HHV-6 Encephalitis in an Immunocompetent Child: A Steroid-Responsive Case Complicated by Cerebral Venous Sinus Thrombosis

Abstract

An 11-year-old male presented with bifrontal headaches that were initially brief and infrequent but progressed to up to 12 episodes daily, associated with photophobia, left eye twitching, and bilateral eye redness. Initial evaluation revealed leukocytosis with normal head CT findings; however, his condition rapidly progressed to refractory seizures. Brain MRI demonstrated increased signal in the left medial temporal lobe, and EEG showed focal spikes and waves in the left hemisphere, consistent with focal epilepsy. Cerebrospinal fluid and serum PCR testing were positive for HHV-6. Despite treatment with anti-epileptics and intravenous immunoglobulin(IVIG), his mental status declined, and repeat MRI revealed cerebral venous sinus thrombosis. Extensive testing was negative. Marked clinical improvement occurred only after corticosteroid initiation. This case highlights a rare presentation of HHV-6–associated encephalitis in an immunocompetent child complicated by status epilepticus and cerebral venous sinus thrombosis, suggesting an immune-mediated mechanism.

Case Presentation

An 11-year-old male presented with a complaint of headaches. The patient had experienced intermittent bifrontal headaches for approximately 3 months prior to presentation, with a notable worsening in severity and frequency during the 3 weeks immediately preceding hospital admission. The headaches lasted only a few minutes, were aggravated by light and noise, and did not respond to acetaminophen. Initially, the frequency was around 2 per day, but gradually increased to 12 episodes daily, lasting longer.

The headaches were also associated with the twitching of the left eye and redness of both eyes. He was previously evaluated by a neurologist and diagnosed with migraine with aura, for which indomethacin was prescribed. A CT head scan was performed and was normal. Lab work showed leukocytosis (WBC 24.8) with a normal BMP.

Initially, the team suspected cluster headaches, and he started on supportive treatment with oxygen and hydration. Neurology was consulted. During that time, the patient continued to have similar headache episodes associated with left eye twitching, but no obvious impairment in consciousness, raising concern for focal seizures. Brain MRI demonstrated a unilateral area of increased signal intensity involving the left medial temporal lobe on T2-weighted and FLAIR sequences (Figure 1), without evidence of mass effect or acute hemorrhage. No diffusion restriction or contrast enhancement was identified, raising concern for an inflammatory or epileptogenic process rather than a space-occupying lesion. These findings prompted consideration of limbic encephalitis in the appropriate clinical context. Continuous EEG monitoring revealed abnormal awake background activity characterized by focal spikes and sharp waves over the left hemisphere. During hyperventilation, generalized 3-Hz spike-and-wave discharges were observed. These findings were consistent with focal epilepsy without impairment of awareness and supported a left temporal epileptogenic focus correlating with MRI abnormalities.

Figure 1.

Increased T2 flair in left medial temporal lobe.

Hospital Course

Due to stable vitals and normal inflammatory markers, no immediate concern for infection or encephalitis was raised. He remained afebrile and had no meningeal signs. Differential diagnoses at that time included mesial temporal sclerosis, superficial glioma, cortical dysplasia, and cerebritis or encephalitis. EEG revealed spikes and waves in the left hemisphere during hyperventilation, consistent with focal epilepsy. He started on Depakote for seizure control.

However, he developed worsening headaches and confusion between episodes. The patient was transferred to the PICU for management of status epilepticus. A lumbar puncture revealed elevated opening pressure of 36 mmHg, and CSF PCR returned positive for HHV-6. Serum PCR also confirmed HHV-6 positivity. At the time, he remained afebrile and neurologically intact without signs of meningism, although the HHV-6 result raised concern for a viral encephalitic process. He subsequently developed hypertension and tachycardia and was treated with hypertonic saline for suspected elevated intracranial pressure and risk of herniation. He was loaded with levetiracetam and continued maintenance dosing.

Given concern for infectious or post-infectious etiology, the patient was started on a 4-day course of IVIG. Around the same time, phenobarbital was added as a third antiepileptic drug due to ongoing electrographic status epilepticus on continuous long-term EEG monitoring. He was also empirically started on vancomycin, ceftriaxone, and doxycycline due to a remote history of tick exposure and prophylactic antibiotics for meningitis. Despite these interventions, his mental status gradually declined, and tapering phenobarbital did not result in improvement.

As his clinical condition worsened, a repeat MRI with venographic sequences was obtained and revealed cerebral venous sinus thrombosis involving the parasagittal superior sagittal sinus and adjacent bridging veins (Figure 2). He immediately started anticoagulation with a heparin drip, which was later transitioned to subcutaneous enoxaparin for continued management. Neurosurgery was consulted, but no procedural intervention was deemed necessary.

Figure 2.

Cerebral venous sinus thrombosis involving the bridging veins and parasagittal superior sagittal sinus previously unseen.

The lack of response to IVIG and the evolving clinical picture raised concern for a possible post-infectious autoimmune encephalitis. An extensive panel including Mayo Clinic autoimmune encephalitis antibodies, NMDA receptor antibodies, anti-ENA, dsDNA, CSF and serum cytokines, oligoclonal bands, UCSF metagenomics, and chitotriosidase levels were performed. All results returned negative. Additional testing for fungal infections, including histoplasmosis and blastomycosis, was also unrevealing.

Despite this comprehensive diagnostic evaluation, no definitive etiology was identified to explain his clinical course, imaging findings, or venous thrombosis. Given the absence of a clear infectious, vascular, or neoplastic cause and his poor response to IVIG, a high-dose corticosteroid regimen was initiated, IV methylprednisolone at 30 mg/kg/day for 5 days followed by a slow taper of oral prednisone.

Following the initiation of steroids, the patient showed marked clinical improvement. His mental status gradually normalized, seizures resolved, and follow-up imaging showed no new abnormalities. He was discharged home on a slow taper of both phenobarbital and oral corticosteroids.

The final diagnosis was HHV-6 associated encephalitis in an immunocompetent child, complicated by underlying left medial temporal sclerosis and cerebral venous sinus thrombosis. In the absence of any confirmed alternative cause and the patient’s clear response to immunosuppressive therapy, the case was concluded to most likely represent a post-viral autoimmune process triggered by HHV-6.

Discussion

Although typically asymptomatic, HHV-6 is most associated with roseola infantum, a self-limited childhood illness, and rarely linked to more severe syndromes. ¹ It can sometimes cause febrile seizures between 2 months to 3 years of age. ² HHV-6 infection was previously thought to primarily affect immunocompromised hosts, either through primary infection or reactivation of latent virus. ³ However, recent data have reported cases of HHV-6 encephalitis occurring in immunocompetent individuals, particularly adults, with limited data in the pediatric age group.^4,5 This case adds to that emerging literature by highlighting HHV-6 encephalitis in an immunocompetent child, where the infection appears to have contributed to a hypercoagulable state, resulting in cerebral venous sinus thrombosis and presenting clinically as refractory status epilepticus. ⁶

A key clinical question in this case is whether the HHV-6 infection was active or part of a post-viral autoimmune process. ¹ Notably, the patient did not receive antiviral therapy. He was initially treated with IVIG without significant improvement in seizure control, but he showed marked clinical improvement after starting immunotherapy with corticosteroids. ³ This response supports the hypothesis of a post-viral autoimmune phenomenon rather than direct viral cytotoxicity. ⁴ Another possibility is that HHV-6 can cause refractory status epilepticus by mesial temporal lobe epilepsy due to hippocampal sclerosis, which was unmasked or triggered by acute HHV-6 infection. ⁷ Regardless of pathophysiology, this case demonstrates that HHV-6 is not always a benign infection in immunocompetent hosts, especially when associated with encephalitic presentations. ⁸

While adult patients with HHV-6 CNS infection have been treated with antivirals such as ganciclovir or foscarnet, there is currently no established data supporting similar treatment strategies in immunocompetent children. ⁹ The lack of evidence-based guidelines poses a challenge in determining the optimal therapeutic approach for pediatric patients. ¹⁰

Cerebral venous thrombosis (CVT) is a known complication of herpes simplex virus (HSV) and varicella-zoster virus (VZV) encephalitis.^1,11 While no such direct evidence currently exists for HHV-6, the general link between infection, inflammation, and hypercoagulability is well established in the literature. ⁹ Inflammatory responses to infection can lead to platelet activation and thrombin generation, contributing to a prothrombotic state. In our case, HHV-6 may have played a similar role inducing cerebral inflammation that subsequently triggered venous thrombosis. ¹⁰ Although causation cannot be definitively proven, this association should be considered, especially in patients whose clinical status continues to deteriorate despite standard therapy. Early recognition of potential thrombotic complications in the setting of HHV-6 encephalitis may prompt timely investigation and management. ⁹

Furthermore, it is essential to distinguish between true HHV-6 infection and chromosomally integrated HHV-6 (iciHHV-6), which can result in false-positive CSF findings. ⁶ Quantitative PCR testing from both blood and CSF samples can help differentiate active infection or viral reactivation from incidental detection due to genetic integration. ⁸ Without this distinction, there is a risk of over diagnosing HHV-6–related CNS disease, which may lead to unnecessary antiviral therapy and misdirected treatment efforts. ³ Therefore, confirmatory testing using viral load quantification plays a key role in guiding appropriate management and avoiding overtreatment in patients with incidental HHV-6 detection. ³

Final Diagnosis and Outcomes

HHV-6–associated encephalitis in an immunocompetent child, complicated by temporal sclerosis and cerebral venous sinus thrombosis. The patient’s marked response to corticosteroids, despite poor improvement with IVIG, supports a post-viral autoimmune process rather than direct viral cytotoxicity, highlighting HHV-6 as a rare but serious pediatric encephalitic trigger. The patient was discharged in stable condition and did not exhibit any neurological or functional sequelae at the time of discharge.

Conclusion

This case illustrates a rare occurrence of immunocompetent child in HHV-6-associated encephalitis complicated by cerebral venous sinus thrombosis and refractory seizures. Although antivirals such as ganciclovir or foscarnet have been used in HHV-6 CNS infections in adults; however, there is currently no strong evidence to support a similar treatment approach in children. The absence of evidence-based guidelines continues to complicate the therapeutic decision-making these cases.