AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In the setting of HIV infection, cytomegalovirus (CMV) can affect both the central and peripheral nervous systems. Neurological manifestations of CMV infection include encephalitis, ventriculitis, myelitis, retinitis, radiculoganglionitis, and peripheral neuropathies.

Pathophysiology

CMV infects the brain or spinal cord, meninges, or nerve roots. This usually occurs in patients with severe immunodeficiency: CD4⁺ lymphocyte counts typically are less than 50/mm³.

Frequency

United States

Prior to the development of highly active antiretroviral therapy (HAART), 2% of HIV-infected patients with CD4⁺ counts less than 50/mm³ developed CMV neurologic disease. The incidence has decreased since HAART became available.

CMV infection of the CNS is recognized at autopsy in 18-28% of patients with AIDS.

Mortality/Morbidity

Untreated, CMV encephalitis typically progresses to death in days to weeks. Death may result from end-stage AIDS rather than the neurological condition.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

HIV-associated CMV encephalitis can present in different ways, including the following:

• Patients with CMV encephalitis characterized by ventriculoencephalitis present with abrupt onset and rapidly progressive confusion and lethargy.

• Cranial nerve palsies, most often oculomotor and facial, and other focal neurologic deficits, occur.
• CMV encephalitis characterized by microglial nodules and focal parenchymal necrosis manifests with a more indolent change in mental status, very similar to AIDS dementia complex (ADC).
• Asymptomatic
• Associated with CMV-associated colitis, esophagitis, retinitis, myelitis, radiculoganglionitis, neuropathy, or adrenal insufficiency; often in patients already receiving ganciclovir.
• • A strong association between CMV retinitis and encephalitis is apparent. In an autopsy series of 47 patients with AIDS, 75% of those with CMV retinitis involving the peripapillary area also had encephalitis.

Physical

• Confusion, cognitive decline
• Rare focal neurological signs
• Cranial nerve palsies

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Metabolic encephalopathies

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Cerebrospinal fluid (CSF) analysis not only can point to the correct diagnosis but also permits exclusion of other diagnostic considerations.
• • Typically, CSF has elevated protein and mononuclear leukocytosis levels.
  
  
  • CMV can be detected by culture, polymerase chain reaction (PCR), CMV antigen, or cytology. In patients without CMV infection, CMV is rarely detected by PCR in the CSF. CSF PCR may be of benefit in confirming the diagnosis.


• Electrolyte disturbances (eg, hypernatremia) consistent with adrenal insufficiency may be observed.

Imaging Studies

• Computed tomography (CT) scan and magnetic resonance imaging (MRI) can aid in the diagnosis and can exclude other diagnostic considerations (eg, absence of parenchymal enhancement, evidence of increased intracranial pressure).
• Head CT and MRI findings include encephalitis involving the cerebral hemispheres and brainstem, ventriculitis, meningitis, and infarcts. Hydrocephalus, ring enhancing lesions, and cerebral atrophy have been reported. Periventricular calcification, a marker of congenital CMV infection, is not seen.
• MRI may show discrete nonspecific abnormalities including ventriculitis, hydrocephalus, and atrophy. Mass lesions due to CMV have been reported but are rare.
• • T2-weighted MRI may show diffuse white matter hyperintensity similar to that seen in HIV encephalopathy and other HIV-associated CNS disorders.
  • Gadolinium contrast MRI may reveal meningeal and ependymal enhancement as well as ring enhancing lesions.

Histologic Findings

Histologic findings include ventriculoencephalitis, microglial nodules, focal parenchymal necrosis, isolated cytomegalic cells, and nuclear inclusions.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Prompt initiation of antiviral drugs is essential. Medical support is required in cooperation with the primary care physician and an infectious disease specialist.
• Because the clinical presentation, CSF studies, and imaging studies may not provide a definitive diagnosis, a high level of suspicion is necessary to avoid a delay in proper therapy.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goal of pharmacotherapy is to shorten the clinical course and prevent or decrease complications, latency, recurrences, transmission, and established latency. Highly active antiretroviral therapy is effective in reconstituting the immune system and preventing CMV reactivation. Ganciclovir and foscarnet are indicated for CMV infections in the induction phase. The 2 may be used in combination. Chronic IV maintenance therapy may be indicated for patients who have a clinical response. Oral valganciclovir has very good bioavailability and can be used in long-term prophylaxis. Patients not responding to ganciclovir should be evaluated for ganciclovir resistance, a common cause of treatment failure. Most of these patients remain sensitive to foscarnet.

Drug Category: Antiviral agents

These agents inhibit viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase, inhibiting DNA synthesis.

Drug Name	Foscarnet (Foscavir)
Description	An organic analog of inorganic pyrophosphate, inhibits viral replication in vitro. Exerts antiviral activity by selective inhibition at pyrophosphate-binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases. Viral resistance should be considered in patients with poor clinical response or persistent viral excretion. Patients who show excellent tolerance of foscarnet may benefit from initiation of maintenance dosage (ie, 120 mg/kg/d) earlier in their treatment. Individualize dosing according to patient's renal function status.
Adult Dose	Induction: 60 mg/kg/dose IV q8h or 100 mg/kg q12h for 14-21 d Maintenance: 90-120 mg/kg/d as single IV infusion for life
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Avoid administration with potentially nephrotoxic drugs (eg, aminoglycosides, amphotericin B, IV pentamidine) may increase nephrotoxicity (do not administer unless potential benefits outweigh risks); coadministration with IV pentamidine may cause hypocalcemia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause decline in renal function; for correct dosing, obtain 24-h serum creatinine level at baseline and continue to monitor (discontinue if serum creatinine level <0.4 mL/min/kg); hydration may reduce nephrotoxicity Carefully monitor electrolytes (eg, calcium, magnesium); assess for electrolyte and mineral level abnormalities if mild perioral numbness, paresthesia symptoms, or seizures; granulocytopenia and anemia may occur (regularly monitor CBC) Infuse foscarnet solutions into veins with adequate blood flow to avoid local irritation; to avoid toxicity, do not administer by rapid or bolus IV injection

Drug Name	Valganciclovir (Valcyte)
Description	L-valyl ester prodrug of ganciclovir used for CMV prophylaxis in various solid organ transplants. Ganciclovir is synthetic analogue of 2'deoxyguanosine, which inhibits replication of human CMV in vitro and in vivo. Viral activity halted due to inhibition of viral DNA synthesis. Has the advantage of qd or bid PO administration. Achieves serum levels comparable to those obtained with IV ganciclovir.
Adult Dose	900 mg PO qd with food; initiate within 10 d following transplantation and continue for 3 mo
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe renal dysfunction or hemodialysis; pregnancy, breastfeeding women; absolute neutrophil count is <500 cells/mm3, platelet count is <25,000/mm3, or hemoglobin is <8 g/dL
Interactions	Interactions are similar to those reported with ganciclovir; coadministration with cytotoxic drugs such as dapsone, vinblastine, Adriamycin, pentamidine, flucytosine, vincristine, amphotericin B, trimethoprim/sulfamethoxazole combinations, or other nucleoside analogs may result in additive toxicity of rapidly dividing cell populations including bone marrow, spermatogonia, germinal layers of skin, and GI mucosa (coadminister only if benefits outweigh risks); coadministration with imipenem-cilastatin may cause generalized seizures (use only if benefits outweigh risks); serum creatinine may increase following concurrent use of ganciclovir with either cyclosporine or amphotericin B; in presence of probenecid, ganciclovir renal clearance is reduced; bioavailability may increase when didanosine is administered either 2 h prior to or simultaneously with ganciclovir; bioavailability of ganciclovir may decrease in presence of zidovudine, while bioavailability of zidovudine is increased in presence of ganciclovir
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Strict adherence to dosage guidelines essential to avoid overdose; valganciclovir tablets may not be substituted for ganciclovir capsules on one-to-one basis; adjust dose according to CrCl in impaired renal function; may cause granulocytopenia, anemia and thrombocytopenia; not indicated for CMV prevention in liver transplantation (higher CMV incidence in liver transplantation compared with prophylaxis with ganciclovir)

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Current guidelines recommend discontinuation of secondary prophylaxis in HAART recipients with a sustained (>6 mo) increase in CD4⁺ T cells to >100-150 cells/mm³.

Prognosis

• Without antiviral therapy, mortality rate is close to 100%.
• With antiviral therapy, more than 50% of patients stabilize or improve. However, overall prognosis is determined by the stage of HIV infection and is usually poor despite treatment.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Delayed diagnosis and treatment can lead to death.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Anduze-Faris BM, Fillet AM, Gozlan J, et al. Induction and maintenance therapy of cytomegalovirus central nervous system infection in HIV-infected patients. AIDS. Mar 31 2000;14(5):517-24. [Medline].
• Bylsma SS, Achim CL, Wiley CA. The predictive value of cytomegalovirus retinitis for cytomegalovirusencephalitis in acquiredimmunodeficiency syndrome. Arch Ophthalmol. 1995;113:89-95. [Medline].
• Erice A. Resistance of human cytomegalovirus to antiviral drugs. Clin Microbiol Rev. Apr 1999;12(2):286-97. [Medline].
• Gendelman HE, Lipton SA, Epstein L. The Neurology of AIDS. New York, NY: Chapman & Hall; 1998.
• Griffiths P. Cytomegalovirus infection of the central nervous system. Herpes. Jun 2004;11 Suppl 2:95A-104A. [Medline].
• Klepser ME, Klepser TB. Drug treatment of HIV-related opportunistic infections. Drugs. Jan 1997;53(1):40-73. [Medline].
• Offiah CE, Turnbull IW. The imaging appearances of intracranial CNS infections in adult HIV and AIDS patients. Clin Radiol. May 2006;61(5):393-401. [Medline].
• Sadler M, Morris-Jones S, Nelson M, Gazzard BG. Successful treatment of cytomegalovirus encephalitis in an AIDS patient using cidofovir. AIDS. Aug 1997;11(10):1293-4. [Medline].
• Said G, Saimont AG, Lacroix C. Neurological complications of HIV and AIDS. Philadelphia, PA: WB Saunders; 1998.
• Springer KL, Weinberg A. Cytomegalovirus infection in the era of HAART: fewer reactivations and more immunity. J Antimicrob Chemother. Sep 2004;54(3):582-6. [Medline].
• Whitley RJ, Jacobson MA, Friedberg DN, et al. Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA. Arch Intern Med. May 11 1998;158(9):957-69. [Medline].
• de Gans J, Portegies P. Neurological complications of infection with human immunodeficiency virus type 1. A review of literature and 241 cases. Clin Neurol Neurosurg. 1989;91(3):199-219. [Medline].

Article Last Updated: May 4, 2007