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PATHOGENS

• Cytomegalovirus

CLINICAL

• CMV disease afflicts up to 40% in untreated AIDS. CMV seroprevalence 50-80%, >90% in active MSM. CNS disease seen only in immune suppressed, HIV CD4 <50-100.
• CMV CNS disease uncommon: pathological evidence in >30% (autopsy series), but <2% with clinical neurological disorders.
• Typically a progressive encephalopathy, usually in pt w/ Hx of prior CMV disease (e.g., retinitis). Acute onset, rapid progression helps distinguish from HIV encephalitis or PML.
• CMV encephalitis subsets: diffuse (decreased memory with dementia like presentations, attention, motor/sensory/CN deficits, ataxia +/- fever and often confused with HIV-related dementia), ventriculo-encephalitis (radiculopathy, CN deficits, nystagmus less neurocognitive features presenting in more aggressive fashion), mass lesion (focal deficits relating to mass).
• CMV polyradiculitis: presents as back pain, sciatica, paresthesia, sphincter dysfunction, distal sensory loss, ascending paralysis. May appear Guillian-Barré-like with lower extremity weakness or include urinary retention/loss of bowel function. Transverse myelitis presentation w/ para- or quadraplegia, sensory deficits. DDx includes HSV-2, VZV.

DIAGNOSIS

• CMV encephalitis: periventricular enhancement (ventriculitis) or diffuse hyperintense T2 images on MRI. Dx based on clinical presentation, imaging studies and CSF PCR (sensitivity 62-100%, specificity 89-100%). Brain Bx: CMV inclusions ("owl's eye") or CMV+ stains. Bx not typically performed given usual brainstem or periventricular locations of disease.
• CMV polyradiculomyelitis: MRI may show enhancement of cauda equina or meninges. Positive CSF CMV PCR.
• CSF studies: findings often nonspecific. Low glucose and/or PMN pleocytosis seen with encephalitis (ventriculo-encephalitis > diffuse) and polyradiculomyelitis.
• CSF CMV viral Cx insensitive, but 100% specific if positive. Role of quantitative CMV PCR (blood) less clear, but high/rising levels may correlate with increased incidence of end-organ disease.

TREATMENT

• Preferred: ganciclovir 5 mg/kg IV q12h.
• Alternative: foscarnet 90 mg/kg IV q12h.
• Decision to use ganciclovir or foscarnet based upon hematologic and renal aspects of pt.
• Combination ganciclovir + foscarnet (above doses) used by some, unclear if superior response (one open label trial showed 94 d median survival vs. 42 d historical control, see Anduze-Faris ref) to monotherapy and regimen poorly tolerated. Due to poor prognosis, combination therapy typically employed by Johns Hopkins Neurology ID service.
• Alternative: cidofovir 5 mg/kg IV q wk x 2wks, then dose q2wks. Note: CSF penetration of cidofovir not well studied.
• Usual induction duration: 2 wks. 
• Immune reconstitution with ART should be concomitant goal.
• Guideline (see MMWR 2009; 58:1-198) warns that although no data exist that IRIS worsens CMV neurologic infections, because of possibility of worsening neurological status, ART should be delayed until clinical improvement.

• Preferred: valganciclovir 900 mg PO twice-daily
• Alternative: ganciclovir 5 mg/kg/d IV.
• Alternative: foscarnet 90-120 mg/kg/d IV.
• Alternative: if using combination therapy, valganciclovir 900 mg PO twice-daily + foscarnet 90 mg/kg/d IV.
• Usual duration of therapy is 3-6 wks if immune reconstitution occurs. Otherwise long-term maintenance therapy recommended with profound immune suppression to reduce risk of relapse. Regimen for maintenance unclear but valganciclovir 900 mg once- or twice-daily preferred due to oral route.
• Oral ganciclovir rarely used because valganciclovir has superior bioavailability.

Drug Comments

FOLLOW UP

• CMV progression despite monotherapy: consider combination therapy ganciclovir + foscarnet (above dosing). Progression despite combination therapy: consider cidofovir.
• Ganciclovir resistance well-described, and may occur even in previously untreated pts.
• Generally poor prognosis for pts w/ AIDS and clinical CNS CMV. Neurological sequelae common, and existing deficits at time of treatment initiation may not reverse.

• Radiculopathy tends to improve within 2-3 wks.
• In severe cases, primary induction/maintenance dosing may need to be continued beyond 6 wks until sufficient clinical response noted. Role of serial CMV PCR testing unclear as to guiding intensity/duration of therapy.

OTHER INFORMATION

• Typical CMV encephalitis pt has had prior CMV disease (e.g., retinitis, GI), lapsed maintenance therapy, advanced HIV w/ low CD4, ventricular/white matter lesions on MRI, and (+) CSF CMV PCR studies.
• Treatment recommendations based on studies of CMV retinitis and colitis given lack of controlled studies on CNS CMV infection.
• CMV viremia may occur in absence of end-organ disease.

Pathogen Specific Therapy

Basis for Recommendations

• Kaplan JE, Benson C, Holmes KH, et al.; Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.; MMWR Recomm Rep; 2009; Vol. 58; pp. 1-207; quiz CE1-4;
  ISSN: 1545-8601;
  PUBMED: 19357635
  Rating: Basis for recommendation
  Comments:Guideline gives moderately weighted recommendations for combination therapy at outset (rated BII), but also acknowledges significant toxicities with this approach.
  
  
• Portegies P, Solod L, Cinque P, et al.; Guidelines for the diagnosis and management of neurological complications of HIV infection.; Eur J Neurol; 2004; Vol. 11; pp. 297-304;
  ISSN: 1351-5101;
  PUBMED: 15142222
  Rating: Basis for recommendation
  Comments:Uses Cinque 1998 and Anduze-Faris 2000 to primarily guide recommendations.
  
  

REFERENCES

REFERENCED WITHIN THIS GUIDE

• Cytomegalovirus