A case report of long-delayed diagnosis of pseudorabies virus encephalitis with endophthalmitis: lessons from metagenomic next generation sequencing.

BACKGROUND: Pseudorabies virus (PRV) was thought to only infect animals. Recent studies have shown that it can also infect human. CASE PRESENTATION: We report a case of pseudorabies virus encephalitis and endophthalmitis, diagnosed 89 days after onset, confirmed with intraocular fluid metagenomic next generation sequencing (mNGS) after the result of two cerebrospinal fluid (CSF) mNGS tests were negative. Although treatment with intravenous acyclovir, foscarnet sodium, and methylprednisolone improved the symptoms of encephalitis, significant diagnostic delay resulted in permanent visual loss. CONCLUSIONS: This case suggests that pseudorabies virus (PRV) DNA in the intraocular fluid may have a higher positivity than that in the CSF. PRV may persist in the intraocular fluid for an extended period and may thus require extended antiviral therapy. Patients with severe encephalitis and PRV should be examined with the focus on pupil reactivity and light reflex. A fundus examination should be performed in patients with a central nervous system infection, specifically, those in a comatose state, to help reduce eye disability.

Uncommon histopathological features of cytomegalovirus encephalitis and measles inclusion body encephalitis on autopsy in two patients with primary immunodeficiency.

PURPOSE: To describe the neuropathological findings in two patients with primary immunodeficiency who had fatal viral encephalitis. MATERIALS AND METHODS: Severe combined immunodeficiency (SCID) was confirmed in case 1 by genetic testing, while case 2 had features suggestive of combined immunodeficiency; however, whole exome sequencing showed no pathogenic variants. Autopsies were performed in both cases after an informed consent. A detailed sampling of the brain including extracranial organs was conducted. Immunohistochemistry and electron microscopy was also performed to confirm the presence of viruses. RESULTS: Besides evidence of cystic encephalomalacia observed in both cases, the brain in case 1 revealed cytomegalovirus (CMV) ventriculoencephalitis accompanied by an exuberant gemistocytic response in the entire white matter. Nuclei of gemistocytes were loaded with several CMV nuclear inclusions, which was confirmed by immunohistochemistry. Case 2 demonstrated features of measles inclusion body encephalitis with several viral inclusions within neurons and astrocytes. Rare giant cells were also seen. Measles virus was confirmed on immunohistochemistry and electron microscopy. Plausibly, there was paucity of microglial nodules in both cases. Superadded bacterial pneumonia with diffuse alveolar damage was also seen in both cases. CONCLUSION: These cases add to the spectrum of unusual histological features of viral encephalitis seen in patients with underlying primary immunodeficiency diseases.

Early clinical features of new-onset refractory status epilepticus (NORSE) in adults.

BACKGROUND: The aim of this study was to identify early clinical features of patients with new-onset refractory status epilepticus (NORSE) that could direct the treatment in the first days of hospitalisation. METHODS: A retrospective cohort study of adult NORSE patients treated in the intensive care units of Helsinki University Hospital 2007-2018. RESULTS: We found 19 adult NORSE patients who divided into three subgroups on the basis of their clinical features: viral encephalitis (n = 5, 26%), febrile infection-related epilepsy syndrome (FIRES) (n = 6, 32%) and afebrile NORSE (n = 8, 42%). FIRES and afebrile NORSE patients remained without confirmed etiology, but retrospectively two paraneoplastic and two neurodegenerative causes were suspected in the afebrile NORSE group. Viral encephalitis patients were median 64 years old (IQR 55-64), and four (80%) had prodromal fever and abnormal findings in the first brain imaging. FIRES patients were median 21 years old (IQR 19-24), all febrile and had normal brain imaging at onset. In the afebrile NORSE group, median age was 67 (IQR 59-71) and 50% had prodromal cognitive or psychiatric symptoms. FIRES patients differed from other NORSE patients by younger age (p = 0.001), respiratory prodromal symptoms (p = 0.004), normal brain MRI (p = 0.044) and lack of comorbidities (p = 0.011). They needed more antiseizure medications (p = 0.001) and anesthetics (p = 0.002), had a longer hospital stay (p = 0.017) and more complications (p < 0.001). CONCLUSIONS: Among febrile NORSE patients, FIRES group was distinctive due to patients' young age, prodromal respiratory symptoms and normal first brain imaging. These features should be confirmed by subsequent studies as basis for selecting patients for early intensive immunotherapy.

Influenza B-associated encephalitis with rapid improvement with oseltamivir.

A 25-year-old female veterinarian presented with 1-week of flu-like symptoms followed by progressive encephalopathy. She was originally from Nicaragua and had been in the USA for 4 months. In the emergency department, she was confused and non-verbal with meningismus and facial myoclonus, but with an otherwise non-focal neurological exam. MRI brain abnormalities were consistent with viral encephalitides. Influenza B was detected via nasopharyngeal swab PCR. Mental status improved rapidly with oseltamivir. In such presentations, especially during flu season, influenza encephalitis must be considered, to facilitate early recognition of this entity and allow for targeted treatment.

Human Herpes Virus 6 Encephalitis Presenting as Fatal Refractory Status Epilepticus: a Case Report and Systematic Review.

PURPOSE: Encephalitis secondary to human herpesvirus 6 (HHV-6) infection is frequently encountered in immunocompromised patients; in contrast, HHV-6 encephalitis in immunocompetent patients is rare. There are only 3 reports of status epilepticus due to HHV-6 encephalitis in immunocompetent adults. In the present study, a case of refractory status epilepticus secondary to HHV-6 encephalitis was reported in an immunocompetent female. CASE REPORT: We report a case of a previously healthy 46-year-old female who presented with a one-week history of back pain, fever and generalized tonic-clonic seizures that progressed to status epilepticus. The video electroencephalography showed epileptiform discharges on both frontotemporal regions. Neuroimaging showed hyperintensities on the bilateral insula and temporal lobes. The cerebrospinal fluid showed elevated pressure and was positive for HHV-6. She was given ganciclovir and a total of eleven antiepileptic drugs. Despite these medications, she developed refractory status epilepticus and eventually succumbed due to multiple medical complications. CONCLUSION: This case highlights HHV-6 encephalitis as an important diagnostic consideration in patients presenting with refractory status epilepticus, regardless of immune status.

COVID-19 and the nervous system.

A pandemic due to novel coronavirus arose in mid-December 2019 in Wuhan, China, and in 3 months' time swept the world. The disease has been referred to as COVID-19, and the causative agent has been labelled SARS-CoV-2 due to its genetic similarities to the virus (SARS-CoV-1) responsible for the severe acute respiratory syndrome (SARS) epidemic nearly 20 years earlier. The spike proteins of both viruses dictate tissue tropism using the angiotensin-converting enzyme type 2 (ACE-2) receptor to bind to cells. The ACE-2 receptor can be found in nervous system tissue and endothelial cells among the tissues of many other organs.Neurological complications have been observed with COVID-19. Myalgia and headache are relatively common, but serious neurological disease appears to be rare. No part of the neuraxis is spared. The neurological disorders occurring with COVID-19 may have many pathophysiological underpinnings. Some appear to be the consequence of direct viral invasion of the nervous system tissue, others arise as a postviral autoimmune process, and still others are the result of metabolic and systemic complications due to the associated critical illness. This review addresses the preliminary observations regarding the neurological disorders reported with COVID-19 to date and describes some of the disorders that are anticipated from prior experience with similar coronaviruses.

COVID-19 virus may have neuroinvasive potential and cause neurological complications: a perspective review.

Coronavirus disease 2019 (COVID-19) was reported at the end of 2019 in China for the first time and has rapidly spread throughout the world as a pandemic. Since COVID-19 causes mild to severe acute respiratory syndrome, most studies in this field have only focused on different aspects of pathogenesis in the respiratory system. However, evidence suggests that COVID-19 may affect the central nervous system (CNS). Given the outbreak of COVID-19, it seems necessary to perform investigations on the possible neurological complications in patients who suffered from COVID-19. Here, we reviewed the evidence of the neuroinvasive potential of coronaviruses and discussed the possible pathogenic processes in CNS infection by COVID-19 to provide a precise insight for future studies.

Parechovirus-A3 encephalitis presenting with focal seizure mimicking herpes simplex virus infection.

BACKGROUND: Febrile neonates and young infants presenting with seizure require immediate evaluation and treatment. Herein we experienced two young infants with parechovirus-A3 (PeV-A3) encephalitis, initially presented with focal seizure suspecting herpes simplex virus (HSV) encephalitis. CASES: We have experienced 2 infantile cases, initially presented with focal seizure. At presentation, HSV encephalitis was strongly suspected and empiric acyclovir therapy was started; however, serum and/or cerebrospinal fluid (CSF) PCR for HSV were negative. Instead, serum and/or CSF PCR for parechovirus-A was positive. PeV-A3 infection was confirmed by genetic sequence analyses. Both cases required multiple anticonvulsant therapy and intensive care for intractable seizure. Diffusion-weighted imaging of brain magnetic resonance imaging (MRI) showed distinct findings; high-intensity lesions in the gray matter of parietal and occipital lobes in Case 1, and bilateral decreased diffusion of the deep white matter and corpus callosum in Case 2. We have followed two cases more than four years; Case 1 developed epilepsy, has been on an anticonvulsant to control her seizure. Case 2 has significant neurodevelopmental delay, unable to stand or communicate with language. CONCLUSIONS: PeV-A3 encephalitis needs to be in differential diagnosis when neonates and young infants present with focal seizure, mimicking HSV encephalitis. Special attention may be necessary in patients with PeV-A3 encephalitis given it could present with intractable seizure with high morbidity in a long-term.

Indoleamine 2,3-dioxygenase 1 deletion promotes Theiler's virus-induced seizures in C57BL/6J mice.

OBJECTIVE: Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3-dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N-methyl-d-aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis. METHODS: C57BL/6J and Ido1 knockout mice (Ido1-KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real-time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry. RESULTS: Infected C57BL/6J mice up-regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1-KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1-KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1-KO mice. SIGNIFICANCE: Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.

Surgical outcomes in patients with epilepsy after viral encephalitis: contribution of SEEG study.

BACKGROUND: Nowadays, few surgery analysis has been reported in cases of epilepsy after viral encephalitis(VE). Herein, this study was to evaluate the efficacy of surgery and capability of stereoelectroencephalography (SEEG) in the definition of the epileptogenic zone (EZ) after VE, and also to explore the relationship between the SEEG features and the surgical outcomes. METHODS: We retrospectively analyzed 10 surgically treated patients that identified to suffer from epilepsy secondary to VE using SEEG, and investigated the SEEG features associated with surgical outcomes in these patients. Besides visual analysis, we used the epileptogenicity index (EI), a semi-quantitative and supplementary tool to evaluate the validity of SEEG in the context of VE. RESULTS: Among the 10 operated patients, 3 of them became completely seizure-free. The patients who got totally seizure free or significant improvement, the seizure onset was located either in the antero-mesial temporal structures or focal gyrus; patients who got worthwhile improvement or no improvement, the seizure started from multiple brain lobes. The number of electrodes classified as epileptogenic visually involved were closely correlated with EI positive onses.Anatomic areas defined and shown as EZ on MRI by visual assessment were also defined as epileptogenic by the EI in these cases. CONCLUSION: Apart from exploring the surgical outcome related to epilepsy after VE, we also bring insight into the relationship between the SEEG features and surgical outcome with the application of the supplementary methods.

Human herpesvirus 6 associated post-transplant acute limbic encephalitis: Clinical observations of biomarkers for risk of seizure in a pediatric population.

BACKGROUND: Human herpesvirus 6 (HHV6) is a cause of post-transplant acute limbic encephalitis (PALE). Seizures are associated with this disorder yet no predictive biomarkers have been identified. The objective of this study was to evaluate lab and neurodiagnostic biomarkers in patients with HHV6 associated PALE. METHODS: A retrospective chart review was performed at our institutions between 2000 and 2017. Patients were identified through a clinical database. Inclusion criteria included: age less than 18 years, HHV6 (quantitative real-time PCR or meningoencephalitis panel) tested in CSF and serum. Biomarkers of serum and CSF viral load, EEG, and MRI were reviewed along with clinical data. RESULTS: In total, 11 patients met inclusion criteria. All patients had undergone hematopoietic stem cell transplantation. Five of 11 patients had seizures as part of their clinical course, all being controlled with antiepileptic monotherapy. Seizure semiology was focal-onset in three cases and generalized in two. Neuroimaging was normal in all patients within seven days but six patients developed T2 signal intensities in the temporal lobes on repeat imaging between 14-28 days. The median CSF HHV6 viral load for all patients was 47 300 copies/mL although the median viral load was 2586 copies/mL in patients who had seizure compared to 473 969 copies/mL in those who had not (P = 0.02). Those with seizures tended to be younger (median 6.5 years compared to 11 years, P = 0.27). All patients with seizures had an EEG with 80% demonstrating abnormalities. CONCLUSION: In patients with post-hematopoietic stem cell transplant HHV6 associated PALE, lower CSF viral load may be associated with a higher likelihood to have seizures. This may indicate a primary infection as opposed to secondary reactivation phenomenon.

Simply influenza A (H3N2)-associated encephalitis with seizure.

Influenza-associated acute encephalopathy (IAE) is more prevalent in children than in adults and often results in neurological sequelae or even death. Diagnosis of IAE is difficult as clinical presentation varies significantly and the influenza virus is rarely detected in cerebrospinal fluid. Moreover, seizures in adults due to influenza infection are rare. Herein, we describe the case of an adult presenting with both acute encephalitis and seizures. A 38-year-old female was admitted to the emergency department with acute respiratory symptoms and fever, followed by quick progression to stupor within 24 h. A rapid antigen test was influenza A-positive, and polymerase chain reaction of nasal secretions confirmed the H3N2 subtype. Brain magnetic resonance imaging showed bilateral water restriction lesions at the thalamus and the cerebellum and an electroencephalogram showed frequent episodic generalized sharp-and-slow waves over the bilateral frontal region. Based on the neuroimaging and laboratory findings, we diagnosed the patient with adult influenza A (H3N2)-related encephalitis complicated by seizure. Treatment with oseltamivir and anticonvulsants led to complete neurologic recovery by day 14. This report describes two unusual neurological manifestations of influenza A, i.e., encephalitis and seizures, in an adult. We emphasize that, in adults presenting with acute viral encephalitis, clinicians should consider influenza infection as part of the differential diagnosis, and that typical neuroimaging in conjunction with laboratory detection of influenza virus and/or intrathecal antibody production suggestive of IAE, may help establish an accurate diagnosis.

A case report of a teenager with severe hand, foot, and mouth disease with brainstem encephalitis caused by enterovirus 71.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is an acute viral infection occurring mostly in infants and children. Enterovirus 71 (EV71) infection mostly occurs in children < 5 years of age. Severe cases, however, are usually encountered in children under the age of 3 years, and exceedingly rare in teenagers > 14 years and adults. CASE PRESENTATION: We report a rare case of HFMD in a 16-year-old male teenager residing in Chonqing, China. The clinical presentation was typical of HFMD and included vesicular lesions and oral mucosal ulcers, macular and vesicular lesions on palms and soles. He developed severe neurological complications that were suggestive of brainstem encephalitis. EV71 RNA was detected in the patient's faecal samples by reverse transcription-polymerase chain reaction. Specific IgM antibody to EV71 was detected in both serum and cerebrospinal fluid by ELISA. Gamma immunoglobulin therapy at 25 g/day was administered for 2 days, along with methylprednisolone, mannitol, ganglioside, and creatine phosphate sodium. The patient showed neurological improvement and recovered completely in 1 month. CONCLUSIONS: This case indicates that EV71 infection may cause HFMD in teenagers with potentially severe neurological involvement. Clinicians should be aware of the possibility of HFMD occurring in adults and teenagers as prompt treatment could be life-saving in these patients.

Hyponatremia Is Predictive of HSV-1 Encephalitis among Patients with Viral Encephalitis.

Encephalitis is an inflammatory process involving the brain parenchyma associated with neurologic dysfunction. The main causes of infectious encephalitis are viruses, including Herpes simplex virus type 1 (HSV-1). As the mortality rate of HSV-1 encephalitis could be reduced with early acyclovir treatment, it is imperative to distinguish HSV-1 encephalitis from other type of viral encephalitis as early as possible. However, sophisticated methods for definitive diagnosis of HSV-1 encephalitis are not readily available. We aimed to explore distinctive clinical and laboratory features of HSV-1 encephalitis. All of the adult patients with viral encephalitis hospitalized between 2011-2017 were enrolled, including 16 patients with HSV-1 encephalitis and 51 patients non-HSV-1 viral encephalitis. Determination of viruses in cerebrospinal fluid was performed by PCR tests. Female sex, hyponatremia, and abnormalities in MRI were independently associated with HSV-1 encephalitis (p < 0.05 for each). In particular, hyponatremia (< 135 mEq/L) was found in nine patients with HSV-1 encephalitis (56.3%) and 10 patients with non-HSV-1 viral encephalitis (19.6%) (p = 0.005). As serum sodium is determined easily and quickly in clinical practice, the presence of hyponatremia among patients with viral encephalitis could be helpful for the early diagnosis of HSV-1 encephalitis before cerebrospinal fluid PCR results were available. Moreover, the presence of positive finding in MRI could further support the diagnosis. This is the first study that compared the serum sodium levels among patients between HSV-1 and non-HSV-1 viral encephalitis. We thus propose the diagnostic value of hyponatremia for HSV-1 encephalitis.

Influenza A(H5N1) Virus Infection in a Child With Encephalitis Complicated by Obstructive Hydrocephalus.

A 2-year-old boy with highly pathogenic avian influenza A(H5N1) virus infection with minimal respiratory symptoms developed encephalitis complicated by obstructive hydrocephalus. Viral RNA was detectable in cerebrospinal fluid. The virus belonged to H5N1 clade 2.3.2.1b and had acquired the mammalian adaptation mutation PB2 Q591K.

Macrophage depletion by liposome-encapsulated clodronate suppresses seizures but not hippocampal damage after acute viral encephalitis.

Viral encephalitis is a major risk factor for the development of seizures and epilepsy, but the underlying mechanisms are only poorly understood. Mouse models such as viral encephalitis induced by intracerebral infection with Theiler's virus in C57BL/6 (B6) mice allow advancing our understanding of the immunological and virological aspects of infection-induced seizures and their treatment. Previous studies using the Theiler's virus model in B6 mice have indicated that brain-infiltrating inflammatory macrophages and the cytokines released by these cells are key to the development of acute seizures and hippocampal damage in this model. However, approaches used to prevent or reduce macrophage infiltration were not specific, so contribution of other mechanisms could not be excluded. In the present study, we used a more selective and widely used approach for macrophage depletion, i.e., systemic administration of clodronate liposomes, to study the contribution of macrophage infiltration to development of seizures and hippocampal damage. By this approach, almost complete depletion of monocytic cells was achieved in spleen and blood of Theiler's virus infected B6 mice, which was associated with a 70% decrease in the number of brain infiltrating macrophages as assessed by flow cytometry. Significantly less clodronate liposome-treated mice exhibited seizures than liposome controls (P<0.01), but the development of hippocampal damage was not prevented or reduced. Clodronate liposome treatment did not reduce the increased Iba1 and Mac3 labeling in the hippocampus of infected mice, indicating that activated microglia may contribute to hippocampal damage. The unexpected mismatch between occurrence of seizures and hippocampal damage is thought-provoking and suggests that the mechanisms involved in degeneration of specific populations of hippocampal neurons in encephalitis-induced epilepsy are more complex than previously thought.

Automated quantification of EEG spikes and spike clusters as a new read out in Theiler's virus mouse model of encephalitis-induced epilepsy.

Intracerebral infection of C57BL/6 mice with Theiler's murine encephalomyelitis virus (TMEV) replicates many features of viral encephalitis-induced epilepsy in humans, including neuroinflammation, early (insult-associated) and late (spontaneous) seizures, neurodegeneration in the hippocampus, and cognitive and behavioral alterations. Thus, this model may be ideally suited to study mechanisms involved in encephalitis-induced epilepsy as potential targets for epilepsy prevention. However, spontaneous recurrent seizures (SRS) occur too infrequently to be useful as a biomarker of epilepsy, e.g., for drug studies. This prompted us to evaluate whether epileptiform spikes or spike clusters in the cortical electroencephalogram (EEG) may be a useful surrogate of epilepsy in this model. For this purpose, we developed an algorithm that allows efficient and large-scale EEG analysis of early and late seizures, spikes, and spike clusters in the EEG. While 77% of the infected mice exhibited early seizures, late seizures were only observed in 33% of the animals. The clinical characteristics of early and late seizures did not differ except that late generalized convulsive (stage 5) seizures were significantly longer than early stage 5 seizures. Furthermore, the frequency of SRS was much lower than the frequency of early seizures. Continuous (24/7) video-EEG monitoring over several months following infection indicated that the latent period to onset of SRS was 61 (range 16-91) days. Spike and spike clusters were significantly more frequent in infected mice with late seizures than in infected mice without seizures or in mock-infected sham controls. Based on the results of this study, increases in EEG spikes and spike clusters in groups of infected mice may be used as a new readout for studies on antiepileptogenic or disease-modifying drug effects in this model, because the significant increase in average spike counts in mice with late seizures obviously indicates a proepileptogenic alteration.

Microhemorrhage identified on 3.0 T MR susceptibility-weighted imaging for prognosis of viral encephalitis.

OBJECTIVE: To evaluate the relationship of microhemorrhage on susceptibility-weighted imaging (SWI) with the severity of clinical symptoms and the prognosis of viral encephalitis. MATERIALS AND METHODS: Thirty patients with clinically diagnosed viral encephalitis were divided into three groups according to the Glasgow Coma Scale (GCS) and the condition of recovery namely, Group I (n = 12): Glasgow Coma Scale (GCS)≥13 and recovered with no sequelae; Group II (n = 11): GCS 9-12 and recovered with some sequelae; Group III (n = 7): GCS 3-8 and recovered with more severe sequelae. The microhemorrhage detectability on SWI and conventional MR imaging in these three groups was compared and their correlations with different seriousness of clinical symptoms and prognosis were analyzed. RESULTS: There was a significant difference in microhemorrhage volume among different MR sequences (p < 0.05). SWI was more sensitive to detect microhemorrhage than conventional MR imaging techniques. Microhemorrhages on SWI were significantly different among the three groups (p < 0.01). The volume of microhemorrhage on SWI was well correlated with the degree of clinical symptoms and the prognosis of viral encephalitis. CONCLUSION: SWI can be used to detect microhemorrhage in patients with viral encephalitis. Assessment of microhemorrhage with SWI can provide useful information for the prognosis evaluation of viral encephalitis.

Human herpes virus-6 encephalitis causing severe anterograde amnesia associated with rituximab, azathioprine and prednisolone combination therapy for dermatomyositis.

Human herpes virus-6 (HHV-6) reactivation is a well-recognised complication following haematological stem cell transplantation, but it is novel in the context of combination immunomodulatory therapy for autoimmune disease. We report a case of severe anterograde amnesia caused by HHV-6 encephalitis in a young female patient on rituximab, azathioprine and prednisolone for dermatomyositis (DM). The use of targeted biologic treatments for systemic autoimmune connective tissue diseases (CTDs) is increasing, particularly when refractory to conventional management. The anti-CD20 B cell depleting monoclonal antibody, rituximab is now increasingly used, often in combination with conventional immunomodulatory treatments, in certain autoimmune neurological conditions and systemic CTDs including DM. Physicians should be aware of the possibility of HHV-6 in those who develop encephalitis while CD20 B cell deplete, especially in the presence of additional immunomodulatory therapies. Prompt diagnosis and treatment of HHV-6 encephalitis with evidence-based anti-viral therapy may help reduce the extent of irreversible morbidity such as amnesia.