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 Guide Editors
 Editor In Chief
    Joel E. Gallant, MD, MPH

Pharmacology Editor
    Paul Pham, PharmD, BCPS

Zambia Guideline Team
   Peter Mwaba MMed PhD FRCP
   Alywn Mwinga MMed
   Isaac Zulu MMed MPH
   Velepie Mtonga MMed
   Albert Mwango MBChB
   Jabbin Mulwanda MMed FCS
 

 

 

Diagnosis>Opportunistic Infections>
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CMV, neurologic

Paul G. Auwaerter, M.D.
02-20-2008

  • CMV is ubiquitous virus and considered endemic in Zambia, but limited data on epidemiology of CMV-related neurologic disease in Zambia.
  • Ability to make definitive Dx of CMV-related neurologic disease challenging in Zambia due to limited MRI, CMV PCR, and viral Cx capacity.
  • In pt with CMV retinitis and neurologic illness, CMV is possible etiological agent, but other potential etiologies should be ruled out.
  • None of typical treatments for CMV-related neurologic disease, besides HAART, readily available in Zambia.
Zambia Information Author: Larry William Chang, MD, MPH

PATHOGENS

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.
  • CMV encephalitis: 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, attention, motor/sensory/CN deficits, ataxia), ventriculoencephalitis (radiculopathy, CN deficits, nystagmus less neurocognitive features), mass lesion (focal deficits relating to mass).
  • CMV polyradiculitis: back pain, sciatica, paresthesia, sphincter dysfunction, distal sensory loss, ascending paralysis. 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 location 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 (ventriculoencephalitis > diffuse) and polyradiculomyelitis.
  • CSF CMV viral Cx insensitive, but 100% specific if positive. Role of CMV pp67 antigen studies or quantitative CMV PCR (blood) not clear, but high/rising levels may correlate with increased incidence of end-organ disease.

TREATMENT

CMV encephalitis/polyradiculomyelitis: primary induction

  • 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 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.
CMV encephalitis/radiculomyelitis: post-primary induction

  • Preferred: valganciclovir 900 mg PO bid.
  • Alternative: ganciclovir 5 mg/kg/d IV.
  • Alternative: foscarnet 90-120 mg/kg/d IV.
  • Alternative: if using combination therapy, valganciclovir 900 mg PO bid + 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 900mg bid/qday preferred due to oral route.
  • Oral ganciclovir rarely used because valganciclovir has superior bioavailability.

Drug Comments

DrugRecommendations/Comments
Acyclovir May have some in vitro and in vivo activity against CMV, but not indicated treatment since more active drugs now available.
Cidofovir 2nd tier choice; probably effective, though renal toxicity and lack of data regarding CSF penetration preclude routine consideration.
Foscarnet Alternative choice for induction, though significant renal dysfunction will preclude use.
Ganciclovir Favored agent for induction therapy, although patients with severe hematological problems despite transfusions/G-CSF etc. may do better with foscarnet.
Valganciclovir Not studied for CNS disease, but probably effective as oral maintenance therapy as drug bioavailability means it approaches daily IV ganciclovir infusion levels.

FOLLOW UP

Encephalitis

  • 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

  • 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.

Pathogen Specific Therapy

Basis for Recommendations

  • 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.

  • Benson CA, Kaplan JE, Masur H, et al.; Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America.; MMWR Recomm Rep; 2004; Vol. 53; pp. 1-112;
    ISSN: 1545-8601;
    PUBMED: 15841069
    Rating: Basis for recommendation
    Comments:Gives moderately weighted recommendations for combination therapy at outset, but acknowledges significant toxicities with this approach.

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