalitis are herpesviruses, notably HSV-1, and arboviruses. Even with the best diagnostic efforts, up to 70% of cases of suspected viral encephalitis remain of unknown etiology (Glaser et al., 2003, 2006; Kupila et al., 2006). Worldwide, there are tens of thousands of deaths from rabies each year (Warrell and Warrell, 2004), and in Asia, 30,000 to 50,000 cases and 10,000 deaths from Japanese encephalitis virus (Solomon, 2004). In the United States, nearly 12,000 cases of West Nile virus neuroinvasive disease, with an estimated 1150 deaths, have occurred since 1999 (Davis et al., 2006; DeBiasi and Tyler, 2006; see also: http://www.cdc.gov/ncidod/dvbid/westnile/index.htm).

Table 53B.2 Additional Causes of Viral Nervous System Infection Resulting from Foreign Exposures

Agent   Geographical Distribution
Nipah virus   Indonesia, Singapore, India
Filovirus Ebola Africa
  Marburg  
Arbovirus    
Togavirus    
Mosquito-borne Eastern equine Caribbean and South America (plus United States)
  Venezuelan equine Central and northern South America (plus United States)
  St. Louis Caribbean, Central and northern South America (plus United States)
  Japanese B Japan, China, Southeast Asia, India
  Kunjin Australia
  Murray Valley Australia and New Guinea
  West Nile Africa and Middle East, parts of Europe (plus United States)
  Ilheus South and Central America
  Rocio Brazil
Sand fly–borne Toscana Italy, Spain, Portugal, France
Tickborne complex Far Eastern Eastern Russia
  Central European Eastern and Central Europe, Scandinavia
  Kyasanur Forest India
  Louping Ill England, Scotland, and Northern Ireland
  Negishi Japan
  Russian spring-summer Eastern Europe, Asia
Bunyavirus Tahyna Czechoslovakia, Yugoslavia, Italy, southern France
  Inkoo Finland
  Rift Valley East Africa
Rhabdovirus Rabies Many developing countries
Enterovirus Poliovirus Nigeria, Afghanistan, India (endemic)

Although the basic clinical features of most types of viral meningitis and encephalitis are generally similar, specific physical examination findings may help narrow the possible viral etiologies of nervous system disease (Tables 53B.3 and 53B.4). It is important to recognize that several nonviral diseases can mimic the clinical features of viral CNS infection (Table 53B.5) (DeBiasi and Tyler, 2006). The treatment, prophylaxis, and immunotherapy of specific viral infections are summarized later in the chapter.

Table 53B.3 Skin/Mucous Membrane Findings Suggesting Specific Viral Central Nervous System Diseases

Exanthem or Mucous Membrane Change Viral Agent Specific Changes
Vesicular eruption Enterovirus “Hand, foot, and mouth disease”: Macules/papules/vesicles on palms, soles, buttocks
  Herpes simplex Grouped small (3 mm) vesicles on an erythematous base
  Varicella-zoster virus Zoster: Vesicles in dermatomal distribution
Primary VZV: Multiple vesicles, papules, pustules in various stages of eruption
Maculopapular eruption Epstein-Barr virus Diffuse maculopapular eruption following ampicillin treatment
  Measles Diffuse maculopapular erythematous eruption beginning on face/chest and extending downward
  HHV-6 Roseola: Diffuse maculopapular eruption following 4 days of high fever
  Colorado tick fever Maculopapular rash in 50%
  LCMV Occasionally occurs with lymphadenopathy
  WNV Diffuse erythematous macular rash on chest and arms
Erythema multiforme (Mycoplasma) Many types of rash
Confluent macular rash Parvovirus Confluent erythema over cheeks (“slapped cheeks”) followed by lacy reticular rash over extremities (late)
Purpura Parvovirus Rare “stocking glove” syndrome: Purpuric lesions on distal extremities
Pharyngitis Enterovirus Herpangina: Vesicles on soft palate
  Adenovirus Pharyngoconjunctivitis
Conjunctivitis St. Louis encephalitis Conjunctivitis
  Adenovirus Conjunctivitis with pharyngitis (see above)

HHV-6, Human herpesvirus type 6; LCMV, lymphocytic choriomeningitis virus; VZV, varicella-zoster virus; WNV, West Nile virus.

Table 53B.4 Other Specific Findings Associated with Viruses Causing Central Nervous System Disease

Finding Viruses
Alopecia LCMV
Arthritis LCMV, parvovirus
Biphasic illness LCMV, Colorado tick fever
Lymphadenopathy LCMV, mumps
Mastitis Mumps
Mononucleosis CMV, EBV
Myelitis WNV, St. Louis encephalitis virus, VZV, herpes B virus, LCMV
Myocarditis/pericarditis Enterovirus, (mumps, LCMV)
Orchitis/oophoritis Mumps (LCMV, EBV)
Paresthesias Colorado tick fever, LCMV, rabies
Parotitis Mumps (LCMV)
Pneumonia Influenza, parainfluenza
Retinitis CMV
Tremors, myoclonus Arbovirus (e.g., WNV)
Urinary problems St. Louis encephalitis virus, VZV, herpes B virus, LCMV

CMV, Cytomegalovirus; EBV, Epstein-Barr virus; LCMV, lymphocytic choriomeningitis virus; VZV, varicella-zoster virus; WNV, West Nile virus.

Deoxyribonucleic Acid Viruses

Herpesviruses

Multiple members of the herpesvirus family cause neurological disease in humans: HSV-1 and HSV-2, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesviruses (HHV-6, HHV-7, and HHV-8), and the simian (“monkey”) herpes B virus.

Herpes Simplex Viruses Type 1 and 2

Herpes Simplex Encephalitis

HSV-1 encephalitis is the most common identified cause of sporadic fatal encephalitis in the United States, accounting for approximately 10% of all cases of encephalitis and occurring with a frequency of about 1 case per 250,000 population per year (Whitley, 2006). Early recognition is important because the efficacy of the antiviral drug acyclovir (ACV) in reducing morbidity and mortality decreases as neurological disease progresses (Whitley et al., 1986). HSV-1 strains cause over 90% of cases of herpes simplex encephalitis (HSE) in adults, with the remainder due to HSV-2. Conversely, HSV-2 is a more common cause of meningitis and neonatal meningoencephalitis than HSV-1. Both HSV types 1 and 2 have been associated with myelitis.

Fever is present in about 90% and headache in about 80% of patients with biopsy or polymerase chain reaction (PCR) assay–proven HSE. Other common features include disorientation (70%), personality change (70%-85%), focal or generalized seizures (40%-67%), memory disturbance (25%-45%) motor deficit (30%-40%), and aphasia (33%) (Domingues et al., 1997; Whitley, 2006; Whitley et al., 1986).

It is important to recognize that no sets of signs or symptoms are pathognomonic of HSE, and multiple infectious and inflammatory processes can mimic HSE (Whitley, 2006; Whitley et al., 1986). Definitive diagnosis of HSE requires demonstration of viral deoxyribonucleic acid (DNA) in cerebral spinal fluid (CSF) using an HSV-specific PCR assay or isolation of virus, or detection of viral antigen or viral nucleic acid from brain tissue at biopsy or autopsy (see later discussion).

Examination of CSF is the single most important diagnostic test in suspected cases of HSE. CSF is usually under increased pressure, with a lymphocytic pleocytosis of 10 to 1000 white blood cells (WBC) per µL. Over 95% of PCR or biopsy-proven cases of HSE have a CSF pleocytosis, although rare cases with an initially normocellular CSF have been reported (Domingues et al., 1997; Whitley et al., 1986). HSE is often hemorrhagic, and both red blood cells and xanthochromia can be detected in CSF, although neither feature occurs with significantly greater frequency in HSE compared to other causes of focal encephalitis (Whitley et al., 1986). CSF protein is usually moderately elevated and glucose is normal in more than 90% of patients with HSE.

Virus cannot be cultured from CSF in over 95% of cases of HSE; however, HSV DNA can be detected in the CSF by PCR assay, and this is the diagnostic procedure of choice. Amplification of HSV DNA from CSF by PCR testing has a sensitivity of 98% and specificity of 94% for the diagnosis of HSE compared to brain biopsy (Lakeman and Whitley, 1995; Tebas et al., 1998) (Table 53B.6). HSV CSF PCR results must be interpreted in light of the pre-test probability that a patient has HSE (Bayesian decision analysis). For example, a negative test in a patient with a low prior probability of HSE (e.g., 5%) reduces the posttest likelihood of HSE to approximately 0.2%, whereas a negative PCR in a patient with a high pre-test likelihood of HSE (e.g., 60%) only reduces the posttest likelihood of HSE to around 6% (Tebas et al., 1998). CSF PCR remains a sensitive technique for the detection of HSE, even in patients who have received up to a week of antecedent antiviral therapy (Lakeman and Whitley, 1995). Despite the high overall sensitivity of CSF HSV PCR, false-negative results have been reported, most notably in patients in whom CSF was obtained within the first 72 hours of illness onset (Weil et al., 2002). For this reason, caution should be used in stopping ACV therapy in patients with suspected HSE on the sole basis of a single negative CSF PCR test obtained within 72 hours of symptom onset, unless a suitable alternative diagnosis has been established.

Table 53B.6 PCR Diagnosis of Viral Nervous System Disease

Virus Sensitivity Specificity
Adenovirus Unknown  
Dengue Unknown  
Enterovirus >95% >95%
Herpesviruses    
CMV 100% in immunocompromised  
  >60% in congenital CMV infection  
EBV 98.5% as tumor marker in HIV patients with CNS lymphoma 100%
HSV-1 and -2 >95% >95%
HHV-6   >95%
VZV >95% >95%
HIV HIV RNA present at all stages Excellent
HTLV I and II 75% 98.5%
Influenza Unknown but > culture Unknown
Japanese encephalitis virus   Unknown
JC virus 50%-90% in PML 98%
LCMV Unknown Unknown
Mumps Unknown Unknown
Measles Unknown Unknown
Parvovirus B-19 Unknown Unknown
Rabies 100% Unknown
WNV 70% Unknown

CMV, Cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpesvirus; HSV, herpes simplex virus; HTLV, human t-cell lymphotropic virus; LCMV, lymphocytic choriomeningitis virus; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy; VZV, varicella-zoster virus; WNV, West Nile virus.

When definitive diagnosis of HSE was dependent on brain biopsy, patients often had significantly depressed levels of consciousness and advanced neurological disease at the time of diagnosis. With routine use of HSV CSF PCR instead of brain biopsy for definitive diagnosis of HSE, patients are often identified at an earlier stage of illness, exhibit less depression of consciousness, and have improved response to therapy. Over 75% of cases with PCR-proven HSE had a Glasgow Coma Score (GCS) above 12 (Domingues et al., 1997), whereas only 30% of cases with biopsy-proven HSE had a GCS above 10 in the Collaborative Antiviral Study Group (CASG) trial of vidarabine versus ACV therapy (Whitley et al., 1986).

Magnetic resonance imaging (MRI) is significantly more sensitive than computed tomography (CT) and is the neuroimaging procedure of choice in patients with suspected HSE. Approximately 90% of patients with PCR-proven HSE will have MRI abnormalities involving the temporal lobes (Domingues et al., 1997; Raschilas et al., 2002) (Fig. 53B.1). The electroencephalogram (EEG) may be abnormal early in the course of disease, demonstrating diffuse slowing, focal abnormalities in the temporal regions, or periodic lateralizing epileptiform discharges (PLEDs). EEG abnormalities involving the temporal lobes are seen in approximately 75% of patients with PCR-proven HSE (Domingues et al., 1997). Brain biopsy is now only rarely performed for diagnosis of HSE. Biopsy is reserved for atypical cases in which the diagnosis remains in question for those who respond poorly to treatment. Biopsy specimens from patients with HSE show hemorrhagic necrosis, HSV antigen in infected cells, and accumulations of viral particles forming acidophilic intranuclear inclusion bodies in neurons (Cowdry type A inclusions) (Fig. 53B.2).

Because of its safety, empirical therapy with ACV should be started immediately in acute cases of focal encephalitis of suspected viral etiology (Table 53B.7). Mortality in untreated cases of HSE is around 70%, but this is reduced to 19% to 28% in patients treated with ACV (Whitley et al., 1986). Morbidity due to HSV-1 encephalitis remains high even in patients receiving ACV, with only 37.5% of all patients surviving with no or only mild deficits (Whitley et al., 1986). However, in specific subpopulations of ACV-treated HSE patients, prognosis can be considerably better. For example, 50% (12/24) of patients in whom treatment with ACV was initiated when their GCS exceeded 6 survived with no or only minor sequelae, and more than 60% who were younger than age 30 and had a GCS above 6 survived with no or only minor sequelae (Whitley et al., 1986). Outcomes have been generally similar in cases of PCR-proven HSE treated with ACV, with 37% to 56% of patients returning to normal functional status or having only mild disability or residual sequelae at 6 months follow-up (Domingues et al., 1997; Raschilas et al., 2002). Survival and prognosis are influenced by several factors including level of consciousness at initiation of therapy (e.g., GCS), patient age, and duration of disease before therapy (Marton et al., 1996; Raschilas et al., 2002; Whitley et al., 1986). In the CASG trial, all (9/9) patients treated with ACV within 4 days of onset of fever, headache, and focal neurological deficits survived, whereas the mortality was 35% in those in whom ACV treatment was initiated when disease was more than 4 days old (Whitley et al., 1986). In another study, the recovery rate was 50% in patients treated within 5 days of illness onset (Marton et al., 1996). In a third study of PCR-proven HSE, 75% of patients with an ultimately favorable outcome had received ACV therapy within 2 days of hospital admission compared to only 30% of those with a poor outcome (Raschilas et al., 2002).

The standard adult dose of acyclovir for HSE is 10 mg/kg, given intravenously (IV) every 8 hours (20 mg/kg every 8 hours in neonates and children) for 14 to 21 days. Renal insufficiency is an infrequent, usually reversible, side effect of ACV therapy. ACV dosing should be adjusted appropriately in patients with renal insufficiency. There are no reliable data on the efficacy of oral antiviral drugs in treatment of HSE, so their use should be avoided. Retrospective studies have suggested that there may be some benefit in adding corticosteroids to ACV treatment (Kamei et al., 2006), although controlled clinical trials are needed before the role of steroid therapy as an adjunct to ACV can be definitively established. Foscarnet is an alternative therapy for patients with suspected or proven ACV-resistant strains or with allergy to ACV.

Neonatal Herpes Simplex Virus Meningoencephalitis

In contradistinction to adults, in whom HSE is usually caused by HSV-1, HSV-2 is the most common causal agent of meningoencephalitis in neonates (although HSV-1 disease may also occur). Neonates who acquire HSV from the birth canal develop infection of the CNS in 50% of cases (Kimberlin, 2005). CNS disease occurs as either a component of an overwhelming sepsis-like disseminated disease with multiorgan involvement (in the first week of life) or as isolated CNS disease that usually presents later (weeks 2-10 of life), with or without accompanying vesicular skin, mucous membrane, or conjunctival lesions (skin, eye, mouth disease). The presence of vesicular skin or mucosal lesions in an infant of this age, even in the absence of fever or systemic symptoms, warrants immediate evaluation of CSF for HSV infection, because up to 30% of infants with presumed isolated skin, eye, and mouth disease are subsequently identified as having CNS involvement. Neonates with possible HSV disease should be treated empirically with IV acyclovir, 20 mg/kg, every 8 hours. Treatment should be continued for 14 days in HSV-infected infants with isolated skin, eye, and mouth disease and 21 days in infants with sepsis or CNS involvement. Relapses of skin, eye, and mouth disease (with the potential for CNS involvement and subsequent neurological deficits) are common in the first year of life following neonatal HSV disease. For this reason, the use of oral ACV prophylaxis for 3 to 6 months following IV therapy is advised by some experts (Kimberlin, 2005).

Varicella-Zoster Virus

Primary Infection

At least 95% of the adult population has been infected with VZV, and the lifetime risk of developing shingles is 3% to 5%. VZV can involve virtually every part of the CNS and PNS (Gilden, 2004; Gilden et al., 2000, 2005; Kleinschmidt-DeMasters and Gilden, 2001). Primary VZV may produce meningitis or encephalitis in immunocompromised patients. An acute self-limited cerebellar ataxia occurs in about 1 in 4000 children (<15 years of age) during or immediately following primary VZV infection (chickenpox). Postinfectious encephalomyelitis follows an estimated 1 in 2500 cases of primary VZV infection.

Reactivation of herpes zoster can produce meningitis, myelitis, and encephalitis in older children and adults. Zoster “encephalitis” can occur in both immunocompetent and immunocompromised hosts and typically results from reactivation of herpes zoster decades after an initial infection with varicella (chickenpox). VZV encephalitis is in fact a vasculopathy rather than a true encephalitis (Gilden, 2004; Gilden et al., 2000, 2005; Kleinschmidt-DeMasters and Gilden, 2001). In older (>60 years) immunocompetent adults, VZV vasculopathy (previously called granulomatous arteritis) typically presents with acute focal stroke-like deficits due to inflammatory involvement of large cerebral arteries, typically occurring in the trigeminal distribution. Most cases are monophasic, although rare cases follow a chronic or relapsing-remitting course (Gilden, 2004; Gilden et al., 2005). CSF shows a lymphocytic pleocytosis. MRI shows a large single infarct, most commonly in the carotid, middle, or anterior cerebral territory. At autopsy, viral particles, antigen, and DNA can be found in the involved artery. Diagnosis can be made by demonstration of VZV DNA in CSF by PCR or by demonstration of VZV immunoglobulin (IgM) or intrathecal synthesis of VZV IgG in CSF.

In immunocompromised individuals, VZV reactivation produces a multifocal vasculopathy predominantly involving small and medium-sized arteries, resulting in a clinical syndrome of mental status changes, focal deficits, and a CSF mononuclear pleocytosis (Gilden, 2004; Gilden et al., 2005). The typical rash of zoster may be absent. Neuroimaging shows multifocal hemorrhagic and ischemic cortical and subcortical infarcts. Diagnosis can be established by VZV CSF PCR or by demonstration of CSF VZV IgM or intrathecal VZV-specific IgG antibody synthesis.

VZV has been increasingly recognized as an important cause of viral meningitis in immunocompetent hosts even in the absence of a characteristic varicella (chickenpox) or zoster (shingles) rash (Kupila et al., 2006; Mogensen and Larsen, 2006). In one recent study, VZV accounted for 8% of viral meningitis cases, making it third in importance behind enteroviruses and HSV-2 (Kupila et al., 2006).

There are no controlled randomized clinical trials of antiviral therapy of CNS VZV infection. Intravenous acyclovir (10 mg/kg every 8 hours) for 7 to 10 days is generally recommended for treatment of immunocompromised children and adults with chickenpox. Patients with VZV CNS disease including vasculopathy should receive the combination of IV acyclovir (10-20 mg/kg or 500 mg/m2 every 8 hrs) for a minimum of 7 (Gilden, 2004) to 14 (Steiner et al., 2005) days, combined with a steroid pulse for 3 to 5 days (e.g., prednisone 60-80 mg/day) (Gilden, 2004; Steiner et al., 2005). HIV-infected individuals with localized (nondisseminated) dermatomal zoster can be treated with oral famciclovir (500 mg 3 times daily) or valacyclovir (1000 mg 3 times daily) for 7 to 10 days.

Herpes Zoster

Following primary infection, VZV becomes latent in cells of the dorsal root ganglia. Reactivation of endogenous latent virus produces herpes zoster (shingles). The virus can reactivate after injury or trauma to the spine or nerve roots or in response to waning cell-mediated immunity to VZV caused by age or immunosuppression related to HIV infection, cancer, cytotoxic drugs, or systemic illness. Herpes zoster is frequently the first clinical presentation of underlying HIV infection, in which case it may be protracted and multidermatomal. The incidence of shingles is up to 25-fold greater in HIV-infected individuals than in the general population.

Herpes zoster typically begins with pain and paresthesias in one or two adjacent spinal or cranial dermatomes (Gilden et al., 2000). Pain is followed in 3 to 4 days by a painful pruritic vesicular eruption in the area supplied by the affected root. The eruption typically lasts 10 to 14 days. Eruption most commonly occurs in the lower thoracic dermatomes but also commonly involves the trigeminal distribution and the cervical or lumbosacral dermatomes. Involvement of the first division of the trigeminal ganglion produces ophthalmic zoster and may be associated with conjunctivitis, keratitis, anterior uveitis, or iridocyclitis. Fortunately, vision loss following herpes zoster ophthalmicus is rare. Involvement of the geniculate ganglion produces otic zoster, or the Ramsay Hunt syndrome—painful facial paresis accompanied by tympanic membrane and external auditory canal vesicular rash. Herpes zoster involving cervical and thoracic levels may be associated with myelitis, and in the lumbosacral region may be accompanied by bladder dysfunction or ileus. Complications of zoster include postherpetic neuralgia, segmental motor atrophy in the affected dermatome, meningitis, myelitis, large-vessel vasculitis (usually involving the carotid or its branches on the side of zoster ophthalmicus), and multifocal leukoencephalitis or encephalitis with generalized cerebral vasculopathy (Gilden, 2004; Gilden et al., 2000, 2005).

Risk factors for postherpetic neuralgia in patients with shingles include age older than 50 years and prodromal sensory symptoms. Treatments are directed toward lessening pain, reducing virus shedding, and shortening healing time. Acyclovir (800 mg orally, 5 times daily for 7 days), famciclovir (200 mg orally, 3 times daily for 7 days), or valacyclovir (1 g orally, 4 times daily for 7 days) accelerate cutaneous healing and decreases acute zoster pain if begun within 72 hours of onset of rash. Whether these agents significantly decrease the incidence, duration, or severity of postherpetic neuralgia is uncertain. In patients without contraindications, a short course of corticosteroids (e.g., 40 mg prednisolone/day, tapered over 3 weeks) may be added to antiviral therapy. Compared with ACV therapy alone, addition of corticosteroids has been shown to improve comfort levels (pain reduction during the acute phase) following herpes zoster, although its efficacy in reducing subsequent risk of postherpetic neuralgia remains uncertain. Intrathecal methylprednisolone and oral gabapentin have been studied as treatments for postherpetic neuralgia and have been efficacious in some studies. A live attenuated varicella vaccine (Oka/Merck) was evaluated in a multicenter placebo-controlled double-blind study in over 38,000 adults older than age 60 for its capacity to reduce the incidence of herpes zoster and secondary postherpetic neuralgia. The vaccine reduced the incidence of herpes zoster by 51% and the incidence of postherpetic neuralgia in those who still developed zoster by 67% (Oxman et al., 2005).

Cytomegalovirus

CMV causes both acute and latent or persistent infections in humans, and 40% to 100% of adults are seropositive, reflecting past infection with this virus. CMV-related neurological complications include retinitis, encephalitis, polyradiculomyelopathy, neuropathy, and Guillain-Barré syndrome (Griffiths, 2004). In immunocompetent hosts, CMV may cause inapparent infection, a mononucleosis syndrome, aseptic meningitis, or the Guillain-Barré syndrome. CMV encephalitis is rare in immunocompetent hosts beyond the neonatal period and usually presents as encephalopathy, with or without focal features, in the context of a subacute febrile illness. However, immunocompromised adults and developing fetuses are at high risk of developing CNS disease due to CMV. CMV infection of peripheral nerves, nerve roots, and spinal cord, particularly in patients with AIDS, causes ascending myeloradiculitis (Miller et al., 1996).

Congenital Cytomegalovirus

CMV infection is the most common human congenital infection and can cause severe injury to the infected fetus. It has been estimated that about 1% of newborns have CMV infection, of whom some 7% have symptomatic disease. The mortality for newborns with symptomatic disease is 10% to 30%, and up to 90% of survivors will have neurological sequelae. The rate of sequelae in newborns with asymptomatic primary infection has been estimated at roughly 15% (Griffiths and McLaughlin, 2004). In addition to congenital cases, there are cases that arise in the perinatal period as a consequence of passage through an infected birth canal or following breastfeeding. Persistent high levels of viral replication in the eye and brain of the developing fetus produce encephalitis, ependymitis, and retinitis, a pattern similar to that seen in patients with opportunistic CMV infection in the setting of HIV infection. Pathologically, encephalitis occurs in a periventricular pattern and may cause polymicrogyria and hydrocephalus (Fig. 53B.3). CT scans show characteristic periventricular calcifications in 20% to 30% of children with symptomatic CMV infection. Retinitis with optic atrophy is seen in about 15% of those affected and results in characteristic hyperpigmented retinal scars. As noted, 90% of survivors of congenital CMV infection have residual neurological sequelae including psychomotor retardation, learning delays, mental retardation, seizures, optic atrophy and retinitis, and hearing loss. Mild or subclinical congenital infections may also manifest later in childhood as sensorineural deafness or developmental delay. Congenital human CMV infection is the most common, nonheritable cause of hearing loss in the United States.

Diagnosis of congenital CMV is made by identification of CMV DNA in urine, saliva, or CSF during the immediate postnatal period. Because urinary excretion of CMV can often persist during the first year of life, isolation of virus or viral DNA from urine may be useful in later diagnosis. CMV inclusion-bearing cells are found in affected organs (Fig. 53B.4) and in stained preparations of urinary sediment and saliva. Serological studies may be difficult to interpret owing to transplacental transfer of antibody from the mother. Detection in the neonate of CSF IgM antibodies or CMV-specific intrathecal antibody synthesis is supportive of acute CNS infection.

In a study evaluating the efficacy of IV ganciclovir therapy (4-6 mg/kg every 12 hours for 6 weeks) in neonates with symptomatic congenital CMV infection, 69% of treated children, compared to only 39% of untreated children, showed improvement in brainstem auditory evoked potentials. More significantly, none of the ganciclovir-treated children, compared to 42% of those not treated, showed worsening hearing loss over the initial 6 months post infection (Kimberlin et al., 2003; Whitley et al., 1997;).

Cytomegalovirus in Immunocompromised Adults

CMV encephalitis in immunocompromised patients with acquired immunodeficiency syndrome (AIDS) or organ transplants (Griffiths, 2004; Tselis and Lavi, 2000) often presents as a nonspecific febrile encephalopathy, with or without focal features. CMV encephalitis typically occurs in AIDS patients with a CD4+ cell count of less than 50 cells/mm3, although patients with counts below 100/mm3 are at increased risk of developing CMV viremia (Griffiths, 2004). AIDS-associated CMV encephalitis presents either as microglial nodular encephalitis with acute onset of confusion and delirium, or as a more slowly progressive ventriculoencephalitis characterized by confusion and cranial nerve palsies. There is a broad pathological spectrum of CMV infection of the brain in AIDS patients, ranging from scattered microglial nodules to widespread necrotizing ependymitis and perivascular infiltrates to necrotizing leukoencephalopathy or focal necrosis deep in parenchyma.

CMV is one of the most important pathogens influencing the outcome of transplantation. In contrast to AIDS patients, allogeneic hematopoietic stem cell transplant patients develop encephalitis alone without retinitis. Risk factors for CNS disease in this group include T-cell depletion, umbilical cord blood transplantation, and a history of recurrent CMV viremia. Active graft-versus-host disease, a risk factor for a variety of late-onset infections after allogeneic stem cell transplantation, may be present (Reddy et al., 2010). Antiviral prophylaxis for prevention of primary infection or recurrence when either or both donor and recipient are seropositive is administered with oral or IV ganciclovir (1000 mg every 8 hours). In donor+/recipient− solid organ transplant, oral valganciclovir, 900 mg/day × 200 days is also used. Preemptive treatment is prevention of development of disease when reactivation has occurred. Induction is with IV ganciclovir 5 mg/kg, 2 or 3 times daily × 2 to 4 weeks, followed by a lower maintenance dose of 5 mg/kg/day × 4 weeks. CNS disease treatment is with IV ganciclovir, 5 to 7.5 mg/kg per dose 2 or 3 times daily, and the addition of IV foscarnet 90 mg/kg twice daily for refractory cases (Ljungman, 2008).

Diagnosis of CMV encephalitis may be difficult, particularly by serological testing, because CMV antibody titers can fluctuate spontaneously. Virus detection methods focus on quantitation of viral load (particularly in peripheral blood leukocytes; i.e., virus DNA in buffy coat) for patients with persistent infection, as well as to help predict which immunosuppressed patients might develop end-organ disease. CSF CMV PCR has a reported sensitivity of 82% and specificity of 99% in AIDS patients with CNS disease due to CMV (Cinque et al., 1997). In AIDS patients, in whom detection of CMV viremia by PCR may predict the development of retinitis, a wide spectrum of neuroimaging results has been reported, ranging from normal findings to detection of generalized atrophy, periventricular abnormalities, and focal discrete white-matter lesions. The most characteristic MRI finding is periventricular increased signal on T2-weighted images and ependymal enhancement following gadolinium administration on T1-weighted images. CMV polyradiculitis manifests as diffuse enhancement of cauda equina nerve roots and is often associated with concurrent CMV infection elsewhere in the body (Miller et al., 1996). Many patients with this syndrome have an almost pathognomonic CSF profile of neutrophilic pleocytosis with a low glucose concentration. The diagnosis is confirmed by PCR amplification of CMV DNA in CSF.

Ganciclovir, foscarnet, and cidofovir all have efficacy against CMV in vitro and in some clinical settings in vivo. In patients with AIDS, immune reconstitution following introduction of highly active antiretroviral therapy (HAART) may help control CMV replication and disease. General recommendations for immunocompromised patients, including those with AIDS, are initial antiviral therapy with IV ganciclovir (5 mg/kg every 12 hours for 2-3 weeks), followed by maintenance dosing with either IV ganciclovir (5 mg/kg/day, 5 days/week) or oral valganciclovir (900 mg daily) for at least an additional 4 weeks. Foscarnet should be reserved for treatment of ganciclovir-resistant CMV because of its nephrotoxicity and IV administration (Griffiths, 2004). Foscarnet dosage is 60 mg/kg IV, 3 times daily for 2-3 weeks for initial therapy, then 90 to 120 mg/kg IV daily for maintenance. Maintenance therapy should be continued in HIV patients until their CD4 count remains above 100 to 150 cells/mm3 for more than 6 months. There are limited clinical data on the use of cidofovir for treatment of CMV CNS disease (Table 53B.8).

Epstein-Barr Virus

Primary EBV infection may be asymptomatic, present as a nonspecific febrile illness, or classically, as the infectious mononucleosis syndrome with cervical lymphadenopathy, exudative pharyngitis, and splenomegaly. The pathogenesis of EBV-associated CNS disease remains uncertain because virus, viral antigen, or viral nucleic acid are only rarely isolated directly from CNS tissue in patients with encephalitis or myelitis, raising the possibility that at least some CNS manifestations may be post- or para-infectious immune-mediated phenomena. However, recent studies suggest that patients with EBV-associated neurological disease frequently have EBV DNA that can be amplified from CSF, and that this is frequently associated with amplifiable viral RNA consistent with lytic viral replication (Weinberg et al., 2002, 2005).

Significant nervous system disease occurs in less than 1% of EBV infectious mononucleosis cases and can manifest as meningitis, encephalitis, cerebellitis, transverse myelitis, optic neuritis, cranial neuropathy, Guillain-Barré syndrome, or as small-fiber sensory or autonomic neuropathy syndromes (Doja et al., 2006). The most common symptomatic EBV-associated CNS infection is meningitis. Cases of asymptomatic laboratory-defined meningitis probably vastly exceed symptomatic cases; up to 25% of patients with acute infectious mononucleosis may have a CSF pleocytosis despite the absence of signs or symptoms of meningitis. There are no unique features of EBV meningitis, although the presence of atypical lymphocytes in CSF may suggest the diagnosis. Diagnosis is typically made by amplification of EBV DNA by CSF PCR. In rare cases, EBV-specific IgM antibodies can be detected in CSF. Attempts to isolate virus from CSF are almost invariably negative. The presence of serum serologies indicative of acute infection supports the diagnosis (e.g., IgM antibodies against viral capsid antigen (VCA), presence of antibodies against early antigen [EA], but not Epstein-Barr nuclear antigen [EBNA]).

In occasional patients, EBV is associated with frank encephalitis, presenting with altered consciousness including coma, seizures, and focal neurological signs and symptoms. EEG abnormalities such as diffuse slowing are common. Cases of EBV CNS disease may occur before, during, or after infectious mononucleosis or even in its absence. In one series of 21 cases of EBV encephalitis in children (Doja et al., 2006), only one patient had classic infectious mononucleosis; the remainder had a nonspecific prodrome that included fever (81%) and headache (66%). Seizures occurred in 48%, and 57% had EEGs with a diffusely slow background. CSF pleocytosis (81%) and MRI abnormalities (71%) were common. Mortality was 10%, with 80% neurologically normal at follow-up and an additional 10% having mild deficits. Some patients have a syndrome suggestive of involvement of the brain, spinal cord, and peripheral nerves or roots (encephalomyeloradiculitis). EBV encephalitis may mimic HSE, and in the CASG studies, EBV encephalitis accounted for about 8% of the HSV-negative cases of focal encephalitis in which an etiology was established. In a registry of childhood (ages 3-17) encephalitis cases at a large children’s hospital, EBV accounted for 6% of total cases (Doja et al., 2006).

EBV myelitis can occur as an isolated syndrome in association with meningoencephalitis. Most patients have CSF mononuclear pleocytosis. Diagnosis is made by amplification of EBV DNA from CSF or by appropriate serological testing (see earlier discussion). Myelitis typically follows mononucleosis, although in some patients the symptoms of the initial infection may be mild or even absent. A variety of clinical forms have been reported and include transverse myelitis, myeloradiculitis, and a poliomyelitis-like syndrome of acute flaccid paralysis. MRI may show increased T2-weighted intramedullary signal or evidence of cord swelling. Nerve root enhancement has been reported in patients with myeloradiculitis. No controlled treatment trials are available, although isolated cases have been treated with IV ACV and ganciclovir with or without the addition of corticosteroids (Tyler, 2004).

Specific diagnosis of CNS EBV disease requires either amplification of EBV DNA from CSF or serological studies indicative of acute infection. In serum, the presence of EBV VCA IgM antibody is indicative of recently acquired active EBV infection. The presence of EBV VCA IgG antibody and antibody against EA in the absence of antibodies against EBNA antibodies is also indicative of recent infection. The presence of serum IgG VCA and EBNA antibodies indicates remote infection, and these antibodies persist for the lifetime of the infected individual.

CSF PCR for EBV is positive during the acute phase of illness in children with infectious mononucleosis and neurological complications such as transverse myelitis, meningoencephalitis, and aseptic meningitis. CSF PCR is negative in EBV-seropositive individuals in the absence of CNS infection. However, positive EBV PCR may be seen in patients with evidence of other viral or nonviral CNS infection, raising the possibility that these infections may trigger viral reactivation. EBV has been one of the most frequent agents associated with dual-positive CSF PCR testing and may not always correlate clinically with the presence of CNS infection known to be caused by this virus (Weinberg et al., 2005).

Treatment with intravenous immunoglobulin (IVIG) may improve EBV-associated small-fiber sensory or autonomic neuropathies if treatment begins during acute disease. None of the currently available antiviral agents, including ACV, ganciclovir, and foscarnet, have significant activity against EBV in vitro. However, there are case reports describing successful treatment of EBV meningoencephalitis complicating bone marrow transplantation with ganciclovir.

Human Herpesvirus Type 6

HHV-6 was first isolated in 1986 from human peripheral blood mononuclear cells of patients with lymphoproliferative disorders. Two variants, HHV-6A and HHV-6B are known. Primary infection with HHV-6 usually occurs during infancy, producing exanthem subitum (or roseola) or a syndrome of generalized lymphadenopathy. Primary HHV-6 infection may cause febrile seizures or acute meningoencephalitis. The role of HHV-6 in other neurological diseases remains uncertain. Cases of focal encephalitis in immunocompetent patients have been attributed to HHV-6, as has a syndrome of acute limbic encephalitis occurring in transplant patients (posttransplant acute limbic encephalitis [PTALE]) (Seeley et al., 2007; Isaacson et al., 2005; McCullers et al., 1995) (Fig. 53B.5). The role, if any, for HHV-6 in inducing medial temporal sclerosis temporal lobe epilepsy (Fotheringham et al., 2007) and as a co-factor in other neurological disorders including multiple sclerosis remains unproven.

HHV-6 isolates generally resemble CMV in their susceptibility to antiviral drugs, with isolates being resistant to ACV and related drugs and sensitive to ganciclovir and foscarnet (Birnbaum et al., 2005; Seeley et al., 2007). Antiviral drugs do not inhibit the development of latency nor do they “clear” latent virus.

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