HSV-associated chronic granulomatous encephalitis in a child

To the Editor: Encephalitis due to herpes simplex virus (HSV) is associated with high mortality and morbidity and can present in acute, subacute, and chronic forms (1). Chronic granulomatous encephalitis is a rare presentation of post-herpetic encephalitis; only a few cases have been reported. We present a case of chronic granulomatous encephalitis in a child who survived neonatal disseminated herpes simplex infection with encephalitis. This case sheds light on the importance of this rare entity and will help the healthcare providers keep this potentially life-threatening complication in mind when encountering patients suspected to be suffering from herpes simplex encephalitis (HSE). Herpes simplex virus encephalitis (HSVE) is the most common form of sporadic viral encephalitis in the western world. Approximately 90% of HSVE cases in adults and children are caused by herpes simplex virus type 1 (HSV-1), whereas HSV-2 is the main cause in neonates and immunocompromised patients (2). Most cases of acute HSE are monophasic but relapses occurring weeks, months or years after initial infection have been reported in ∼25% of cases. Viral DNA cannot always be detected in the cerebrospinal fluid (CSF) in association with clinical deterioration and a post-infectious immune response must be considered in these patients because HSE is increasingly recognized as a trigger of an autoimmune reaction. The best described post-HSV immune phenomenon in children is anti-N-methyl-D-aspartate receptor encephalitis (3). Thus, HSE can be a longstanding CNS disorder. The diagnosis of postherpetic granulomatous encephalitis should be one of the most important considerations in a child presenting with encephalitis months to years after HSE. The precise pathogenetic mechanisms of this process are not known but dysregulation of the inflammasome response, which may lead to granuloma formation is hypothesized to play a role in the prolonged neuroinflammation (4). Chronic granulomatous encephalitis is a rare, but well-known complication associated with HSE (5–7). Our patient was a 2-year-old female child, who was found face down on the floor. According to the grandparents who were taking care of the child, she probably rolled over on her stomach and presumably suffocated. She was down for an unknown period of time but not more than 20-30 minutes. Apparently, there was no history of any recent significant disease. The grandparents then called the EMS. According to the EMS the child was in asystole and therefore they started CPR. A return of spontaneous circulation was achieved. The child was intubated and was flown via Air Care to Wake Forest Baptist Medical Center where she was admitted to the pediatric intensive care unit. Her total leukocyte count was high (36 × 103/µL with absolute lymphocyte count of 29.8 × 103/µL); however, her blood culture came back negative. Unfortunately, the child remained unresponsive and had fixed unresponsive pupils on examination. She had some bilateral hand twitching and therefore she was placed on long-term electroencephalographic monitoring, which showed low amplitude waves. There were no clinical signs of brain activity. She developed refractory shock, metabolic acidosis, severe hypoxemic respiratory failure, and acute respiratory distress syndrome refractory to all interventions. The family ultimately elected to withdraw care and perform comfort measures and she was pronounced dead shortly thereafter. The baby was sent to the Department of Forensic Pathology to determine the cause of her rapid clinical deterioration and death. The medical records indicated that she was born prematurely at home due to the mother being unaware that she was pregnant. The mother had active HSV2-associated vulvar lesions and substance use disorder. The baby and mother were taken to the hospital where the child was found to be positive for amphetamines and cannabinoids. The baby was discharged home after being in the hospital for several of weeks. Around 10 days later, she developed seizures and became apneic and was returned to the hospital. She underwent imaging studies, extensive blood work and a lumbar puncture, which came back positive for HSV-2. Her blood, urine, and CSF tests results were negative for other viral, fungal, and bacterial organisms. Based upon the history, clinical examination and laboratory tests, she was diagnosed with disseminated HSV-2 infection with encephalitis. Although she survived, she was in a permanent severely devastated neurological condition and required total support from the caregivers. At autopsy, the subdural space showed 150–175 ml of serosanguineous fluid. The leptomeninges were glistening and clear. The cerebral cortex demonstrated diffuse, severe cystic encephalomalacia (Fig. 1). The basal vasculature and cranial nerves were in their normal anatomical locations. Coronal sections through the cerebrum demonstrated global remote cerebral infarction with essentially no recognizable cortex or white matter. The deep brain nuclei were markedly atrophic. The brainstem showed marked atrophy of the cerebral peduncles, pons basis, and pyramids. The cerebellum was grossly unremarkable. Microscopic sections from the brainstem, particularly the medulla demonstrated chronic granulomatous inflammation with focal necrosis and mineralization. Scattered perivascular lymphocytic infiltrates, microglial nodules, neuronophagia, and non-necrotizing granulomas with giant cells were also identified (Fig. 2A, B). Immunohistochemical stain for HSVI/II demonstrated scattered positive neurons, histiocytes, and glial cells in brainstem sections (Fig. 2C). Her lungs exhibited aspiration pneumonia. No injuries were present that would have caused or contributed to the child’s death. Toxicological analysis of antemortem blood detected therapeutic levels of diazepam and gabapentin. Upon reviewing the electronic medical records, we did not find any evidence of other infectious (bacterial, fungal, HIV, measles, other viral) or autoimmune disease. Gross photo of the brain. Cerebral cortex showed diffuse cystic encephalomalacia, while the cerebellum and brainstem (which cannot be seen in this photo), appeared grossly unremarkable. (A) Microscopic section from medulla shows multinucleated giant cells. (B) CD68 expression in multinucleated giant cells. (C) Immunohistochemical stain for HSV shows scattered immunopositive neurons (green arrow) and an epithelioid histiocyte (blue arrow). (D) A representative histologic section from control tissue demonstrates scattered HSV-positive cells (red arrows) by immunohistochemical stain. MRI can show enhancing granulomas with background gliosis and calcification in cases of chronic granulomatous HSE. However, these findings can raise the possibility of neoplastic process, in which case brain biopsy would be more appropriate especially when the CSF PCR is also negative (8). Histopathological examination of the brain tissue demonstrates chronic granulomatous inflammation with multinucleated giant cells, necrotic areas with multicystic appearance, and mineralization. Immunohistochemical stains for HSV may be negative at the time of biopsy or autopsy but the viral DNA may be identifiable by PCR (9). According to one study, HSV is demonstrable for up to 3 weeks after the onset of encephalitis, but the number of immunoreactive cells significantly decreases after 2 weeks (10). In our case, histologic examination of the brainstem sections (especially sections from the medulla and midbrain) demonstrated chronic granulomatous inflammation with multinucleated giant cells, mineralization, perivascular lymphocytic infiltration, and microglial nodules. We were also able to find scattered HSV positive neurons, histiocytes, and glial cells in medullary sections by immunohistochemical stains. Based upon the histologic, immunohistochemical and laboratory tests (especially the raised total leukocyte count of 36 × 103/µL with absolute lymphocyte count of 29.8 × 103/µL and negative blood cultures), we believe our patient developed chronic granulomatous encephalitis due to the reactivation of HSV2. Patients who are immunocompromised due to chemoradiation therapy or steroid treatment, or have an underlying immunodeficiency syndrome have increased propensity to develop chronic granulomatous encephalitis (11). Host differences may play an important role in developing chronic granulomatous HSE including polymorphism of the toll-like receptor 3 (TLR-3) pathway (5). Toll-like receptor is part of the innate immune system, which is activated by different external microbes and is critical for antiviral immunity (12). Toll-like receptor-3 is found in the CNS and is considered an important component of natural immunity against HSV-1. According to Zhang et al (13), neurotrophic viruses such as HSV-1 had contributed to maintenance of the TLR-3 allele in evolution and patient with genetic deficiency of TLR-3 have increased predisposition to develop chronic HSV encephalitis. Our patient was not tested for TLR-3 status; however, we believe knowing TLR-3 status may be helpful in identifying patients requiring close follow-up. Without appropriate treatment, the mortality rate due to HSE is ∼70%; only 2.5% of the surviving patients regain normal neurological function without therapy (14). Varatharaj et al (15) demonstrated that patients presenting with acute/subacute cognitive decline and an enhancing lesion in the temporal lobe, focal granulomatous HSV-1 encephalitis should be considered. The authors also found out that despite negative CSF PCR for HSV-1 and no response to acyclovir, the diagnosis of focal granulomatous HSV-1 encephalitis should be considered in appropriate clinical and radiological settings. According to the author, the diagnosis is based on finding HSV-1 DNA in brain tissue and antibody against HSV-1 in paired serum and CSF samples. The author further demonstrated the potential beneficial role of corticosteroid therapy in this setting (15). Chronic granulomatous encephalitis is one of the complications associated with HSE that may progress to multicystic encephalomalacia with a devastating outcome. The entity should be considered as one of the differential diagnoses especially in children who survive neonatal HSE, in the appropriate clinical and radiological settings. Appropriate laboratory investigations including brain biopsy should be performed to timely diagnose and treat these patients. In our case, the child quickly deteriorated and passed away. Law enforcement requested an autopsy as they were concerned that this was a possible pediatric neglect case. The diagnosis of granulomatous encephalitis involving the brainstem was the immediate cause of death, which helped exonerate the caregivers of any criminal wrongdoing. The authors have no duality or conflicts of interest to declare.