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

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).

Fig. 53B.1 Herpes simplex encephalitis. T2-weighted magnetic resonance image showing increased signal in left medial temporal lobe, inferior frontal lobe, and insular cortex.

(Courtesy J. Healy.)

Fig. 53B.2 Hippocampal granule cell neurons in herpes simplex 1 encephalitis. Many nuclei contain acidophilic Cowdry type A intranuclear inclusions, which are surrounded by halos and marginate nuclear chromatin. (Hematoxylin-eosin stain, ×350.)

(Courtesy R. Kim.)

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).

Herpes Simplex Virus Meningitis

HSV meningitis accounts for approximately 10% of acute viral meningitis in adults. At the time of their first episode of genital herpes (generally due to HSV-2), approximately 36% of women and 11% of men have symptoms of meningitis including fever, headache, and nuchal rigidity. Of these patients, 20% will develop recurrent episodes of meningitis. Patients with HSV-2 meningitis only rarely have concomitant genital lesions, and in one study more than 80% had no history of genital lesions and no active genital lesions at presentation (O’Sullivan et al., 2003). CSF viral cultures are invariably negative during recurrent episodes of meningitis, although the virus may be isolated during the first (primary) episode. Other neurological complications such as paresthesias, urinary retention, and transverse myelitis have been described with HSV-2 infections.

CSF PCR has identified HSV-2 as the primary etiological agent in patients with benign recurrent lymphocytic meningitis (Mollaret meningitis) (Shalabi and Whitley, 2006; Tedder et al., 1994). This syndrome may be associated with the presence in the CSF of large cells of monocyte-macrophage lineage (Mollaret cells).

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).

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.

Fig. 53B.3 Human cytomegalovirus ventriculitis. Axial gadolinium-enhanced T1-weighted magnetic resonance image showing contrast enhancement of ependyma of lateral ventricles.

(Courtesy J. Healy.)

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.

Fig. 53B.4 Ballooned cell with eccentric nucleus in human cytomegalovirus encephalitis. An acidophilic Cowdry type A intranuclear inclusion body (with its surrounding halo) marginates nuclear chromatin. Cytoplasm also contains granular inclusion material. (Hematoxylin-eosin stain, ×350.)

(Courtesy R. Kim).

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).