Limbic encephalitis in a COVID-19 patient?

We describe the case of a 79-year-old woman infected by SARS-CoV-2 and purely neurological confusional syndrome without clinically relevant respiratory disease and NMR alterations of the limbic system.

Limbic Encephalitis Brain Damage Induced by Cocal Virus in Adult Mice Is Reduced by Environmental Enrichment: Neuropathological and Behavioral Studies.

We previously demonstrated, using the Piry virus model, that environmental enrichment promotes higher T-cell infiltration, fewer microglial changes, and faster central nervous system (CNS) virus clearance in adult mice. However, little is known about disease progression, behavioral changes, CNS cytokine concentration, and neuropathology in limbic encephalitis in experimental models. Using Cocal virus, we infected C57Bl6 adult mice and studied the neuroanatomical distribution of viral antigens in correlation with the microglial morphological response, measured the CNS cytokine concentration, and assessed behavioral changes. C57Bl6 adult mice were maintained in an impoverished environment (IE) or enriched environment (EE) for four months and then subjected to the open field test. Afterwards, an equal volume of normal or virus-infected brain homogenate was nasally instilled. The brains were processed to detect viral antigens and microglial morphological changes using selective immunolabeling. We demonstrated earlier significant weight loss and higher mortality in IE mice. Additionally, behavioral analysis revealed a significant influence of the environment on locomotor and exploratory activity that was associated with less neuroinvasion and a reduced microglial response. Thus, environmental enrichment was associated with a more effective immune response in a mouse model of limbic encephalitis, allowing faster viral clearance/decreased viral dissemination, reduced disease progression, and less CNS damage.

Diagnóstico de encefalite límbica não paraneoplásica de etiologia imunomediada: estudo de caso e revisão de literatura / Diagnosis of immune-mediated non-paraneoplastic limbic encephalitis: case report and literature review

A encefalite límbica vem sendo descrita como um distúrbio neurológico raro, que afeta seletivamente as estruturas do sistema límbico. Clinicamente, é caracterizada como uma desordem neurológica debilitante, que se desenvolve como encefalopatia rapidamente progressiva, causada por inflamação encefálica. Objetivamos aqui relatar um caso de encefalite do sistema límbico de provável etiologia autoimune para melhor conhecimento da comunidade médica, bem como averiguar métodos diagnósticos deste quadro. Paciente do sexo masculino, 59 anos, admitido em nosso serviço com queixa de confusão mental. O exame clínico evidenciou desorientação, disartria, paresia e parestesia no hemicorpo esquerdo, dificuldade de marcha, desvio de rima e histórico de epilepsia há 2 anos. No estudo por ressonância magnética do crânio, foram observadas extensas lesões que acometiam a região mesial do lobo temporal direito, todo o hipocampo e giro para-hipocampal direito, estendendo-se pelo fórnix até a porção posterior do hipocampo esquerdo, substância branca do lobo frontal bilateral. Mediante os resultados da investigação complementar, o paciente foi tratado com pulsoterapia de metilpredinisolona por 5 dias, resultando na regressão parcial dos sintomas. Atualmente, o paciente se encontra em seguimento ambulatorial para acompanhamento. A encefalite límbica é uma doença rara, porém muito importante de ser investigada e diagnosticada precocemente, uma vez que a progressão da doença pode causar incapacidade e sequelas irreversíveis.

Limbic encephalitis has been described as a rare neurological disorder affecting the limbic system structures selectively. Clinically, it is characterized as a debilitating neurological syndrome that develops as a quickly progressive encephalopathy caused by brain inflammation. This paper reports a case of limbic encephalitis, probably of autoimmune etiology, aiming to improve the knowledge of the medical community, and to promote a debate on diagnosis methods for this pathology. The patient is male, 59 years old, and was admitted at our service complaining of mental confusion. The clinical examination showed disorientation, dysarthria, left hemiparesis and paresthesia, gait difficulties, light asymmetrical smile, and history of epilepsy 2 years ago. The magnetic resonance imaging of skull showed extensive lesions affecting the mesial region of the right temporal lobe, the entire hippocampus, and right parahippocampal gyrus, extending through the fornix to the posterior portion of the left hippocampus, white matter of bilateral frontal lobe. Based on the complementary investigation results, the patient was treated with intravenous methylprednisolone for five days. Currently, he is being followed in the outpatient's department. Although being rare, limbic encephalitis shall be investigated and diagnosed early because its progression can lead to disability and irreversible sequelae

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.

Limbic Encephalitis Associated with Human Herpesvirus-7 (HHV-7) in an Immunocompetent Adult: The First Reported Case in Japan.

A 35-year-old male who had not previously suffered any major illnesses was admitted to our hospital because of general fatigue, fever, headache, vomiting, consciousness disturbance, and seizures. A neurological examination showed that he was in a semi-comatose state and exhibited neck stiffness. Brain magnetic resonance imaging detected high-intensity areas in the bilateral hippocampi and periventricular white matter. A cerebrospinal fluid examination revealed mononuclear pleocytosis, an elevated protein level, and positivity for human herpesvirus-7 (HHV-7) DNA. The patient's condition improved after the administration of methylprednisolone, intravenous immunoglobulins, and acyclovir. This is the first known case of limbic encephalitis associated with HHV-7 in an immunocompetent Japanese adult.

Roseolovirus-associated encephalitis in immunocompetent and immunocompromised individuals.

The roseoloviruses, human herpesvirus (HHV)-6A, HHV-6B, and HHV-7, can cause severe encephalitis or encephalopathy. In immunocompetent children, primary HHV-6B infection is occasionally accompanied by diverse clinical forms of encephalitis. Roseolovirus coinfections with heterologous viruses and delayed primary HHV-7 infection in immunocompetent adults result in very severe neurological and generalized symptoms. Recovery from neurological sequelae is slow and sometimes incomplete. In immunocompromised patients with underlying hematological malignancies and transplantation, frequent single or simultaneous reactivation of roseoloviruses elicit severe, lethal organ dysfunctions, including damages in the limbic system, brain stem, and hippocampus. Most cases have been due to HHV-6B with HHV-6A accounting for 2-3%. The most severe manifestation of HHV-6B reactivation is post-transplantation limbic encephalitis. Seizures, cognitive problems, and abnormal EEG are common. Major risk factors for HHV-6B-associated encephalitis include unrelated cord blood cell transplantation and repeated hematopoietic stem cell transplantation. Rare genetic disorders, male gender, certain HLA constellation, and immune tolerance to replicating HHV-6 in persons carrying chromosomally integrated HHV-6 might also predispose an individual to roseolovirus-associated brain damage. At this time, little is known about the risk factors for HHV-7-associated encephalitis. Intrathecal glial cell destruction due to virus replication, overexpression of proinflammatory cytokines, and viral mimicry of chemokines all contribute to brain dysfunction. High virus load in the cerebrospinal fluid, hippocampal astrogliosis, and viral protein expression in HHV-6B-associated cases and multiple microscopic neuronal degeneration in HHV-7-associated cases are typical laboratory findings. Early empirical therapy with ganciclovir or foscarnet might save the life of a patient with roseolovirus-associated encephalitis.

Non-paraneoplastic limbic encephalitis and central nervous HHV-6B reactivation: Causality or coincidence?

Autoantibody-related encephalopathies represent an important differential diagnosis in adult onset epilepsy. Here, we report the case of a 25-year-old patient with new-onset epilepsy and psychotic syndrome, who underwent biopsy resection for etiological classification. MRI analysis and neuropathological examination showed a T-lymphocytic dominated encephalitis with involvement of the limbic system. An indirect immunohistochemistry approach identified autoantibodies against glutamic acid decarboxylase (GAD) in cerebral spinal fluid and serum, which were confirmed by affinity purification / mass spectrometry analysis. Further examinations revealed evidence of chromosomally integrated human herpes virus type 6B (HHV-6B). However, astrocytic expression of HHV-6 lytic protein was detected by double immunofluorescence analysis. The cerebral expression of HHV-6 antigen, a clinical improvement under antiviral therapy as well as an initial finding of HHV-6 IgM antibodies strongly argue for an additional active HHV-6B infection. Review of the literature reveals singular reports of patients with GAD antibody-positive limbic encephalitis and central nervous system infections with HHV-6B. Since herpes simplex virus encephalitis has been recently reported as a trigger of N-methyl-D-aspartate receptor antibody encephalitis, it is tempting to speculate that HHV-6B infections may trigger a non-paraneoplastic form of limbic encephalitis in a parallel cascade.

Epileptic encephalopathy after HHV6 post-transplant acute limbic encephalitis in children: confirmation of a new epilepsy syndrome.

Generalised epilepsy and cognitive deterioration were recently described in three children following human herpesvirus 6 (HHV6)-associated post-transplant acute limbic encephalitis (PALE). Magnetic resonance imaging (MRI) showed bilateral signal change and/or atrophy in the medial temporal structures and there was no evidence of an ongoing viral or immune-mediated process. We report another child who developed this condition after cord blood transplantation for congenital neutropenia at the age of three. He presented with epileptic spasms four months after HHV6-associated PALE. Cognitive regression, prominent electroencephalographic abnormalities and different types of generalised seizures ensued during the following months and proved refractory to antiepileptic and immunomodulating treatment, which included steroids, immunoglobulin and rituximab. MRI was normal at onset of epilepsy but subsequently showed the development of right hippocampal sclerosis. Results from serial blood and cerebrospinal fluid (CSF) analyses were inconclusive, including lack of patient's CSF and serum reactivity with cultures of dissociated rat hippocampal neurons. This report confirms the existence of a new epilepsy syndrome featuring generalised seizures and epileptic encephalopathy after HHV6-associated PALE in children. Presentation with epileptic spasms, lack of CSF and serum reactivity with cultured rat hippocampal neurons, and rituximab inefficacy are novel features that contribute to delineate the syndrome and argue against an immune-mediated basis of this condition.

Severe hyponatremia caused by syndrome of inappropriate secretion of antidiuretic hormone developed as initial manifestation of human herpesvirus-6-associated acute limbic encephalitis after unrelated bone marrow transplantation.

Severe hyponatremia is a critical electrolyte abnormality in allogeneic stem cell transplantation (allo-SCT) recipients and >50% of cases of severe hyponatremia are caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here, we present a patient with rapidly progressive severe hyponatremia as an initial sign and symptom of human herpesvirus-6-associated post-transplantation acute limbic encephalitis (HHV-6 PALE) after allo-SCT. A 45-year-old woman with acute lymphoblastic leukemia received unrelated bone marrow transplantation from a one locus-mismatched donor at the DR locus. On day 21, she developed a generalized seizure and loss of consciousness with severe hyponatremia, elevated serum antidiuretic hormone (ADH), and decreased serum osmolality. A high titer of HHV-6 DNA was detected in cerebrospinal fluid. Treatment with foscarnet sodium and hypertonic saline was started with improvement of neurological condition within several days. Although an elevated serum ADH, low serum osmolality, and high urinary osmolality persisted for 2 months, she had no other recurrent symptoms of encephalitis. Our experience suggests that hyponatremia accompanied by SIADH should be recognized as a prodromal or concomitant manifestation of HHV-6 PALE, and close monitoring of serum sodium levels in high-risk patients for HHV-6 PALE is necessary for immediate diagnosis and treatment initiation.

Sequential FDG PET and MRI findings in a case of human herpes virus 6 limbic encephalitis.

A 50-year-old woman developed a human herpes virus 6 limbic encephalitis characterized by memory loss and somnolence, 3 weeks after a cord blood-derived stem cell transplantation. Sequential scalp electroencephalogram failed to detect seizure activity. Cerebrospinal fluid polymerase chain reaction assay demonstrated human herpes virus 6 deoxyribonucleic acid (positive, 3.74 log). Acute phase FDG PET imaging showed bilateral intense FDG uptake in both hippocampi and amygdalae. After antiviral treatment (gancyclovir followed by foscarnet), neurologic symptoms disappear gradually. Late phase FDG PET imaging showed a regression in FDG uptake representing hippocampal hypometabolism because of hippocampal sclerosis.

Cord-blood hematopoietic stem cell transplant confers an increased risk for human herpesvirus-6-associated acute limbic encephalitis: a cohort analysis.

Human herpesvirus-6 (HHV-6) frequently reactivates after allogeneic hematopoietic stem cell transplantation (HSCT); its most severe manifestation is the syndrome of posttransplantation acute limbic encephalitis (HHV-6-PALE). The epidemiology, risk factors, and characteristics of HHV-6-PALE after unrelated cord-blood transplantation (UCBT) are not well characterized. We analyzed 1344 patients undergoing allogeneic HSCT between March 2003 and March 2010 to identify risk factors and characteristics of HHV-6-PALE. The cohort included 1243 adult-donor HSCT and 101 UCBT recipients. All patients diagnosed with HHV-6-PALE had HHV-6 DNA in cerebrospinal fluid (CSF) specimens in addition to symptoms and studies indicating limbic encephalitis. Nineteen cases (1.4%) of HHV-6-PALE were identified during this study: 10 after UCBT (9.9%) and 9 after adult-donor HSCT (0.7%), for an incidence rate of 1.2 cases/1000 patient-days compared to 0.08 cases/1000 patient-days (P < .001), respectively. Risk factors for HHV-6-PALE on multivariable Cox modeling were UCBT (adjusted hazard ratio [aHR], 20.0; 95% confidence interval [CI], 7.3-55.0; P < .001), time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (aHR, 7.5; 95% CI, 2.8-19.8; P < .001), and adult-mismatched donor (aHR, 4.3; 95% CI, 1.1-17.3; P = .04). Death from HHV-6-PALE occurred in 50% of affected patients undergoing UCBT and no recipients of adult-donor cells. Patients receiving UCBT have increased risk for HHV-6-PALE and greater morbidity from this disease.

[Acute human herpesvirus 6 (HHV-6) infections: when and how to treat?]. / Infections aiguës à herpèsvirus humain 6 (HHV-6) : quand et comment traiter ?

The pathogenicity of human herpesvirus 6 (HHV-6) still raises numerous questions. Acute HHV-6 infections correspond to primary infections, reactivations or exogenous reinfections. The expression of related clinical symptoms is highly variable but may be extremely severe, particularly among immunocompromised patients. The prototypic severe disease associated with these infections is limbic encephalitis occurring in stem cell transplant recipients. The diagnosis of acute HHV-6 infections relies on the quantitation of viral load in whole blood by means of quantitative PCR. The demonstration of HHV-6 causative role in the genesis of clinical symptoms requires additional investigations such as the search for HHV-6 DNA in cerebrospinal fluid in case of encephalitis. The chromosomal integration of HHV-6 DNA is a rare event among HHV-6-infected subjects but may alter the interpretation of virological results. Therapy with ganciclovir, foscarnet or cidofovir has not yet clear indications but, at the current stage of knowledge, only concerns the treatment of highly symptomatic infections. The usefulness of prophylactic or pre-emptive antiviral chemotherapy has not yet been convincingly demonstrated. Treatment efficacy must be checked through a clinical and virological follow up, based in part on quantitative PCR approaches. Controlled studies are urgently needed with the goal of evaluating the cost-effectiveness of HHV-6 follow up and therapy in different clinical situations.

Detection of DNA of six human herpesviruses in the cerebrospinal fluid of immunocompetent non-herpetic acute limbic encephalitis patients.

In order to determine whether six other human herpesviruses, aside from herpes simplex virus, are associated with non-herpetic acute limbic encephalitis in immunocompetent individuals, real-time PCR was used to detect the DNA of herpesviruses in CSF collected from 61 patients with this form of encephalitis. Five of the human herpesviruses tested were not detected in any of the 61 CSF samples. EBV DNA was detected in one CSF sample. The EBV DNA-positive patient was a 36-year-old woman who presented with fever, headache, mild somnolence, and the typical neuroimaging findings.

[Limbic encephalitis caused by herpes simplex virus infection after vaccination against the influenza virus].

Various causative factors, including viral infection, autoimmunity, and paraneoplasia, are considered to be involved in the pathomechanism of limbic encephalitis. We encountered a patient who developed limbic encephalitis after vaccination against the influenza virus. In Japan, an influenza epidemic occurs every winter, and vaccination against the influenza virus is recommended. However, there have been reports of serious side effects such as the development of Guillain-Barré syndrome and acute disseminated encephalomyelitis after influenza vaccination; these findings indicate the activation of an autoimmune pathomechanism after vaccination. Here, we discuss the relationship between limbic encephalitis and influenza vaccination from the perspective of viral infection and autoimmunity. We considered that limbic encephalitis was caused by the herpes simplex virus, and hypothesized that this clinical condition rarely develops as a sole consequence of influenza vaccination but rather develops because of the activation of an autoimmune pathomechanism after vaccination.