Neuropsychiatric Symptoms After HHV-6 Encephalitis in an Immunocompetent Child: A Case Report

Introduction

Human herpesvirus 6 (HHV-6) is a common pathogen known to cause roseola infantum in children and has been implicated in encephalitis, particularly among immunocompromised individuals [1,2]. Most children acquire primary HHV-6 infection between 9 and 21 months of age [3]. Two variants, HHV-6A and HHV-6B, have been identified. HHV-6B is most commonly associated with primary infection in infants and young children; HHV-6A is less prevalent in early childhood and is more frequently linked to neurological disease and viral reactivation [4]. After primary infection, HHV-6 establishes latency through integration into host telomeres [5] and interacts with T cells by inducing regulatory T cells and modulating cytokine production to evade immune responses [6]. These interactions are crucial for maintaining viral latency and may enable reactivation under conditions of immune suppression [7–9]. HHV-6 is a leading cause of encephalitis in patients undergoing allogeneic hematopoietic stem cell transplantation [10]; however, HHV-6 encephalitis in immunocompetent children is rare and typically self-limiting [11]. Neurological symptoms such as altered consciousness, seizures, and status epilepticus have been reported in HHV-6 encephalitis [12,13], but neuropsychiatric manifestations – particularly hyperkinetic catatonia – are extremely uncommon. Hyperkinetic, or excited-type, catatonia is characterized by agitation, aggressiveness, excessive speech, repetitive behaviors, grimacing, and echophenomena [14]. This report describes a 4-year-old boy who developed acute neuropsychiatric symptoms after a viral infection. The differential diagnosis included pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), HHV-6 encephalitis, and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. His condition was ultimately attributed to HHV-6 encephalitis. Diagnostic and therapeutic implications are discussed.

Case Report

A 4-year-old healthy Lebanese boy presented with a 2-month history of acute behavioral changes. These changes began 1 week after a febrile illness characterized by rhinorrhea and a generalized erythematous rash with a slapped-cheek appearance. The symptoms had an abrupt onset and included anxiety, insomnia lasting approximately 5 h with aimless nocturnal movements, irritability, oppositional and aggressive behavior, mumbling, unprovoked laughter, decreased responsiveness, hand flapping, fidgeting, and occasional compulsive handwashing. The overall presentation was consistent with hyperkinetic catatonia. Additionally, the patient self-isolated at school and exhibited excessive daydreaming. His parents denied recent travel or similar prior episodes. No previous HHV-6 infection was documented. The parents were non-consanguineous, and there was no family history of genetic, neurological, or psychiatric disorders.

On examination, the patient appeared fidgety but was alert and oriented, with intermittent responsiveness. Neurological examination findings were unremarkable.

Infectious disease testing revealed qualitatively positive HHV-6 polymerase chain reaction results in cerebrospinal fluid (CSF) according to the FilmArray Meningitis/Encephalitis Panel (BioFire Diagnostics, Salt Lake City, UT, USA). Viral load in the CSF was not quantified. HHV-6A was detected in blood at 7,187 copies/mL. Antistreptolysin O (ASO) antibody levels were elevated at 544 IU/mL, and rapid antigen testing showed Group A Streptococcus positivity. Anti-dsDNA IgG titers were low. HHV-6 antibody titers were not assessed. The autoimmune workup, including CSF testing for anti-NMDAR antibodies, showed negative findings (Table 1). Urine toxicology and electroencephalography features were normal. Brain magnetic resonance imaging showed a faint high fluid-attenuated inversion recovery (FLAIR) signal along the left insula, likely artifactual and not indicative of prior infection (Figure 1).

The elevated ASO titer and streptococcal antigen positivity initially suggested a diagnosis of PANDAS. However, the absence of tics or obsessive-compulsive behaviors and the stable symptom severity ruled out this diagnosis. The differential diagnosis included HHV-6 encephalitis and anti-NMDAR encephalitis. Because autoimmune antibody test results were negative and the patient did not meet diagnostic criteria for seronegative autoimmune encephalitis, HHV-6 encephalitis was established as the working diagnosis.

The patient received intravenous amoxicillin 25 mg/kg twice daily for 7 days for streptococcal tonsillitis, ganciclovir 5 mg/kg per dose twice daily for 14 days targeting HHV-6 infection, and intravenous immunoglobulin 2 g/kg over 2 days administered empirically before exclusion of autoimmune encephalitis. A trial of oral lorazepam 0.5 mg for catatonia resulted in improved interaction and calmer behavior. He was maintained on lorazepam 0.25 mg 3 times daily, which was well tolerated without adverse effects. After 2 weeks of hospitalization, the patient was discharged. At that time, he was playful and interactive, with occasional brief episodes of unresponsiveness and mumbling lasting a few minutes. At evaluation 1.5 months after discharge, he had returned to baseline except for persistent insomnia (Figure 2). Lorazepam was discontinued 2 months after discharge. No follow-up laboratory tests or imaging studies were performed; follow-up was clinical only.

Although the patient’s symptoms occurred after a viral infection, para-infectious immune-mediated mechanisms could theoretically contribute to central nervous system (CNS) dysfunction. In this case, however, the positive HHV-6 polymerase chain reaction results in blood and CSF, along with negative autoimmune test findings and clinical improvement after ganciclovir and lorazepam therapy, support a direct viral effect as the principal pathogenic mechanism.

Discussion

This report describes an immunocompetent child who developed acute psychiatric symptoms, including catatonia, secondary to HHV-6 encephalitis. The symptoms gradually improved with antiviral therapy and continued treatment for catatonia.

One differential diagnosis for acute neuropsychiatric symptoms is anti-NMDAR encephalitis [15]. Children with autoimmune anti-NMDAR encephalitis usually present with neuropsychiatric changes, seizures, and focal CNS findings [16]. The patient in the present case lacked anti-NMDAR antibodies and did not meet diagnostic criteria for anti-NMDAR encephalitis. He also did not fulfill criteria for seronegative autoimmune encephalitis [15,16]. Paraclinical findings, including normal electroencephalography, thyroid peroxidase antibody, thyroglobulin antibody, and CSF white blood cell count (Table 1), did not support probable antibody-negative autoimmune encephalitis [15]. PANDAS was also considered as a diagnosis, given the elevated ASO titer and streptococcal antigen positivity. However, the absence of tics or obsessive-compulsive behaviors, together with the stable symptom severity, argued against this diagnosis.

This is the first reported case of neuropsychiatric manifestations, including catatonia, as a complication of HHV-6 CNS infection in an immunocompetent child. Primary HHV-6 infection is a leading cause of acute febrile illness in young children, and the virus primarily targets CD4+ T cells for replication. It enters host cells through the CD46 receptor, resulting in immune modulation and viral persistence within peripheral blood mononuclear cells [4]. HHV-6 has been implicated in CNS infection [17]; febrile seizure is the most commonly encountered complication [18,19]. HHV-6 CNS infection or reactivation may lead to cerebellar ataxia, cognitive dysfunction, encephalitis, and limbic encephalitis [2,17,20]. Although HHV-6 encephalitis is rare in immunocompetent patients, cases have been reported in the literature [21,22]. Known symptoms in healthy children include altered mental status, irritability, seizures, focal neurological deficits, and encephalopathy [23,24]. Neuropsychiatric manifestations have been described in adults; such presentations, particularly catatonia, have not been reported in pediatric patients.

Birnbaum et al. described a 21-year-old woman with HHV-6 encephalitis who displayed severe psychosis and auditory hallucinations [25]. Berzero et al. reported a 9-month-old immunocompetent boy with HHV-6 encephalitis, behavioral changes, fever, and irritability [23]. Crawford et al. described a healthy 3-year-old girl with HHV-6 encephalitis who exhibited irritability, violent behavior, tremors, and opsoclonus-myoclonus [24]. The present case broadens the clinical spectrum of HHV-6 encephalitis and emphasizes the importance of considering viral etiologies in children with acute behavioral changes. One limitation is that chromosomally integrated HHV-6 could not be excluded, leaving the distinction between reactivation and primary infection unresolved.

Conclusions

This report describes HHV-6 CNS infection in an immunocompetent 4-year-old child who presented with acute neuropsychiatric symptoms, including hyperkinetic catatonia. Although HHV-6 infection is common in children, CNS involvement in healthy pediatric patients is rare and typically mild; neuropsychiatric manifestations are exceptionally uncommon. HHV-6 encephalitis should therefore be considered in the differential diagnosis of sudden-onset behavioral changes, catatonia, or other neuropsychiatric symptoms in children, even in the absence of classical signs of encephalitis. Early recognition and appropriate antiviral and symptomatic therapy can lead to rapid clinical improvement, as observed in the present case. Awareness of this rare presentation may facilitate early diagnosis and prevent unnecessary interventions. This case further expands the recognized clinical spectrum of HHV-6 CNS infection in pediatric populations.