Human Herpesvirus 6 Encephalitis in Immunocompetent and Immunocompromised Hosts

Immunocompetent Hosts

The median age in the group of immunocompetent patients was 2.7 years (range: 0.0–77.0 years). Fever and rash were present in 9 (9/17, 53%) and 3 (3/17, 18%) patients, respectively. Neurologic symptoms included altered mental status (6/17, 35%), seizures (3/17, 18%), and focal deficits (8/17, 47%). Eight patients tested positive for HHV-6 DNA in both CSF and blood (8/17, 47%), 2 patients tested positive in the CSF but were not tested in blood (2/17, 12%), and 7 patients tested positive only in blood (7/17, 41%). Regardless of HHV-6 positivity in the CSF, all immunocompetent individuals had a CSF/blood replication ratio <1. Final diagnosis was of febrile seizures/encephalitis in the context of primary HHV-6 infection in 4 patients (4/17, 24%) and other condition unrelated to HHV-6 in the remaining 13 cases (13/17, 76%) (figure 1).

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Figure 1 Flowchart Diagram Illustrating Final Diagnoses Depending on the Immunologic Status of the Host and the Compartment(s) of Viral Replication

ciHHV-6 = chromosomally integrated human herpesvirus 6.

Febrile Seizures/Encephalitis in the Context of Primary HHV-6 Infection

The main clinical and biological features in the 4 immunocompetent individuals meeting the diagnostic criteria for febrile seizures/encephalitis during primary HHV-6 infection are summarized in table 2. All 4 patients were infants or children younger than 2 years presenting with fever, with or without rash. Neurologic manifestations included seizures in 2 patients and irritability in other 2. All 4 patients tested positive for HHV-6 in both blood and CSF, with a median viral load of 410 copies/mL in the CSF (range: 40–14,060 copies/mL) and 85,230 copies/mL in blood (range: 4,750–495,540 copies/mL), resulting in a CSF/blood replication ratio <<1 in all cases. CSF pleocytosis was present in 1 case of 3. A single patient underwent brain MRI (patient 1 in table 2), which showed normal findings. None of the patients received specific antiviral treatment. All of them recovered completely within a week from hospital admission.

Alternative Diagnoses

Alternative diagnoses in the 13 immunocompetent patients who did not meet the criteria for febrile seizures or encephalitis during primary HHV-6 infection included post/para-infectious neurologic syndromes (n = 6), MS (n = 1), aseptic meningitis (n = 1), Listeria monocytogenes meningoencephalitis (n = 1), febrile convulsions (n = 1), primary CNS lymphoma (n = 1), cranial mononeuritis (n = 1), and bacterial spondylodiscitis (n = 1).

In 4 patients, HHV-6 DNA detection in blood and CSF reflected chromosomal integration. Patients with ciHHV-6 had positive PCR results in both the CSF and blood, with viral loads in the order of magnitude of millions copies of HHV-6 DNA in blood (median: 6,630,575 copies/mL, range: 1,081,400–7,700,000 copies/mL) and thousands copies in the CSF (median: 6,640 copies/mL, range: 2,640–18,520 copies/mL). The median viral load in the 9 patients without ciHHV-6 was instead of 3,330 copies/mL in blood (range: 300–33,930) and 0 copies/mL in the CSF (range: 0–40). Individual patient data for patients in this group are reported in table e-2 (links.lww.com/NXI/A384).

Immunocompromised Hosts

The median age in the group of immunocompromised patients was 14.3 years (range: 2.0–88.6 years). The underlying condition of immune suppression was represented by a hematologic disorder in 27 of the 28 cases. Patients in this group had been heavily treated, having previously received high-dose chemotherapy (25/27, 93%), monoclonal antibodies (9/17, 53%), and hematopoietic stem cell transplantation (23/27, 85%). The remaining patient was a solid organ transplant recipient who was still receiving immune suppressants for the prevention of graft vs host disease. Fever was an accompanying feature in 4 cases (4/28, 14%) and rash in 2 (2/28, 7%). Neurologic symptoms included altered mental status (17/28, 61%), seizures (11/28, 39%), and focal deficits (5/28, 18%). Fourteen patients tested positive for HHV-6 DNA in both CSF and blood (14/28, 50%), 2 patients tested positive only in the CSF (2/28, 7%), 1 patient tested positive in the CSF but blood was not investigated (1/28, 4%), and 11 patients tested positive only in blood (11/28, 39%). Final diagnosis was of HHV-6 encephalitis due to viral reactivation in 7 patients (7/28, 25%), other condition unrelated to HHV-6 in 14 patients (14/28, 50%), and remained undetermined in 7 cases (7/28, 25%) (figure 1).

HHV-6 Encephalitis Due to Viral Reactivation

Table 3 summarizes the main clinical and paraclinical features in the 7 immunocompromised patients who met the criteria for HHV-6 encephalitis due to viral reactivation. Five patients were adults, and 2 were adolescents. All patients were affected with hematologic conditions, and 6 of the 7 had received allogeneic HSCT (median delay from HSCT to neurologic symptoms: +91 days, range: 20–630). A single patient had systemic symptoms including fever, pruritus, and rash (patient 7 in table 3).

All 7 patients presented with altered mental status, which was associated with seizures (3/7, 43%), vigilance impairment (3/7, 43%), behavioral changes (2/7, 29%), hyponatremia (2/7, 29%), anterograde amnesia (1/7, 14%), and/or dysautonomia (1/7, 14%). CSF pleocytosis was detected in only half of cases (2/4, 50%) (patients 1 and 3 in table 3). Initial brain MRI, performed from 2 to 4 days after symptom onset, was altered in only 2 patients of 6 (2/6, 33%) (patients 3 and 7 in table 3). However, a second brain MRI, performed a median of 2 weeks after the first, disclosed radiologic alterations compatible with HHV-6 encephalitis in 2 additional patients who initially had normal findings (figure 2).

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Figure 2 MRI Findings in 2 HSCT Transplant Recipients Developing HHV-6 Encephalitis

Panels A–F (patient 1 in table 4): on initial brain MRI, performed 3 days after symptom onset, no abnormal findings were detected on axial FLAIR (panels A and B) and coronal T2-weighted (panel C) images, though in the presence of motion artifacts. At control MRI, performed 16 days after symptom onset, a quite marked hyperintensity was evident at the level of the left temporo-mesial region, with swelling of the amygdala and the ipsilateral insular cortex on axial FLAIR (panels D and E) and coronal T2-weighted (panel F) images. No diffusivity restriction or gadolinium enhancement was evident (not shown). Panels G–I (patient 7 in table 4): brain MRI performed 4 days after neurologic symptom onset showed bilateral hyperintensity of temporo-mesial structures, prevalent on the right side, on axial FLAIR images (panel G), with a correspondent b1000 hypersignal (panel H) and some areas of true low ADC signal (panel I) but predominant T2 shine through effect. FLAIR = fluid-attenuated inversion recovery; HHV-6 = human herpesvirus 6; HSCT = hematopoietic stem cell transplantation.

HHV-6 replication was limited to the CSF in 2 patients, whereas the remaining 5 also tested positive in blood. The median viral load in the CSF was 49,200 copies/mL (range: 40–6,959,200 copies/mL), and the median viral load in blood was 4,230 copies/mL (range: 0–378,900 copies/mL). The CSF/blood replication ratio was >1 in all patients except for the one showing systemic symptoms of HHV-6 infection (fever, rash, and pruritus), in whom HHV-6 viral load prevailed in blood.

All patients received IV ganciclovir, with or without associated foscarnet, except for a single patient who died before receiving antiviral treatment (patient 5 in table 3). A total of 4 patients died during the acute phase as a consequence of intervening systemic complications or general status deterioration (4/7, 57%). The remaining 3 patients survived the infection but experienced mild to moderate cognitive sequelae (3/7, 43%).

Alternative Diagnoses

Fourteen immunocompromised patients received alternative diagnoses, including posterior reversible encephalopathy syndrome (n = 2), CNS localizations of their underlying hematologic malignancies (n = 4), cytomegalovirus infection (n = 2), metabolic encephalopathy (n = 2), ischemia (n = 2), inflammatory encephalomyelitis (n = 1) and migraine (n = 1). All patients in this group had HHV-6 viral loads largely prevailing in blood (CSF/blood replication ratio <1).

In 3 patients, HHV-6 DNA detection in blood and CSF reflected chromosomal integration. Patients with ciHHV-6 had viral loads in the order of magnitude of millions copies in blood (median: 572,220 copies/mL, range: 497,200–8,650,000 copies/mL) and thousands copies in the CSF (median: 53,240 copies/mL, range: 1,360–141,140 copies/mL). The median HHV-6 viral load in the 11 remaining patients was of 6,175 copies/mL in blood (range: 100–365,400 copies/mL) and 60 copies/mL in the CSF (range: 0–20,000 copies/mL).

Undetermined Diagnoses

Seven immunocompromised patients remained without a definite etiologic diagnosis despite a comprehensive work-up that included an extensive research for infectious, neoplastic, metabolic, vascular, and autoimmune etiologies. The clinical and paraclinical characteristics of these 7 patients are summarized in table 4. Four patients were children, and 3 were adults. All patients had an underlying hematologic disorder, 6 of the 7 having received allogeneic HSCT. All patients tested positive for HHV-6 only in blood (median: 9,180 copies/mL, range: 400–126,000 copies/mL). Two patients with stupor or seizures arising in a context of fever were diagnosed with systemic HHV-6 reactivation, for which they received IV ganciclovir that led to full recovery (patients 1 and 2 in table 4). Four patients presenting with seizures, encephalopathy, or cerebellar dysfunction had no accompanying fever or rash and spontaneously recovered within few days without specific treatment (patients 3–6 in table 4). The remaining patient (patient 7 in table 4) presented with confusion and anterograde amnesia 1 month after completing HSCT. She had extensive MRI alterations involving temporo-mesial structures and the mammillary bodies of the hypothalamus. HHV-6 viral load was positive in blood (126,000 copies/mL) but undetectable in the CSF. In the inability to distinguish between Wernicke encephalopathy and HHV-6 infection, the patient received both vitamin B1 supplementation and IV foscarnet, but, unfortunately, she died few weeks later because of general status deterioration.