Paul G. Auwaerter, M.D.
- 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
- 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.
- 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.
- 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.
- Preferred: valganciclovir 900 mg PO bid.
- Alternative: ganciclovir 5 mg/kg/d IV.
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.
||May have some in vitro and in vivo activity against CMV, but not indicated treatment since more active drugs now available.
||2nd tier choice; probably effective, though renal toxicity and lack of data regarding CSF penetration preclude routine consideration.
||Alternative choice for induction, though significant renal dysfunction will preclude use.
||Favored agent for induction therapy, although patients with severe hematological problems despite transfusions/G-CSF etc. may do better with foscarnet.
||Not studied for CNS disease, but probably effective as oral maintenance therapy as drug bioavailability means it approaches daily IV ganciclovir infusion levels.
- 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.
- 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.
- Portegies P, Solod L, Cinque P, et al.;
Guidelines for the diagnosis and management of neurological complications of HIV infection.;
Eur J Neurol;
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;
Basis for recommendation
Comments:Gives moderately weighted recommendations for combination therapy at outset, but acknowledges significant toxicities with this approach.