What is the diagnosis and management for an immunocompromised adult patient with hypodensities in grey and white matter at the left frontoparietal, left inferior frontal, and right frontoparietal lobe associated with Human Herpesvirus 6 (HHV-6) infection?

HHV-6 Encephalitis: Diagnosis and Management in Immunocompromised Adults

Diagnosis

The diagnosis of HHV-6 encephalitis in an immunocompromised adult with hypodensities in grey and white matter at the left frontoparietal, left inferior frontal, and right frontoparietal lobes should be based on HHV-6 DNA detection in cerebrospinal fluid (CSF) by PCR, coinciding with acute-onset altered mental status, short-term memory loss, or seizures, after excluding other infectious and non-infectious causes. 1

Diagnostic Criteria

The following elements establish the diagnosis:

• CSF PCR for HHV-6 DNA is the primary diagnostic test, with a sensitivity of 95% 1
• Exclude chromosomally integrated HHV-6 (CIHHV-6) by testing blood PCR levels to distinguish between chromosomal integration and acute infection 1
• Rule out other pathogens including HSV-1/2, VZV, CMV, EBV, and other opportunistic infections 1
• Clinical presentation typically includes confusion, encephalopathy, short-term memory loss, seizures, or syndrome of inappropriate antidiuretic hormone secretion (SIADH) 1

Neuroimaging Findings

MRI findings are often normal in HHV-6 encephalitis, which is a critical pitfall. 1 When abnormalities are present:

• Typical pattern: Circumscribed, non-enhancing, hyperintense lesions on T2-weighted and FLAIR sequences in the medial temporal lobes, especially hippocampus and amygdala 1
• Atypical pattern: Hyperintense T2-weighted signal in white matter of frontal and parietal lobes, as described in your case 1
• Limbic encephalitis pattern: Edema extending to temporal lobes and limbic system 1
• CT head is often normal and should not be relied upon 1

Important Diagnostic Pitfalls

• High false-positive rate: HHV-6 CSF PCR has a positive predictive value of only 30% in healthy adults due to latent infection detection 1
• Asymptomatic CSF detection: HHV-6 DNA can be found in CSF of patients without CNS symptoms 1
• Correlation with blood levels: A plasma HHV-6 DNA level ≥10,000 copies/mL correlates with encephalitis onset with 100% sensitivity and 64.6% specificity 1

Management

If disease in an immunocompromised patient is determined to be caused by HHV-6, ganciclovir or foscarnet should be used as treatment options, using schedules and doses similar to those for CMV disease. 1

First-Line Treatment

• Ganciclovir (induction: 5 mg/kg IV every 12 hours) is the preferred initial agent 1, 2, 3
• Foscarnet is an alternative for ganciclovir-resistant cases or when bone marrow toxicity is a concern 1
• Treatment duration: Typically 3 weeks, though prolonged treatment may be needed in immunocompromised patients to achieve viral clearance 1, 3

Alternative Agents

• Cidofovir can be considered, as HHV-6 replication is inhibited by foscarnet, cidofovir, and ganciclovir at achievable plasma levels 1
• Valganciclovir may be used for oral therapy after initial IV treatment 1

Management of Treatment Failure

• Switch antiviral classes (e.g., from ganciclovir to foscarnet) if treatment failure occurs 1
• Mutations conferring resistance to ganciclovir, cidofovir, and foscarnet have been described 1

Monitoring

• Monitor for bone marrow suppression (neutropenia, thrombocytopenia) with ganciclovir 1
• Monitor renal function closely with foscarnet and cidofovir 1
• Repeat CSF PCR may be considered to document viral clearance, though clinical improvement is the primary endpoint 1

Prognosis

The prognosis is guarded, with memory defects and neuropsychological sequelae occurring in 20-60% of survivors, and death from progressive encephalitis in up to 25% of all HSCT recipients and up to 50% of cord blood recipients. 1

Risk Factors for Poor Outcome

• Cord blood transplantation (adjusted hazard ratio 20.0) 1
• Acute graft-versus-host disease grades II-IV (adjusted hazard ratio 7.5) 1
• Mismatched unrelated donors (adjusted hazard ratio 4.3) 1
• T-cell depleted allografts and glucocorticoid treatment 1

Case Reports Supporting This Presentation

Multiple case reports document HHV-6 encephalitis in immunocompromised adults with varied neuroimaging findings:

• Atypical white matter involvement: A 70-year-old immunocompromised woman (on leflunomide and methotrexate) presented with cerebellar ataxia and an enhancing midbrain lesion, successfully treated with 3-week ganciclovir course 3
• Immunocompetent cases: A 26-year-old healthy male with HHV-6 encephalitis treated successfully with ganciclovir 2, and a 48-year-old immunocompetent male with HHV-6 meningitis 4
• Spectrum of imaging findings: Limbic encephalitis, atypical interstitial pneumonia, and other manifestations documented in immunocompromised patients 5
• Recurrent disease: A 63-year-old immunocompetent female with recurrent HHV-6 encephalitis successfully treated with IV ganciclovir 6