Organic or psychiatric disorder? Acute atypical psychotic episode in the context of suspected herpetic encephalitis with HHV-6

Introduction

Viral encephalitis, though relatively rare, can lead to significant neuropsychiatric complications, making timely identification and intervention crucial. Human herpesvirus 6 (HHV-6) is a DNA virus that infects over 80% of children by the age of 2 years old, typically causing either an asymptomatic infection or a typical rash, and only occasionally leading to febrile seizures, encephalitis, or meningitis⁽⁵⁾. HHV-6 encephalitis is rarely encountered as a primary manifestation in teenagers or young adults who are immunocompetent. A common presentation of viral encephalitis manifests by fever, seizures, irritability or unusual behavior, focal neurologic signs, decreased consciousness⁽¹⁾, but it very rarely presents with psychiatric symptoms, specifically psychotic symptoms. There are very few mentions in the literature about acute viral encephalitis with primary psychotic symptoms⁽²⁾.

Case presentation

A 17-year-old male presented at the Child and Adolescent Psychiatric Department of the “Prof. Dr. Alexandru Obregia” Clinical Hospital of Psychiatry, Bucharest, Romania, with a recommendation for hospitalization in our clinic, after being evaluated in a pediatric department of another hospital. There he was evaluated for marked psychomotor agitation, behavioral disturbances, disorganized movements of the limbs with a clonic appearance and spontaneous emission of urine. After conducting a clinical evaluation, hematological tests, and a brain CT scan – which all showed normal results except for mild leukocytosis and neutrophilia –, a transfer to our clinic was requested.

The information related to the patient’s life history was obtained with difficulty from the family. According to the data obtained from the parents and from the medical letters provided by them, about a year ago, the patient had presented to a psychiatry clinic in a city in Spain with withdrawal and social isolation, sad mood, hypnotic disorders and decreased appetite, spending most of his time alone on his phone. There, they had also noticed signs of intellectual disability and decided to evaluate his cognitive function with the Wechsler Intelligence Scale for Children which stated an intelligence quotient of 42. He was diagnosed with depressed mood, ADHD and intellectual disability. Pharmacological treatment with fluoxetine 20 mg/day, methylphenidate 18 mg/day and quetiapine 15 mg/day was recommended, but the patient and the family were not adherent to the treatment. The family also described psychotic symptomatology six months prior to his first evaluation in our clinic, with delusional thoughts and visual and auditory hallucinations, but only lasting for a few days.

One week before the hospitalization in our clinic, the patient had presented to a hospital in Spain with the following symptoms: fever that did not yield to the administration of paracetamol, frontoparietal headache, and insomnia with acute onset 48 hours before presentation. The investigations carried out were within normal limits. The patient was discharged with the recommendation to administer anti-inflammatory and antipyretics medication. Later they returned to Romania, where they went to another pediatric evaluation from which they were directed to our clinic.

In our clinic, the patient manifested severe psychomotor agitation, marked hetero-aggressiveness towards the medical staff and his family, irritability, and nervosity. In addition to the previously described symptomatology, the patient accused spontaneous movements of the limbs with a clonic appearance and spontaneous emission of urine, and according to parents, these spontaneous movements and emission of urine always appeared together. Following the acute treatment with intramuscular haloperidol and Diazepam®, a daily treatment with 5 mg of olanzapine and 1 mg of lorazepam per day was initiated. On the first day of hospitalization, blood tests were done, and the results were within normal limits and without detectable specific infectious symptoms. The second day, he was clinically evaluated in the neurological department of our hospital, with a neurological examination conclusion within normal limits. Furthermore, the electroencephalogram didn’t identify any epileptic discharge. Later that day, he started to develop a fever that decreased with the administration of 500 mg of paracetamol. The blood tests on the third day were modified, with C-reactive protein increased 10 times from 0.9 mg/dl in the first day to 9.5 mg/dl during the third day of hospitalization. However, there was a favorable evolution of symptoms, such as psychomotor agitation and irritability which have decreased in intensity. On the third day of hospitalization, the overall global symptomatology was modified by apathy, fatigue, lethargy, hypo-responsiveness, confusion, and psychomotor slowness. During the Brudzinski and Kernig maneuvers, the patient presented difficulties with hyperextension of the head and neck stiffness. Therefore, the suspicion of infectious meningoencephalitis was raised, and the transfer of the patient to an infectious disease hospital was requested.

At the infectious disease hospital, they performed a thorough somatic clinical, paraclinical and imaging evaluation, identifying the following: interstitial pneumonia with scissural reaction, acute enterocolitis with negative coproculture, cerebrospinal fluid (CSF) with normal cellularity and biochemistry, but positive multiplex PCR for human herpesvirus type 6 (HHV-6). No other bacteria, viruses or fungi were identified in the CSF, blood, urine or stool sample. At first, they initiated the treatment with valganciclovir, but it was stopped the next day because the patient was not immunosuppressed (negative HIV serology). Moreover, the etiology of the current febrile episode was not established as being caused by a recent infection with HHV-6, because at that time IgM and IgG were still in progress, and the data from the medical literature did not highlight a benefit of this medication in acute HHV-6 infection in immunocompetent patients. In addition, the results for blood HHV-6 IgG came out positive. 

At the follow-up in our clinic and the last evaluation three months later, the patient was calm, conscious and cooperative, with euthymic disposition and spontaneous speech within the limits of cognitive abilities. He denies agitation, disturbances of perception or thinking. According to the parents, he no longer had episodes of psychomotor agitation, anxiety decreased in frequency and intensity, he spent less time alone and became more involved in pleasant activities, his appetite was within normal limits, and he had a complete remission of sleep disorders. Upon discharge, he left with the recommendation to continue the pharmacological treatment with olanzapine and with the cessation of the administration of lorazepam.

Discussion

Even though HHV-6 has been increasingly reported in the cerebrospinal fluid, his clinical significance remains highly unclear⁽³⁾. A study about patients with suspected meningitis and encephalitis stated that most positive results for HHV-6 were identified in children, and it was the second most frequently identified viral pathogen after enterovirus in this age group⁽⁴⁾. In adults with HHV-6 detected in their CSF, almost all of them had advanced HIV infection⁽³⁾. However, it should also be taken into account that, thanks to this FilmArray® (BioFire) analysis technology, the incidence of HHV-6 detection has increased significantly, but most cases are asymptomatic and very few of them develop encephalitis or meningitis, and even then, it is difficult to make a direct association with the aforementioned pathologies⁽⁵⁾.

This case is distinctive due to the presence of multiple discordant and various symptoms, both in their presentation and the timeline of their occurrence. Additionally, there is a lack of specificity between the symptoms and the clinical, paraclinical and imaging findings. Besides that, the family’s low socioeconomic factors complicated the understanding of this case, and this fact must also be considered.

From a chronological perspective, some psychiatric symptoms had begun a year before the visit to our clinic, as atypical depressive symptoms in a patient with a history of a neurodevelopmental disorder. The details gathered from the family and the medical letters from Spain frequently conflicted, especially concerning the symptoms, the frequency of treatment, and the response to therapy. Additionally, there was no regular evaluation of symptoms management and treatment outcomes. Despite starting a pharmacological treatment, which he followed inconsistently, there was no noticeable improvement in his symptoms.

Furthermore, six months after his initial presentation, his clinical condition took on a psychotic aspect, though the timing and severity of the symptoms were nonspecific. However, these symptoms reportedly went into remission a few days later. The case took an unexpected turn when somatic symptoms resembling those of a common viral infection developed on top of the existing psychiatric conditions. These symptoms did not respond well to conventional anti-inflammatory treatments. Moreover, the somatic symptoms, while resistant to anti-inflammatory and antipyretic drugs, fluctuated over time, oscillating between periods of seeming remission and exacerbation. In addition, according to the anamnesis with his parents, he also developed some atypical movements of the limbs with a clonic appearance that overlapped with episodes of spontaneous emission of urine, episodes that did not manifest during the hospitalization in our clinic, and no abnormal findings were seen on the EEG, but even so, they could not be dismissed.

Shortly after this, the infectious symptoms appeared to stabilize, but more psychiatric symptoms emerged. An atypical acute psychotic episode developed, with elements of significant and challenging-to-control hetero-aggressiveness, which was unusual for this patient. Moreover, this symptomatology of psychotic aspect had an apparently spontaneous and very rapid remission with a completely opposite shift towards lethargy, confusion, and slow psychomotor functioning. Due to these symptomatic changes and atypical manifestations, there was suspicion of possible encephalitis or meningitis, leading to the patient’s transfer to an infectious disease hospital. There, the only significant findings – aside from hematological inflammatory markers – were in the cerebrospinal fluid, which tested positive for HHV-6. Subsequently, serological tests also showed positivity for HHV-6 IgG. This finding increased the confusion regarding the case, as neither the patient’s clinical presentation, nor the available scientific literature provided conclusive evidence for or against an episode of encephalitis or meningitis even after several evaluations. Although the initial infection may be associated with neurological symptoms like febrile seizures and encephalitis, there is ongoing debate about whether HHV-6 can induce encephalitis in older children and adults. Like other herpesviruses, HHV-6 can remain latent in the host after the primary infection and has the potential to reactivate, usually during periods of immunosuppression. In a study on HHV-6 encephalitis, where 42 patients tested positive for HHV-6 in CSF, seven of them developed encephalitis due to HHV-6 reactivation, and they were all immunocompromised⁽⁶⁾. The most common neuropsychiatric finding in these cases was an altered mental status (confusion, stupor, etc.), followed by seizures, behavioral disturbances, agitation and amnesia⁽⁶⁾. The confusion regarding the presence of HHV-6 in CSF goes even further, as in immunocompetent patients the presence of HHV-6 in the cerebrospinal fluid can merely represent a sign of genome integration rather than an acute CNS infection⁽⁷⁾.

Conclusions

We described the case of a patient with known psychiatric history of ADHD, intellectual disability and mood changes, with sudden onset of atypical psychotic symptoms following fever episodes, where the suspicion of possible encephalitis or meningoencephalitis was raised. This was suspected due to a sudden change in his overall general condition, with a shift towards lethargy, apathy, hypo-responsiveness, confusion and difficulty in hyperextension of the neck and neck stiffness.  In his cerebrospinal fluid, white cell count and protein levels were normal, but the BioFire® FilmArray Meningitis/Encephalitis (FilmArray-ME) panel identified HHV-6 positive. Being immunocompetent, the patient was treated with psychotropic treatment, without receiving any antiviral therapy. The HHV-6 meningoencephalitis was classified as possible, but without the certainty that all the symptoms that appeared were determined by the HHV-6 reactivation, or they coincidentally occurred together.  

Autori pentru corespondenţă: Ilinca Mihăilescu E-mail: ilinca.mihailescu@umfcd.ro

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.