Paraneoplastic encephalitis.

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.

Relapsing polychondritis presenting with sero-negative limbic encephalitis.

The presented case highlights a rare instance of relapsing polychondritis (RP) manifesting as seronegative limbic encephalitis, an uncommon neurological complication. A 70-year-old female patient with a history of RP-related inflammation, along with neuropsychiatric symptoms, was diagnosed through multidisciplinary collaboration. Swift administration of steroid therapy, followed by azathioprine, led to remarkable physical and cognitive recovery. This case emphasises the importance of a multidisciplinary approach in diagnosing and treating complex autoimmune disorders with neurological manifestations.

Encefalitis límbica secundaria a neuro-Behçet: una presentación insólita / Limbic encephalitis secondary to neuro-Behçet disease: an uncommon presentation

Introducción: La encefalitis límbica (EL) puede tener un amplio abanico de etiologías, más frecuentemente la infecciosa (sobre todo viral) o autoinmune. La enfermedad de Behçet (EB) puede presentarse con manifestaciones neurológicas heterogéneas. Sin embargo, la EL no se considera una presentación típica del neuro-Behçet (NB). Caso clínico: Un varón de 40 años consultó por cefalea de novo subaguda, problemas de memoria y apatía. La anamnesis por sistemas reveló una historia no conocida previamente de aftas orales recurrentes durante años, fiebre y afectación general reciente, así como un episodio de panuveítis bilateral cuatro meses antes de la presentación. Su exploración general y neurológica reveló febrícula, una afta oral aislada, amnesia anterógrada y signos de vasculitis retiniana bilateral. La resonancia magnética mostró un patrón de afectación de meningoencefalitis límbica y su líquido cefalorraquídeo presentaba inflamación mononuclear. El paciente cumplía los criterios diagnósticos de la EB. Considerando que la EL es una presentación muy rara del NB, se buscaron exhaustivamente y se excluyeron otras etiologías alternativas, incluyendo las encefalitis infecciosas, autoinmunes y paraneoplásicas. En consecuencia, el paciente se diagnosticó de NB y mostró una buena recuperación con tratamiento inmunosupresor. Discusión: Sólo dos casos de NB con presentación en forma de EL se han publicado previamente. Comunicamos el tercer caso de esta rara manifestación clínica de la EB y lo comparamos con los dos anteriores, con el objetivo de destacar dicha asociación y contribuir a expandir el rico espectro clínico del NB.(AU)

Introduction: Limbic encephalitis (LE) can have a wide range of etiologies, most frequently infectious (especially viral) or autoimmune. Behçet’s disease (BD) can present with heterogeneous neurological manifestations. However, LE is not considered a typical presentation of neuro-Behçet’s disease (NBD). Case report: A 40-years-old male presented with new-onset subacute headaches, memory problems and apathy. A review of systems revealed an unrecorded past history of recurrent oral sores for years, recent malaise and fever, as well as an episode of bilateral panuveitis four months before presentation. His general and neurologic examination revealed slight fever, an isolated oral aphtha, anterograde amnesia and signs of bilateral retinal vasculitis. Brain magnetic resonance imaging displayed a pattern of limbic meningoencephalitis, and his cerebrospinal fluid showed mononuclear inflammation. The patient met BD diagnostic criteria. Considering LE is a very rare presentation of NBD, alternative etiologies were thoroughly assessed and excluded, including infectious, autoimmune and paraneoplastic encephalitis. Therefore, he was diagnosed with NBD, and he recovered well after immunosuppression. Discussion: Only two cases of NBD presenting with LE have been previously reported. We report a third case of this rare presentation and compare it with the previous two. We aim to highlight this association and contribute to enlarge the rich clinical spectrum of NBD.(AU)

Neurosyphilis presenting as limbic encephalitis.

A man in his 50s presented with focal seizures and was found to have an inflammatory cerebrospinal fluid (CSF) with bilateral mesiotemporal lobe hyperintensity on magnetic resonance imaging (MRI) of the brain. Corticosteroid treatment was initiated for management of limbic encephalitis. Focal seizures, imaging abnormalities and inflammatory CSF persisted despite treatment and the patient was found to have neurosyphilis after developing neuropsychiatric symptoms. Syphilis is a sexually transmitted bacterial infection with multisystem involvement including neurological and psychiatric manifestations. Case reports have emerged of neurosyphilis presenting as limbic encephalitis with CSF pleocytosis and temporal lobe hyperintensity on MRI of the brain. Persistence of CSF or MRI abnormalities despite immunosuppressive therapy for limbic encephalitis should prompt investigation for alternate causes of chronic meningoencephalitis, which can occasionally include neurosyphilis.

Fatal limbic encephalitis as paraneoplastic neurological syndrome in a patient with lung adenocarcinoma positive for antiamphiphysin antibody after durvalumab treatment.

A 69-year-old Japanese male with advanced lung adenocarcinoma developed neurological symptoms after chemoradiotherapy and durvalumab maintenance therapy. He was positive for serum antiamphiphysin antibody, which is rarely seen in patients with lung adenocarcinoma. Additionally, his brain magnetic resonance images showed limbic encephalitis which led to the diagnosis of classic paraneoplastic neurological syndrome (PNS). Immune checkpoint inhibitors (ICIs) activate T cells and may also activate antineuronal antibodies that cause PNS. Durvalumab, which is an ICI, may have led to antiamphiphysin antibody-positive PNS in our patient. Treatment with systemic high-dose methylprednisolone was unsuccessful and he died 2 months later. PNS should be considered as one of the differential diagnoses in patients with lung cancer and neurological symptoms during, or after, ICI treatment.

[A case of neurosyphilis presenting as sudden onset of limbic encephalitis].

A 52-year-old male was carried to hospital by ambulance, because of an abrupt abnormal behavior and impaired consciousness. Soon after the arrival, the patient started a generalized seizure. Although the seizure was stopped by Midazolam, amnesia were observed. With meningeal irritation signs, in addition to the clinical course, the patient was thought to develop limbic encephalitis. The cause of the encephalitis was diagnosed as neurosyphilis because of the positive serum and CSF syphilis reactions, and the patient was treated with penicillin G from the first admission day on. Steroid pulse therapy was also conducted, followed by acyclovir since herpes encephalitis could not be ruled out; the brain MRI showed left-side dominant T2/FLAIR high intensity lesions in the bilateral temporal lobes and left hippocampus. With the treatment progression, the amnestic syndrome improved and the patient returned to work. Although neurosyphilis is a rare cause of acute onset limbic encephalitis, it is important to keep the possibility of this disease in mind in making a treatment plan.

Case Report: Anti-mGluR5 antibody-negative Ophelia syndrome with failed lymph node biopsy due to steroid therapy.

Ophelia syndrome is paraneoplastic limbic encephalitis (PLE) with Hodgkin lymphoma. Some Ophelia syndrome patients have been reported as testing positive for anti-metabotropic glutamate receptor 5 (mGluR5) antibodies. However, we experienced a case of anti-mGluR5 antibody-negative Ophelia syndrome. The type of onset, neurological symptoms, and imaging as well as electroencephalographic findings were like previous reports except for a normal cell count in cerebrospinal fluid (CSF). Unfortunately, a lymph node biopsy failed and could not diagnose the patient before death because steroid treatment for limbic encephalitis had shrunk lymph nodes. We believe it is essential to accumulate cases of this syndrome and clarify the association between PLE and Hodgkin lymphoma so chemotherapy can be initiated even if malignant lymphoma cannot be pathologically proven or when antibodies cannot be measured or are negative.

Panhypopituitarism as the first sign of paraneoplastic limbic encephalitis in a patient with cured testicular cancer: a case report.

BACKGROUND: Paraneoplastic limbic encephalitis is a rare neurologic syndrome that affects patients with cancer and commonly presents with symptoms of personality changes, visual disturbances, seizures, vertigo, and memory loss. It has an immune-mediated pathophysiology and is associated with antibodies directed against both the tumor and limbic structures in the nervous system. Here, we report a case of paraneoplastic limbic encephalitis with an unusual presentation with initial symptoms of panhypopituitarism. CASE PRESENTATION: A 28-year-old Caucasian man with history of testicular cancer in remission for almost 2 years was admitted to our hospital for altered mental status, syncope, vertical gaze palsy, ataxia, and tremor. Three months prior to admission, he began to have initial symptoms of fatigue, weight gain, and hypogonadism. A few weeks before admission, he also developed worsening neurological symptoms that led him to present to the hospital. While hospitalized, he had an episode of syncope. Evaluation of his syncope revealed that he was hypovolemic due to polyuria, concerning for diabetes insipidus. While the patient did not meet criteria for diabetes insipidus, further endocrine laboratory testing to evaluate his central hormonal axes revealed panhypopituitarism. He also underwent a neurologic work-up with brain magnetic resonance imaging and lumbar puncture, with results consistent with encephalitis. He received high-dose steroids, plasmapheresis, and intravenous immunoglobulin, which did not significantly improve his physical examination or mental status. Extensive testing did not show any recurrence of his testicular cancer. Paraneoplastic antibodies were also ordered, with anti-Ma2 antibodies eventually returning positive, consistent with anti-Ma2 paraneoplastic limbic encephalitis. CONCLUSION: Paraneoplastic limbic encephalitis is often a difficult diagnosis due to its variable presentation and timeline of presentation, leading to delays in both diagnosis and treatment. While paraneoplastic limbic encephalitis usually presents with neurological symptoms, it may also present with panhypopituitarism. A high index of suspicion is warranted for paraneoplastic syndromes in patients with history of malignancy, even if the malignancy is in remission.

Neurosyphilis presenting as autoimmune limbic encephalitis: A case report and literature review.

RATIONALE: Neurosyphilis presenting as limbic encephalitis (LE) is an important differential diagnosis of autoimmune LE (ALE) defined by Graus in 2016. However, data on the clinical differences and similarities between neurosyphilis presenting as LE and ALE are limited. Herein, we report neurosyphilis presenting as ALE that fulfilled the main items of the Graus ALE criteria. Moreover, a literature review of neurosyphilis presenting as LE was performed. PATIENT CONCERNS: A 66-year-old Japanese man developed nonconvulsive status epilepticus. He presented with progressive personality change and working memory deficits within 3 months prior to admission. A hyperintense lesion localized in the bilateral medial temporal area was observed on T2-weighted fluid-attenuated inversion recovery brain magnetic resonance imaging. Cerebrospinal fluid analysis showed mild pleocytosis and the presence of oligoclonal band. However, in-house assays did not detect antineuronal antibodies. Electroencephalogram showed lateralized rhythmic delta activity in the right temporal area. The serum and cerebrospinal fluid serological and antigen tests for syphilis had positive results. DIAGNOSIS: ALE was initially suspected based on the patient's symptoms and ancillary test findings that fulfilled the Graus ALE criteria. However, based on the positive confirmatory test results for syphilis, a diagnosis of neurosyphilis was eventually made. INTERVENTION: The patient received intravenous midazolam, oral levetiracetam, and lacosamide to control nonconvulsive status epilepticus. In addition, he was treated with intravenous benzylpenicillin at a dose of 24 million units/day for 14 days. OUTCOMES: The patient's cognitive function relatively improved after antibiotic treatment. However, he presented with persistent mild working memory deficit, which was evaluated with the Wechsler Adult Intelligence Scale, 3rd edition. Therefore, on day 103 of hospitalization, he was transferred to another hospital for rehabilitation and long-term care due to limitations in performing activities of daily living. LESSONS: The present case was diagnosed with neurosyphilis presenting as ALE, but meanwhile, in most case, neurosyphilis presenting as LE developed at a slower progressive rate, and it had a broader or restricted involvement on brain MRI than ALE based on the literature review. Therefore, an appropriate differential diagnosis of LE can be obtained by identifying clinical differences between the 2 conditions.

Seronegative limbic encephalitis in association with Sjögren's syndrome: a rare case report.

Limbic encephalitis is often due to an autoimmune or paraneoplastic disease and is always a diagnostic challenge. We report a 31-year-old lady who presented with fever and proximal weakness to start with and afterwards developed refractory focal onset seizures and worsening cognition despite optimum treatment. Evaluation revealed hypokalemia with a normal anion gap metabolic acidosis. Magnetic resonance imaging (MRI) brain showed features of limbic encephalitis. Cerebrospinal fluid (CSF) showed lymphocytosis and CSF autoimmune, paraneoplastic and viral encephalitis panel were negative. However a blood ANA profile clinched the diagnosis when SS-A and Ro 52 were strongly positive. She was given steroids and subsequently plasma exchange. A labial gland biopsy confirmed the diagnosis of Sjögren syndrome. In cases of autoimmune limbic encephalitis with no identifiable cause, serological screening for rheumatological disorders is recommended. Sjögren syndrome is a rare aetiology for autoimmune limbic encephalitis. A detailed history and a step wise approach is always the key to the right diagnosis.

Musicogenic epilepsy in paraneoplastic limbic encephalitis: a video-EEG case report.

Musicogenic epilepsy (ME), a peculiar form of reflex epilepsy, represents a neurological rarity and yet another demonstration of the extraordinary power of music on the human brain. Despite the heterogeneity of the reported musical triggers, patients' emotional response to music is thought to play a crucial role in provoking seizures. Accordingly, the mesial temporal structures (especially of the non-dominant hemisphere) appear most involved in seizure generation, although a more complex fronto-temporal epileptogenic network was documented in some cases. Autoimmune encephalitis has been recently included among the many possible aetiologies of ME based on a few reports of music-induced seizures in patients with anti-glutamic acid decarboxylase 65 antibodies. Here, we describe the case of a 25-year-old man, educated in music over a long period of time, who had suffered from drug-resistant temporal lobe epilepsy following seronegative limbic encephalitis related to non-Hodgkin lymphoma. Along with spontaneous events, the patient also developed musicogenic seizures later in the disease course. After detecting five music-induced episodes via 24-hour ambulatory EEG, we performed prolonged video-EEG monitoring during which the patient presented a right temporal seizure (characterized by déjà-vu, piloerection and gustatory hallucinations) while listening to a hard rock song through headphones (which he had not previously heard). This observation allowed us to confirm the provoking effect of the music on our patient's seizures, despite the lack of any emotional drive, which suggests that a "cognitive" trigger was more likely in this case. Our report further highlights that autoimmune encephalitis should be investigated as a novel potential cause of musicogenic epilepsy, regardless of autoantibody status.

Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis.

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) and anti-leucine-rich glioma-inactivated 1 encephalitis (anti-LGI1E) are the two most common types of antibody-mediated autoimmune encephalitis. We performed a comprehensive analysis of the B-cell immune repertoire in patients with anti-NMDARE (n = 7) and anti-LGI1E (n = 10) and healthy controls (n = 4). The results revealed the presence of many common clones between patients with these two types of autoimmune encephalitis, which were mostly class-switched. Additionally, many differences were found among the anti-NMDARE, anti-LGI1E, and healthy control groups, including the diversity of the B-cell immune repertoire and gene usage preference. These findings suggest that the same adaptive immune responses occur in patients with anti-NMDARE and anti-LGI1E, which deserves further exploration.

Limbic encephalitis in a child with ovarian teratoma and influenza B. Case report and critical review of the history of autoimmune anti-N-methyl-d-aspartate receptor encephalitis.

We report the appearance of clinical symptoms and signs of N-methyl-d-Aspartate (NMDA) receptor encephalitis in a patient presenting just days after contraction of influenza B. The offending mature ovarian teratoma was identified and removed on the 10th day after the appearance of symptoms, with subsequent nearly complete resolution of symptoms over the subsequent 6 months. We provide a focused literature review of the clinical and pathophysiologic literature of anti-NMDA receptor encephalitis pertaining to influenza B virus and the pediatric population. Taken together, this study contributes to the pathophysiological understanding of anti-NMDA receptor encephalitis and aids clinicians in its early recognition and management.

[Paraneoplastic limbic encephalitis complicating pulmonary adenocarcinoma: a case report]. / Encéphalite limbique paranéoplasique compliquant un adénocarcinome pulmonaire: à propos d'un cas.

Limbic encephalitis (LE) is a rare disease often of paraneoplastic origin. It is frequently associated with bronchopulmonary cancer. Diagnosis is based on brain magnetic resonance imaging (MRI). We here report the case of a 54-year-old female patient with a history of active smoking, presenting with chronic dry cough. Chest X-ray showed suspicious right lung opacity. Bronchial fibroscopy and bronchial biopsies were not contributory. Thoraco-abdomino-pelvic computed tomography (CT)-scan and brain CT-scan showed a mass in the right upper lobe classified as T4N2M1a. CT-guided lung biopsy confirmed the diagnosis of bronchopulmonary adenocarcinoma. The patient had reported a recent history of memory disturbances associated with depressed mood, anxiety and paroxysmal confusion. Metabolic screening and tests for detecting infection were normal and brain MRI suggested limbic encephalitis. The evolution was characterized by rapid disease progression; the patient died in about ten days.

Anti-GABAB receptor encephalitis associated with combined small cell lung carcinoma.

Autoimmune encephalitis with antibodies against the gamma-aminobutyric acid-B receptor is a relatively rare disease. We report a case with characteristic symptoms of limbic encephalitis associated with combined small cell lung carcinoma. The brain magnetic resonance imaging showed bilateral temporal lesions and the photoemission tomography revealed regional heterogenous metabolism across the brain. The double labeling of anti-gamma-aminobutyric acid-B receptor autoantibodies both in the tissues of neuroendocrine and small cell neoplasia was a unique feature of this patient.

Rare paraneoplastic syndrome of prostatic cancer: limbic encephalitis: a case report.

INTRODUCTION: Limbic encephalitis is an autoimmune neurologic disorder, often of paraneoplastic origin, that seldom complicates prostatic tumors. The nonspecificity of symptoms makes the diagnosis sometimes difficult to establish. Prognosis is essentially determined by comorbidities and sensorineural and cognitive sequelae. CLINICAL CASE: A 66-year-old Caucasian patient known to have prostatic small-cell neuroendocrine adenocarcinoma under hormonal therapy developed complex partial epileptic seizures associated with rapidly aggravating severe memory impairment. The tripod of autoimmune limbic encephalitis diagnosis was based on the clinical aspect of brain's functional deterioration, electroencephalography aspect, and γ-aminobutyric acid type B anti-receptor antibody positivity. Clinical, diagnostic, and therapeutic management as well as evolutionary risks were further analyzed. CONCLUSION: Limbic encephalitis is an extremely rare presentation of neurologic paraneoplastic syndromes. A better knowledge of this entity would help better manage diagnostic and therapeutic difficulties and reduce the risk of possible sequelae.

Hypothalamic Inflammation as a Potential Pathophysiologic Basis for the Heterogeneity of Clinical, Hormonal, and Metabolic Presentation in PCOS.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. It is a heterogeneous condition characterized by reproductive, endocrine, metabolic, and psychiatric abnormalities. More than one pathogenic mechanism is involved in its development. On the other hand, the hypothalamus plays a crucial role in many important functions of the body, including weight balance, food intake, and reproduction. A high-fat diet with a large amount of long-chain saturated fatty acids can induce inflammation in the hypothalamus. Hypothalamic neurons can sense extracellular glucose concentrations and participate, with a feedback mechanism, in the regulation of whole-body glucose homeostasis. When consumed nutrients are rich in fat and sugar, and these regulatory mechanisms can trigger inflammatory pathways resulting in hypothalamic inflammation. The latter has been correlated with metabolic diseases, obesity, and depression. In this review, we explore whether the pattern and the expansion of hypothalamic inflammation, as a result of a high-fat and -sugar diet, may contribute to the heterogeneity of the clinical, hormonal, and metabolic presentation in PCOS via pathophysiologic mechanisms affecting specific areas of the hypothalamus. These mechanisms could be potential targets for the development of effective therapies for the treatment of PCOS.

Paraneoplastic limbic encephalitis as initial presentation of testicular neoplasm: A case report.

Paraneoplastic limbic encephalitis (PLE) is an immunopathologic syndrome associated with malignancy and represents a rare remote outcome of tumor on the nervous system. We report a case of PLE caused by a regressed testicular germ cell tumor in an otherwise healthy young man, who presented with acute-onset confusion, memory impairment and anterograde amnesia. Prompt recognition of PLE is critical as it allows early treatment of both the primary tumor and PLE-related neurologic impairments, which can be severe and irreversible if treatment is delayed. Complete tumor treatment response offers the best chance for neurologic recovery in patients with PLE. To our knowledge, this is the second reported case of PLE with radiologic-pathologic correlation in the setting of a regressed testicular germ cell tumor.

CSF-Neurofilament Light Chain Levels in NMDAR and LGI1 Encephalitis: A National Cohort Study.

Background and Objectives: The two most common autoimmune encephalitides (AE), N-methyl-D-Aspartate receptor (NMDAR) and Leucine-rich Glioma-Inactivated 1 (LGI1) encephalitis, have been known for more than a decade. Nevertheless, no well-established biomarkers to guide treatment or estimate prognosis exist. Neurofilament light chain (NfL) has become an unspecific screening marker of axonal damage in CNS diseases, and has proven useful as a diagnostic and disease activity marker in neuroinflammatory diseases. Only limited reports on NfL in AE exist. We investigated NfL levels at diagnosis and follow-up in NMDAR and LGI1-AE patients, and evaluated the utility of CSF-NfL as a biomarker in AE. Methods: Patients were included from the National Danish AE cohort (2009-present) and diagnosed based upon autoantibody positivity and diagnostic consensus criteria. CSF-NfL was analyzed by single molecule array technology. Clinical and diagnostic information was retrospectively evaluated and related to NfL levels at baseline and follow-up. NMDAR-AE patients were subdivided into: idiopathic/teratoma associated or secondary NMDAR-AE (post-viral or concomitant with malignancies/demyelinating disease). Results: A total of 74 CSF samples from 53 AE patients (37 NMDAR and 16 LGI1 positive) were included in the study. Longitudinal CSF-NfL levels was measured in 21 patients. Median follow-up time was 23.8 and 43.9 months for NMDAR and LGI1-AE respectively. Major findings of this study are: i) CSF-NfL levels were higher in LGI1-AE than in idiopathic/teratoma associated NMDAR-AE at diagnosis; ii) CSF-NfL levels in NMDAR-AE patients distinguished idiopathic/teratoma cases from cases with other underlying etiologies (post-viral or malignancies/demyelinating diseases) and iii) Elevated CSF-NfL at diagnosis seems to be associated with worse long-term disease outcomes in both NMDAR and LGI1-AE. Discussion: CSF-NfL measurement may be beneficial as a prognostic biomarker in NMDAR and LGI1-AE, and high CSF-NfL could foster search for underlying etiologies in NMDAR-AE. Further studies on larger cohorts, using standardized methods, are warranted.