ABSTRACT
Rasmussen's encephalitis (RE) stands as a rare neurological disorder marked by progressive cerebral hemiatrophy and epilepsy resistant to medical treatment. Despite extensive study, the primary cause of RE remains elusive, while its histopathological features encompass cortical inflammation, neuronal degeneration, and gliosis. The underlying molecular mechanisms driving disease progression remain largely unexplored. In this case study, we present a patient with RE who underwent hemispherotomy and has remained seizure-free for over six months, experiencing gradual motor improvement. Furthermore, we conducted molecular analysis on the excised brain tissue, unveiling a decrease in the expression of cell-cycle-associated genes coupled with elevated levels of BDNF and TNF-α proteins. These findings suggest the potential involvement of cell cycle regulators in the progression of RE.
Subject(s)
Encephalitis , Humans , Encephalitis/genetics , Encephalitis/pathology , Encephalitis/metabolism , Male , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Brain/pathology , Brain/metabolism , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Cerebral Cortex/pathology , Cerebral Cortex/metabolism , Female , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/genetics , Cell Cycle/geneticsSubject(s)
Caloric Restriction , Animals , Mice , Darkness , Encephalitis/etiology , Encephalitis/immunology , Encephalitis/pathology , Brain/pathology , HumansABSTRACT
BACKGROUND: Antibodies against leucine-rich glioma inactivated protein 1 (LGI1) constitute a common form of autoimmune encephalitis. On MR imaging, it may show T2 FLAIR hyperintensities of the medial temporal lobe (T2 FLAIR-MTL), involve the basal ganglia, or be unremarkable. PURPOSE: We performed a systematic review and meta-analysis to obtain prevalence estimates of abnormal findings on MR imaging in anti-LGI1 encephalitis. A human brain map of the LGI1 microarray gene expression was derived from the Allen Human Brain Atlas. DATA SOURCES: PubMed and Web of Science were searched with the terms "LGI1" and "encephalitis" from inception to April 7, 2022. STUDY SELECTION: Thirty-one research publications, encompassing case series and retrospective cohort and case-control studies, with >10 patients with anti-LGI1 encephalitis and MR imaging data were included. DATA ANALYSIS: Pooled prevalence estimates were calculated using Freeman-Tukey double-arcsine transformation. Meta-analysis used DerSimonian and Laird random effects models. DATA SYNTHESIS: Of 1318 patients in 30 studies, T2 FLAIR-MTL hyperintensities were present in 54% (95% CI, 0.48-0.60; I2 = 76%). Of 394 patients in 13 studies, 27% showed bilateral (95% CI, 0.19-0.36; I2 = 71%) and 24% unilateral T2 FLAIR-MTL abnormalities (95% CI, 0.17-0.32; I2 = 61%). Of 612 patients in 15 studies, basal ganglia abnormalities were present in 10% (95% CI, 0.06-0.15; I2 = 67%). LGI1 expression was highest in the amygdala, hippocampus, and caudate nucleus. LIMITATIONS: Only part of the spectrum of MR imaging abnormalities in anti-LGI1 encephalitis could be included in a meta-analysis. MR imaging findings were not the main outcomes in most studies, limiting available information. I2 values ranged from 62% to 76%, representing moderate-to-large heterogeneity. CONCLUSIONS: T2 FLAIR-MTL hyperintensities were present in around one-half of patients with anti-LGI1. The prevalence of unilateral and bilateral presentations was similar, suggesting unilaterality should raise the suspicion of this disease in the appropriate clinical context. Around 10% of patients showed basal ganglia abnormalities, indicating that special attention should be given to this region. LGI1 regional expression coincided with the most frequently reported abnormal findings on MR imaging. Regional specificity might be partially determined by expression levels of the target protein.
Subject(s)
Autoantibodies , Encephalitis , Magnetic Resonance Imaging , Humans , Magnetic Resonance Imaging/methods , Encephalitis/diagnostic imaging , Encephalitis/immunology , Encephalitis/pathology , Autoantibodies/immunology , Intracellular Signaling Peptides and Proteins/immunology , Intracellular Signaling Peptides and Proteins/metabolismSubject(s)
Brain Stem , Encephalitis , Immunoglobulin G , Magnetic Resonance Imaging , Myelin-Oligodendrocyte Glycoprotein , Humans , Myelin-Oligodendrocyte Glycoprotein/immunology , Brain Stem/diagnostic imaging , Brain Stem/pathology , Encephalitis/diagnostic imaging , Encephalitis/immunology , Encephalitis/pathology , Female , Autoantibodies/immunology , Male , AdultABSTRACT
BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear inclusion disease (NIID) belong to polyglycine diseases and present similar clinical, radiological, and pathological features, making it difficult to distinguish these diseases. Reversible encephalitis-like attacks are often observed in NIID. It is unclear whether they are presented in FXTAS and can be used for differential diagnosis of NIID and FXTAS. CASE PRESENTATION: A 63-year-old Chinese male with late-onset gait disturbance, cognitive decline, and reversible attacks of fever, consciousness impairment, dizziness, vomiting, and urinary incontinence underwent neurological assessment and examinations, including laboratory tests, electroencephalogram test, imaging, skin biopsy, and genetic test. Brain MRI showed T2 hyperintensities in middle cerebellar peduncle and cerebrum, in addition to cerebellar atrophy and DWI hyperintensities along the corticomedullary junction. Lesions in the brainstem were observed. Skin biopsy showed p62-positive intranuclear inclusions. The possibilities of hypoglycemia, lactic acidosis, epileptic seizures, and cerebrovascular attacks were excluded. Genetic analysis revealed CGG repeat expansion in FMR1 gene, and the number of repeats was 111. The patient was finally diagnosed as FXTAS. He received supportive treatment as well as symptomatic treatment during hospitalization. His encephalitic symptoms were completely relieved within one week. CONCLUSIONS: This is a detailed report of a case of FXTAS with reversible encephalitis-like episodes. This report provides new information for the possible and rare features of FXTAS, highlighting that encephalitis-like episodes are common in polyglycine diseases and unable to be used for differential diagnosis.
Subject(s)
Ataxia , Encephalitis , Fragile X Syndrome , Tremor , Humans , Ataxia/diagnosis , Ataxia/genetics , Diagnosis, Differential , Encephalitis/diagnosis , Encephalitis/complications , Encephalitis/genetics , Encephalitis/pathology , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Fragile X Syndrome/diagnosis , Fragile X Syndrome/complications , Intranuclear Inclusion Bodies/pathology , Neurodegenerative Diseases/diagnosis , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/complications , Tremor/diagnosis , Tremor/genetics , Tremor/etiologyABSTRACT
INTRODUCTION: Primary central nervous system lymphoma (PCNSL) presents a diagnostic enigma due to the inherent absence of lymphoid tissue in the central nervous system (CNS). The hypothesis posits that lymphocytes infiltrating the CNS during inflammatory responses could represent a cellular source for PCNSL, challenging traditional understandings of its etiology. PATIENT CONCERNS: In 2 illustrative cases, patients presented with neurological symptoms initially misdiagnosed as encephalitis and demyelinating disease, respectively. These diagnoses were established based on clinical assessments and initial biopsy findings. DIAGNOSIS: Subsequent biopsies, conducted months after the first signs of disease, confirmed the diagnosis of PCNSL in both patients. Identifying CD20-positive tumor cells was pivotal, indicating a B-cell lymphoma origin. INTERVENTIONS: Treatment strategies included high-dose methotrexate chemotherapy for both patients. In addition, the second patient underwent adjuvant whole-brain radiotherapy after the chemotherapy regimen. OUTCOMES: The therapeutic approach significantly reduced tumor size in both cases, with no evidence of recurrence observed during the follow-up period. This outcome underscores the potential efficacy of the chosen interventions. CONCLUSION: In response to inflammatory lesions, lymphocyte infiltration into the CNS may serve as a pivotal origin for tumor cells in PCNSL. These cases highlight the complexity of diagnosing CNS disorders and suggest that various forms of encephalitis in the early stages could influence the prognosis of lymphoma. This insight into the cellular origins and treatment responses of PCNSL contributes to a broader understanding of its pathophysiology and management.
Subject(s)
Central Nervous System Neoplasms , Methotrexate , Humans , Male , Middle Aged , Biopsy , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/diagnosis , Diagnosis, Differential , Encephalitis/pathology , Encephalitis/diagnosis , Lymphoma, B-Cell/pathology , Lymphoma, B-Cell/diagnosis , Magnetic Resonance Imaging , Methotrexate/therapeutic useABSTRACT
The first reports of encephalitis associated with cancer date to the 1960s and were characterized by clinical and pathologic involvement of limbic areas. This specific association was called limbic encephalitis (LE). The subsequent discovery of several "onconeural" antibodies (Abs), i.e., Abs targeting an antigen shared by neurons and tumor cells, supported the hypothesis of an autoimmune paraneoplastic etiology of LE and other forms of rapidly progressive encephalopathy. Over the past 20 years, similar clinical pictures with different clinical courses have been described in association with novel Abs-binding neuronal membrane proteins and proved to be pathogenic. The most well-known encephalitis in this group was described in 2007 as an association of a complex neuro-psychiatric syndrome, N-methyl-d-aspartate (NMDA) receptor-Abs, and ovarian teratoma in young women. Later on, nonparaneoplastic cases of NMDA receptor encephalitis were also described. Since then, the historical concept of LE and Ab associated encephalitis has changed. Some of these occur in fact more commonly in the absence of a malignancy (e.g., anti-LG1 Abs). Lastly, seronegative cases were also described. The term paraneoplastic encephalitis nowadays encompasses different syndromes that may be triggered by occult tumors.
Subject(s)
Encephalitis , Limbic Encephalitis , Humans , Female , Encephalitis/etiology , Encephalitis/pathology , Limbic Encephalitis/etiology , Autoantibodies , Receptors, N-Methyl-D-AspartateABSTRACT
PURPOSE: Rasmussen encephalitis (RE) is a very rare chronic neurological disorder of unilateral inflammation of the cerebral cortex. Hemispherotomy provides the best chance at achieving seizure freedom in RE patients, but with significant risks and variable long-term outcomes. The goal of this study is to utilize our multicenter pediatric cohort to characterize if differences in pathology and/or imaging characterization of RE may provide a window into post-operative seizure outcomes, which in turn could guide decision-making for parents and healthcare providers. METHODS: This multi-institutional retrospective review of medical record, imaging, and pathology samples was approved by each individual institution's review board. Data was collected from all known pediatric cases of peri-insular functional hemispherotomy from the earliest available electronic medical records. Mean follow-up time was 4.9 years. Clinical outcomes were measured by last follow-up visit using both Engel and ILAE scoring systems. Relationships between categorical and continuous variables were analyzed with Pearson correlation values. RESULTS: Twenty-seven patients met study criteria. No statistically significant correlations existed between patient imaging and pathology data. Pathology stage, MRI brain imaging stages, and a combined assessment of pathology and imaging stages showed no statistically significant correlation to post-operative seizure freedom rates. Hemispherectomy Outcome Prediction Scale scoring demonstrated seizure freedom in only 71% of patients receiving a score of 1 and 36% of patients receiving a score of 2 which were substantially lower than predicted. CONCLUSIONS: Our analysis did not find evidence for either independent or combined analysis of imaging and pathology staging being predictive for post peri-insular hemispherotomy seizure outcomes, prompting the need for other biomarkers to be explored. Our data stands in contrast to the recently proposed Hemispherectomy Outcome Prediction Scale and does not externally validate this metric for an RE cohort.
Subject(s)
Encephalitis , Hemispherectomy , Magnetic Resonance Imaging , Humans , Hemispherectomy/methods , Female , Male , Magnetic Resonance Imaging/methods , Encephalitis/surgery , Encephalitis/diagnostic imaging , Encephalitis/pathology , Child, Preschool , Child , Retrospective Studies , Infant , Treatment Outcome , AdolescentABSTRACT
We have recently characterized experimental autoimmune encephalomyelitis (EAE) induced in DA rats with spinal cord homogenate without complete Freund's adjuvant (CFA). The main advantage of this multiple sclerosis model is the lack of CFA-related confounding effects which represent the major obstacles in translating findings from EAE to multiple sclerosis. Here, antigen specificity of the cellular and humoral immune response directed against the central nervous system was explored. The reactivity of T and B cells to myelin basic protein, myelin oligodendrocyte glycoprotein, and ß-synuclein was detected. Having in mind that reactivity against ß-synuclein was previously associated with autoimmunity against the brain, the infiltration of immune cells into different brain compartments, i.e. pons, cerebellum, hippocampus, and cortex was determined. T cell infiltration was observed in all structures examined. This finding stimulated investigation of the effects of immunization on DA rat behavior using the elevated plus maze and the open field test. Rats recovered from EAE displayed increased anxiety-like behavior. These data support CFA-free EAE in DA rats as a useful model for multiple sclerosis research.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Spinal Cord , Animals , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Rats , Spinal Cord/immunology , Spinal Cord/metabolism , Spinal Cord/pathology , Disease Models, Animal , Myelin-Oligodendrocyte Glycoprotein/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Multiple Sclerosis/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Myelin Basic Protein/immunology , Myelin Basic Protein/metabolism , Brain/pathology , Brain/immunology , Brain/metabolism , Female , Encephalitis/immunology , Encephalitis/etiology , Encephalitis/pathology , Encephalitis/metabolism , Freund's Adjuvant/immunology , Neuroinflammatory Diseases/immunology , Neuroinflammatory Diseases/etiology , Neuroinflammatory Diseases/pathologyABSTRACT
Importance: Rapid and accurate diagnosis of autoimmune encephalitis encourages prompt initiation of immunotherapy toward improved patient outcomes. However, clinical features alone may not sufficiently narrow the differential diagnosis, and awaiting autoantibody results can delay immunotherapy. Objective: To identify simple magnetic resonance imaging (MRI) characteristics that accurately distinguish 2 common forms of autoimmune encephalitis, LGI1- and CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E), from 2 major differential diagnoses, viral encephalitis (VE) and Creutzfeldt-Jakob disease (CJD). Design, Setting, and Participants: This cross-sectional study involved a retrospective, blinded analysis of the first available brain MRIs (taken 2000-2022) from 192 patients at Oxford University Hospitals in the UK and Mayo Clinic in the US. These patients had LGI1/CASPR2-Ab-E, VE, or CJD as evaluated by 2 neuroradiologists (discovery cohort; n = 87); findings were validated in an independent cohort by 3 neurologists (n = 105). Groups were statistically compared with contingency tables. Data were analyzed in 2023. Main Outcomes and Measures: MRI findings including T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities, swelling or volume loss, presence of gadolinium contrast enhancement, and diffusion-weighted imaging changes. Correlations with clinical features. Results: Among 192 participants with MRIs reviewed, 71 were female (37%) and 121 were male (63%); the median age was 66 years (range, 19-92 years). By comparison with VE and CJD, in LGI1/CASPR2-Ab-E, T2 and/or FLAIR hyperintensities were less likely to extend outside the temporal lobe (3/42 patients [7%] vs 17/18 patients [94%] with VE; P < .001, and 3/4 patients [75%] with CJD; P = .005), less frequently exhibited swelling (12/55 [22%] with LGI1/CASPR2-Ab-E vs 13/22 [59%] with VE; P = .003), and showed no diffusion restriction (0 patients vs 16/22 [73%] with VE and 8/10 [80%] with CJD; both P < .001) and rare contrast enhancement (1/20 [5%] vs 7/17 [41%] with VE; P = .01). These findings were validated in an independent cohort and generated an area under the curve of 0.97, sensitivity of 90%, and specificity of 95% among cases with T2/FLAIR hyperintensity in the hippocampus and/or amygdala. Conclusions and Relevance: In this study, T2 and/or FLAIR hyperintensities confined to the temporal lobes, without diffusion restriction or contrast enhancement, robustly distinguished LGI1/CASPR2-Ab-E from key differential diagnoses. These observations should assist clinical decision-making toward expediting immunotherapy. Their generalizability to other forms of autoimmune encephalitis and VE should be examined in future studies.
Subject(s)
Autoantibodies , Encephalitis , Intracellular Signaling Peptides and Proteins , Magnetic Resonance Imaging , Membrane Proteins , Nerve Tissue Proteins , Humans , Male , Female , Aged , Intracellular Signaling Peptides and Proteins/immunology , Middle Aged , Magnetic Resonance Imaging/methods , Cross-Sectional Studies , Autoantibodies/immunology , Encephalitis/diagnostic imaging , Encephalitis/immunology , Encephalitis/pathology , Retrospective Studies , Nerve Tissue Proteins/immunology , Membrane Proteins/immunology , Adult , Aged, 80 and over , Creutzfeldt-Jakob Syndrome/diagnostic imaging , Creutzfeldt-Jakob Syndrome/immunology , Creutzfeldt-Jakob Syndrome/pathology , Diagnosis, Differential , Brain/diagnostic imaging , Brain/pathology , Hashimoto Disease/diagnostic imaging , Hashimoto Disease/immunology , Young AdultABSTRACT
OBJECTIVES: Neuronal intranuclear inclusion disease (NIID) exhibited significant clinical heterogeneities. However, the clinical features, radiographic changes, and prognosis of patients with encephalitis-like NIID have yet to be systematically elucidated. METHODS: Clinical data including medical history, physical examination, and laboratory examinations were collected and analyzed. Skin and sural nerve biopsies were conducted on the patient. Repeat-primed PCR (RP-PCR) and fluorescence amplicon length PCR (AL-PCR) were used to detect the expansion of CGG repeat. We also reviewed the clinical and genetic data of NIID patients with cortical enhancement. RESULTS: A 54-year-old woman presented with encephalitis-like NIID, characterized by severe headache and agitative psychiatric symptoms. The brain MRI showed cortical swelling in the temporo-occipital lobes and significant enhancement of the cortical surface and dura, but without hyperintensities along the corticomedullary junction on diffusion-weighted image (DWI). A biopsy of the sural nerve revealed a demyelinating pathological change. The intranuclear inclusions were detected in nerve and skin tissues using the p62 antibody and electron microscopy. RP-PCR and AL-PCR unveiled the pathogenic expansion of CGG repeats in the NOTCH2NLC gene. A review of the literature indicated that nine out of the 16 patients with cortical lesions and linear enhancement exhibited encephalitis-like NIID. CONCLUSION: This study indicated that patients with encephalitis-like NIID typically exhibited headache and excitatory psychiatric symptoms, often accompanied by cortical edema and enhancement of posterior lobes, and responded well to glucocorticoid treatment. Furthermore, some patients may not exhibit hyperintensities along the corticomedullary junction on DWI, potentially leading to misdiagnosis.
Subject(s)
Encephalitis , Intranuclear Inclusion Bodies , Neurodegenerative Diseases , Humans , Female , Middle Aged , Intranuclear Inclusion Bodies/pathology , Neurodegenerative Diseases/pathology , Neurodegenerative Diseases/complications , Neurodegenerative Diseases/diagnostic imaging , Neurodegenerative Diseases/genetics , Encephalitis/pathology , Encephalitis/diagnostic imaging , Encephalitis/complications , Brain Edema/diagnostic imaging , Brain Edema/pathologyABSTRACT
INTRODUCTION: Balamuthia amoebic encephalitis (BAE), caused by Balamuthia mandrillaris, is a rare and life-threatening infectious disease with no specific and effective treatments available. The diagnosis of BAE at an early stage is difficult because of the non-specific clinical manifestations and neuroimaging. CASE DESCRIPTION: A 52-year-old male patient, who had no previous history of skin lesions, presented to the emergency department with an acute headache, walking difficulties, and disturbance of consciousness. The patient underwent a series of examinations, including regular cerebrospinal fluid (CSF) studies and magnetic resonance imaging, and tuberculous meningoencephalitis was suspected. Despite being treated with anti-TB drugs, no clinical improvement was observed in the patient. Following corticosteroid therapy, the patient developed a rapid deterioration in consciousness with dilated pupils. Metagenomic next-generation sequencing (mNGS) revealed an unexpected central nervous system (CNS) amoebic infection, and the patient died soon after the confirmed diagnosis. CONCLUSION: This study highlights the application of mNGS for the diagnosis of patients with suspected encephalitis or meningitis, especially those caused by rare opportunistic infections.
Subject(s)
Amebiasis , Balamuthia mandrillaris , Central Nervous System Protozoal Infections , Encephalitis , Infectious Encephalitis , Male , Humans , Middle Aged , Infectious Encephalitis/diagnosis , Encephalitis/diagnosis , Encephalitis/pathology , Balamuthia mandrillaris/genetics , Central Nervous System Protozoal Infections/diagnosis , Amebiasis/diagnosis , High-Throughput Nucleotide SequencingABSTRACT
The activities of HIV-1 in the central nervous system (CNS) are responsible for a dysregulated neuroinflammatory response and the subsequent development of HIV-associated neurocognitive disorders (HAND). The use of post-mortem human brain tissue is pivotal for studying the neuroimmune mechanisms of CNS HIV infection. To date, numerous studies have investigated HIV-1-induced neuroinflammation in post-mortem brain tissue. However, from the commonly investigated studies in this line of research, it is not clear which neuroinflammatory markers are consistently associated with HIV neurocognitive impairment (NCI) and neuropathology (i.e., HIV-encephalitis, HIVE). Therefore, we conducted a systematic review of the association between neuroinflammation and NCI/HIVE from studies investigating post-mortem brain tissue. Our aim was to synthesise the published data to date to provide commentary on the most noteworthy markers that are associated with NCI/HIVE. PubMed, Scopus, and Web of Science databases were searched using a search protocol designed specifically for this study. Sixty-one studies were included that investigated the levels of inflammatory markers based on their gene and protein expression in association with NCI/HIVE. The findings revealed that the (1) transcript expressions of IL-1ß and TNF-α were consistently associated with NCI/HIVE, whereas CCL2 and IL-6 were commonly not associated with NCI/HIVE, (2) protein expressions of CD14, CD16, CD68, Iba-1, IL-1ß and TNF-α were consistently associated with NCI/HIVE, while CD45, GFAP, HLA-DR, IL-1 and IL-6 were commonly not associated with NCI/HIVE, and (3) gene and protein expressions of CNS IL-1ß and TNF-α were consistently associated with NCI/HIVE, while IL-6 was consistently not associated with NCI/HIVE. These markers highlight the commonly investigated markers in this line of research and elucidates the neuroinflammatory mechanisms in the HIV-1 brain that are involved in the pathophysiology of NCI/HIVE. These markers and related pathways should be investigated for the development of improved diagnostics, prognostics, and therapeutics of HAND.
Subject(s)
Encephalitis , HIV Infections , HIV Seropositivity , HIV-1 , Humans , HIV Infections/metabolism , Neuroinflammatory Diseases , Tumor Necrosis Factor-alpha , Interleukin-6/metabolism , Brain/pathology , Encephalitis/complications , Encephalitis/metabolism , Encephalitis/pathology , HIV Seropositivity/complications , HIV Seropositivity/metabolism , HIV Seropositivity/pathologyABSTRACT
OBJECTIVE: The underlying pathology of autoimmune encephalitis is not well characterized due to the limited opportunities to study tissue specimens. Autopsy specimens available at prion surveillance centers from patients with suspected Creutzfeldt-Jakob disease offer a unique opportunity to study the pathology of autoimmune encephalitis. Our objective was to describe pathological findings of autoimmune encephalitis specimens submitted to the U.S. National Prion Disease Pathology Surveillance Center. METHODS: Pathology reports were obtained from the National Prion Center. Specimens negative for prion disease were screened for inflammatory pathology and those suggestive of autoimmune encephalitis were analyzed. Cases identified on autopsy were compared to institutional cases with fatal seronegative autoimmune encephalitis and available brain biopsy. RESULTS: Between 1998 and 2022, 7934 specimens were evaluated of which 2998 (38%) were negative for prion protein. Querying the database for alternative diagnoses of encephalitis/encephalopathy yielded 43 cases that were screened by an experienced neuropathologist yielding 14 (0.5%) cases consistent with autoimmune encephalitis. Most specimens showed diffuse inflammation involving the limbic system (86%), basal ganglia (86%), cortex (71%), diencephalon (71%), and in some cases the brainstem (43%) and cerebellum (43%). Lymphocytic inflammatory infiltrate was predominantly perivascular with parenchymal extension in 64%. Microglial activation/nodules were seen in 64% of cases. Neuronal loss was present only in 50%. Pathological findings were identical to biopsy specimens from our institutional cohort. DISCUSSION: Seronegative AE may have consistent pathology with diffuse or multifocal perivascular inflammation and microglial activation. Half the patients do not have neuronal loss suggesting a potential for neurological recovery. These findings are preliminary and require further confirmation.
Subject(s)
Autoimmune Diseases of the Nervous System , Creutzfeldt-Jakob Syndrome , Encephalitis , Nervous System Diseases , Prion Diseases , Prions , Humans , Brain/pathology , Creutzfeldt-Jakob Syndrome/diagnosis , Creutzfeldt-Jakob Syndrome/pathology , Encephalitis/pathology , Prions/metabolism , Nervous System Diseases/pathology , Autoimmune Diseases of the Nervous System/pathology , Autopsy , Inflammation/metabolism , Prion Diseases/metabolism , Prion Diseases/pathologyABSTRACT
Aging, tau pathology, and chronic inflammation in the brain play crucial roles in synaptic loss, neurodegeneration, and cognitive decline in tauopathies, including Alzheimer's disease. Senescent cells accumulate in the aging brain, accelerate the aging process, and promote tauopathy progression through their abnormal inflammatory secretome known as the senescence-associated secretory phenotype (SASP). Tau oligomers (TauO)-the most neurotoxic tau species-are known to induce senescence and the SASP, which subsequently promote neuropathology, inflammation, oxidative stress, synaptic dysfunction, neuronal death, and cognitive dysfunction. TauO, brain inflammation, and senescence are associated with heterogeneity in tauopathy progression and cognitive decline. However, the underlying mechanisms driving the disease heterogeneity remain largely unknown, impeding the development of therapies for tauopathies. Based on clinical and preclinical evidence, this review highlights the critical role of TauO and senescence in neurodegeneration. We discuss key knowledge gaps and potential strategies for targeting senescence and TauO to treat tauopathies. HIGHLIGHTS: Senescence, oligomeric Tau (TauO), and brain inflammation accelerate the aging process and promote the progression of tauopathies, including Alzheimer's disease. We discuss their role in contributing to heterogeneity in tauopathy and cognitive decline. We highlight strategies to target senescence and TauO to treat tauopathies while addressing key knowledge gaps.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Encephalitis , Tauopathies , Humans , Alzheimer Disease/pathology , tau Proteins/metabolism , Tauopathies/pathology , Brain/pathology , Encephalitis/complications , Encephalitis/pathology , Cognitive Dysfunction/pathology , InflammationABSTRACT
BACKGROUND: Bilateral Rasmussen encephalitis is a rare variant of a debilitating, typically unihemispheric disease with limited treatment options. Few cases with bilateral histopathology have been reported, all with poor seizure control following surgery. Here we report a favorable outcome following hemispherotomy in a four-year-old male with biopsy-confirmed bilateral disease. CASE: The patient presented with right hemispheric focal seizures with behavioral arrest and over a year progressed to left lower extremity clonic seizures, epilepsia partialis continua, and loss of ambulation, with transient response to steroids and tacrolimus. Histopathology confirmed bilateral disease. The patient developed super-refractory status epilepticus and underwent right functional hemispherotomy 4.5 years after initial presentation. In a 2.5-year follow-up period, an Engel 1D outcome classification was observed with substantially improved quality of life. CONCLUSION: Previous reports of bilateral Rasmussen encephalitis describe universally poor outcomes, and hemispherotomy is often considered contraindicated. However, hemispherotomy in a patient with bilateral Rasmussen encephalitis may have a good outcome if seizures are unihemispheric.
Subject(s)
Encephalitis , Inflammation , Quality of Life , Male , Humans , Child, Preschool , Encephalitis/pathology , Seizures , Steroids , Treatment Outcome , Magnetic Resonance ImagingABSTRACT
This study investigated a 'de Novo' medicinal herb, Ferula asafetida (FA), against toxoplasma encephalitis either alone or combined with spiramycin (SP). Female Swiss-Webster mice (n = 72) were divided into three batches. Batch-I received no DMS to serve as an immunocompetent control, batch-II was immune-suppressed with the DMS (0.25 mg/g/day) for 14 days pre-infection, whilst batch-III was immune-suppressed with the DMS on the same day of infection. All experimental mice were inoculated with Toxoplasma gondii ME49 cysts (n = 75). Each batch was split into four subgroups: Mono-SP, mono-FA, combined drug (SP + FA), or neither. Therapies were administered on day zero of infection in batches (I and II) and 35 days post-infection in batch (III). Treatments lasted for 14 days, and mice were sacrificed 60 days post-infection. Histopathological changes, cysts load, and CD4 and CD8 T-cells were counted in brain tissues. The cyst-load count in mice receiving SP + FA was significantly (p < .0001) the least compared to the mono treatments in all protocols. Interestingly, the combined therapy demolished the T-cell subsets to zero in immunocompetent and immunocompromised infected mice. In conclusion, F. asafetida might be a powerfully natural, safe vehicle of SP in the digestive system and/or across the brain-blood barrier to control toxoplasmosis even through immunodeficient conditions.
Subject(s)
Encephalitis , Ferula , Spiramycin , Toxoplasma , Toxoplasmosis, Animal , Toxoplasmosis, Cerebral , Female , Mice , Animals , Spiramycin/therapeutic use , Brain , Toxoplasmosis, Animal/drug therapy , Encephalitis/drug therapy , Encephalitis/pathologyABSTRACT
INTRODUCTION: Viral infections are a frequent cause of disseminated non-suppurative encephalitis in dogs. However, using routine diagnostic methods, the specific virus may remain unknown due to extensive or complete viral clearance or because the virus is unexpected or new. A metatranscriptomics-based approach of combining high-throughput sequencing (HTS) and bioinformatics analysis was used to investigate the viral etiology in archival cases of dogs with non-suppurative encephalitis. In formalin-fixed paraffin embedded (FFPE) brain material from the years 1976 to 2021 a high incidence of tick-borne encephalitis virus (TBEV) was detected. Moreover, canine distemper virus (CDV) was identified without typical demyelinating lesions and canine vesivirus (CaVV) was detected as an unexpected virus associated with non-suppurative encephalitis. We demonstrated the viral presence in brain tissues at the sites of inflammation by immunohistochemistry (IHC) and in situ hybridization (ISH). These results highlight the value of emerging sequencing technologies in veterinary diagnostics and expand our knowledge on the etiologies of encephalitis in dogs.
INTRODUCTION: Les infections virales sont une cause fréquente d'encéphalite non suppurée disséminée chez le chien. Cependant, en utilisant les méthodes de diagnostic de routine, le virus spécifique peut rester inconnu en raison d'une clairance virale importante ou complète ou parce que le virus est inattendu ou nouveau. Une approche métatranscriptomique combinant le séquençage à haut débit et l'analyse bioinformatique a été utilisée pour étudier l'étiologie virale dans des cas archivés de chiens atteints d'encéphalite non suppurée. Une incidence élevée du virus de l'encéphalite à tiques (TBEV) a été détectée dans le matériel cérébral fixé au formol et inclus dans la paraffine (FFPE) des années 1976 à 2021. En outre, le virus de la maladie de Carré (CDV) a été identifié sans lésions démyélinisantes typiques et le vésivirus canin (CaVV) a été détecté comme un virus inattendu associé à une encéphalite non suppurative. Nous avons démontré la présence virale dans les tissus cérébraux au niveau des sites d'inflammation par immunohistochimie (IHC) et hybridation in situ (ISH). Ces résultats soulignent la valeur des technologies de séquençage émergentes dans le diagnostic vétérinaire et élargissent nos connaissances sur les étiologies de l'encéphalite chez les chiens.
Subject(s)
Distemper , Dog Diseases , Encephalitis Viruses, Tick-Borne , Encephalitis, Tick-Borne , Encephalitis , Animals , Dogs , Encephalitis Viruses, Tick-Borne/genetics , Switzerland/epidemiology , Incidence , Distemper/epidemiology , Distemper/pathology , Encephalitis/complications , Encephalitis/pathology , Encephalitis/veterinary , Encephalitis, Tick-Borne/diagnosis , Encephalitis, Tick-Borne/epidemiology , Encephalitis, Tick-Borne/veterinary , Dog Diseases/diagnosis , Dog Diseases/epidemiologyABSTRACT
Hypopharyngeal cancer (HPC) has one of the most unfavorable prognoses among head and neck squamous cell carcinomas. Immunotherapy in combination with chemotherapy, the same as conventional induction chemotherapy, has emerged as a vital part of the induction therapy protocol for HPC. Meanwhile, the incidence of immune-related adverse events is increasing. In this light, we present the first reported case of immune-associated encephalitis in a patient with hypopharyngeal cancer treated with Camrelizumab (a PD-1 inhibitor). After receiving immunotherapy combined with chemotherapy as induction therapy, along with concurrent chemoradiotherapy, the patient presented with symptoms of fatigue, tremors, drowsiness, and an abnormal signal in the right temporal lobe as shown on a brain magnetic resonance imaging (MRI). Despite the minor elevation in protein and IgG index observed in the lumbar puncture, there is no evidence of abnormal autoantibodies or evidence of pathogenic infection. Following a thorough multidisciplinary consultation, the patient is suspected to be afflicted with immune-related autoimmune encephalitis. Intravenous methylprednisolone was prescribed as an empirical treatment at an initial dosage of 120 mg/day for 3 days, followed by steroid tapering. Finally, the patient experienced complete neurologic and radiographic (brain MRI) recovery. This case serves as a critical reminder that encephalitis is a potential diagnosis that should never be overlooked in patients undergoing immunotherapy who present with abnormal signs of the brain. The timely diagnosis and initiation of immunosuppressive therapy are key components of treating ICI-associated encephalitis.