Neurological Immunotoxicity from Cancer Treatment.

The emergence of immune-based treatments for cancer has led to a growing field dedicated to understanding and managing iatrogenic immunotoxicities that arise from these agents. Immune-related adverse events (irAEs) can develop as isolated events or as toxicities affecting multiple body systems. In particular, this review details the neurological irAEs from immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell immunotherapies. The recognition and treatment of neurological irAEs has variable success, depending on the severity and nature of the neurological involvement. Understanding the involved mechanisms, predicting those at higher risk for irAEs, and establishing safety parameters for resuming cancer immunotherapies after irAEs are all important fields of ongoing research.

Vaccine-associated paralytic poliomyelitis in a patient with acute lymphocytic leukemia.

We report a case of vaccine-associated paralytic poliomyelitis (VAPP) in an immunocompromised patient with acute lymphocytic leukemia who was initially diagnosed with aseptic meningitis. Isolation of Sabin-like type 1 poliovirus from the patient's cerebrospinal fluid made this a case of vaccine-related poliovirus (VRPV) infection. The patient developed paralysis and respiratory distress and deceased a few months after onset of paralysis with respiratory failure. This tragic case report highlights the emergence of VAPP and indicates the importance of timely diagnosis of VRPV infections to improve clinical management of VRPV-infected patients and to prevent the devastating consequences of silent introduction of VRPVs in treatment wards and eventually in the society.

Fatal Meningitis in Swine after Intrathecal Administration of Adeno-associated Virus Expressing Syngeneic Interleukin-10.

Interleukin-10 (IL-10) delivered by intrathecal (i.t.) gene vectors is a candidate investigational new drug (IND) for several chronic neurological disorders such as neuropathic pain. We performed a preclinical safety study of IL-10. A syngeneic large animal model was used delivering porcine IL-10 (pIL-10) to the i.t. space in swine by adeno-associated virus serotype 8 (AAV8), a gene vector that was previously found to be nontoxic in the i.t. space. Unexpectedly, animals became ill, developing ataxia, seizures, and an inability to feed and drink, and required euthanasia. Necropsy demonstrated lymphocytic meningitis without evidence of infection in the presence of normal laboratory findings for body fluids and normal histopathology of peripheral organs. Results were replicated in a second animal cohort by a team of independent experimenters. An extensive infectious disease and neuropathology workup consisting of comprehensive testing of tissues and body fluids in a specialized research veterinary pathology environment did not identify a pathogen. These observations raise the concern that i.t. IL-10 therapy may not be benign, that previously used xenogeneic models testing the human homolog of IL-10 may not have been sensitive enough to detect toxicity, and that additional preclinical studies may be needed before clinical testing of IL-10 can be considered.

Lymphocytic choriomeningitis virus in employees and mice at multipremises feeder-rodent operation, United States, 2012.

We investigated the extent of lymphocytic choriomeningitis virus (LCMV) infection in employees and rodents at 3 commercial breeding facilities. Of 97 employees tested, 31 (32%) had IgM and/or IgG to LCMV, and aseptic meningitis was diagnosed in 4 employees. Of 1,820 rodents tested in 1 facility, 382 (21%) mice (Mus musculus) had detectable IgG, and 13 (0.7%) were positive by reverse transcription PCR; LCMV was isolated from 8. Rats (Rattus norvegicus) were not found to be infected. S-segment RNA sequence was similar to strains previously isolated in North America. Contact by wild mice with colony mice was the likely source for LCMV, and shipments of infected mice among facilities spread the infection. The breeding colonies were depopulated to prevent further human infections. Future outbreaks can be prevented with monitoring and management, and employees should be made aware of LCMV risks and prevention.

Trimethoprim-sulfamethoxazole-induced aseptic meningitis-not just another sulfa allergy.

OBJECTIVE: To review the literature on trimethoprim-sulfamethoxazole (TMP-SMX)-induced aseptic meningitis (TSIAM) and discuss the features, possible mechanisms, evaluation, and treatment options relevant for the allergist. DATA SOURCES: A MEDLINE search was performed using the terms aseptic meningitis, trimethoprim-sulfamethoxazole, trimethoprim, and sulfamethoxazole. STUDY SELECTIONS: Cases were included that fit the case definition of headache, neck pain, or change in mental status with elevated cerebrospinal fluid white blood cell count or protein attributable to TMP-SMX or either medication alone. RESULTS: Forty-one patient cases were reviewed. There was a predominance of female patients and patients with autoimmune disease reported. Fever, headache, neck pain, and altered mental status were the most common findings reported in TSIAM reactions. Severe reactions ranged from hypotension to seizure and unconsciousness or coma. Typical cerebrospinal fluid findings included elevated white blood cell count with neutrophil predominance, elevated protein, and normal glucose. Symptoms quickly remitted with withdrawal of TMP-SMX, typically over 48 to 72 hours. Full recovery was typically experienced, although permanent paraplegia was reported in 1 case. The mechanism of reaction is unknown, although an IgE-mediated reaction is unlikely. Many patients experienced multiple TSIAM reactions before the diagnosis was made. Diagnosis can be confirmed with drug challenge or graded test dosing when necessary. Patients with TSIAM subsequently reacted to TMP and SMX alone and therefore should be advised to avoid these 2 classes of medication after diagnosis. CONCLUSION: TMP-SMX is the most common antibiotic to cause drug-induced aseptic meningitis. By being aware of this reaction, allergists are well poised to diagnose TSIAM and prevent future reoccurrences for the patient.

Complete factor I deficiency due to dysfunctional factor I with recurrent aseptic meningo-encephalitis.

PURPOSE: Complement regulators control the activated complement system. Defects in this homeostasis can result in tissue damage and autoimmune diseases with a heterogeneity in clinical presentation. Complement factor I (FI), a serine protease, is an important regulator of alternative pathway activation. We report a diagnostic work-up of a patient with relapsing inflammatory mediated meningo-encephalitis. Our work-up revealed a rare genetic factor I (FI) deficiency. So far, all cases of reported complete factor I deficiency have absent serum levels of FI. We present here a unique case of a complete factor I deficiency based on a functional FI defect. METHODS: Complement assays and measurement of FI activity were performed in the patient, her family, factor H-deficient patients, a patient with C3-nephritic factor and 11 healthy controls. Genetic sequencing of the FI coding regions in the patient and her parents was performed. RESULTS: The patient had absent alternative pathway activity with low levels of C3 and normal serum level of FI. The patient's plasma FI did not degrade C3b, with normalisation of C3b degradation after adding purified FI. Mutation analysis of the complement factor I gene revealed two heterozygous mutations (I322T and D506V). CONCLUSION: To our knowledge, this paper describes a complete FI deficiency caused by a defect of FI activity for the first time. Normal FI concentration does not exclude a complete FI defect, additional functional analysis of FI is required in any patient with a defect of complement activation. Recurrent aseptic meningo-encephalitis is a rare clinical presentation of complete FI deficiency.

Is recurrent aseptic meningitis a manifestation of familial Mediterranean fever? A systematic review.

OBJECTIVES: Familial Mediterranean fever (FMF) causes recurrent episodes of fever and painful serositis. It has been suggested that FMF can cause recurrent aseptic meningitis (RAM). Due to the rarity of both diseases, this claim cannot be assessed with epidemiological methods. We therefore decided to perform a systematic review of the literature to assess the number and validity of published case reports. METHODS: Medline, Embase, Pascal, Web of Science and the proceedings of relevant conferences were searched. Two independent investigators selected reports asserting RAM in FMF patients, abstracted data and rated the strength of evidence with a custom tool designed to assess: (a) the diagnosis of FMF; (b) the diagnosis of RAM; and (c) the link between FMF and RAM. A causal link was supported by (i) evidence of inflammation and/or clinical FMF features during episodes of RAM; (ii) effectiveness of colchicine to prevent further bouts of meningitis; and (iii) the exclusion of other causes of RAM. RESULTS: Among 944 retrieved references, 917 were rejected by title and abstract screening and 15 after full text review. The strength of evidence of 12 alleged cases of RAM due to FMF was assessed. FMF was unsupported in 4 cases and RAM in 3 further cases. Four of the 5 remaining cases did not provide adequate evidence to support a causal relationship between FMF and RAM. CONCLUSIONS: The possibility of RAM due to FMF is poorly supported by a single fairly documented case report that does not, however, meet current diagnostic standards.

Prolonged Fever: An Atypical Presentation in MOG Antibody-Associated Disorders.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelinating disorders (MOGAD) are increasingly being recognized in the pediatric age group. Over time, unusual presentations have expanded the clinical presentation. We report 12 cases of MOGAD where prolonged fever (PF) was an important part of the symptom complex during the course of the illness. METHODS: After initial recognition of this atypical clinical presentation, more patients were recruited over 2 years and followed up prospectively. RESULTS: Eight of twelve patients had no clinical/imaging evidence of demyelination until much later in the course. Three clinical presentations recognized were fever of unknown origin (4 of 12), aseptic meningitis (4 of 12), and PF seen concurrently with established acute demyelination syndrome (4 of 12). Leukocytosis, raised inflammatory markers, and cerebrospinal fluid pleocytosis were almost universal. The first two presentations frequently caused diagnostic confusion, as MOGAD was not considered until several weeks after disease onset. The third group was more a therapeutic conundrum on how to manage the PF. Early seizures without encephalopathy were not uncommon and were probably independent of the later-appearing demyelination. CONCLUSIONS: This case series highlights PF as an important component of the pediatric MOGAD symptom complex. MOGAD could be considered in the differential diagnosis of these clinical presentations.

Aseptic meningitis and leptomeningeal enhancement associated with anti-MOG antibodies: A review.

BACKGROUND: Aseptic meningitis can be caused by autoimmune diseases, such as lupus and sarcoidosis. Aseptic meningitis with leptomeningeal enhancement can be the initial presentation of a neuroinflammatory syndrome associated with antibodies to myelin oligodendrocyte glycoprotein (MOG-abs). MOG-abs is a serum biomarker for MOG-associated disorder (MOG-AD), an acquired demyelinating syndrome that includes features of neuromyelitis optica, multiple sclerosis, optic neuritis, and acute disseminated encephalomyelitis. The purpose of this study is to review cases of aseptic meningitis and leptomeningeal enhancement associated with MOG-abs. METHODS: Systematic review using PubMed, Embase, Ovid MEDLINE, Web of Science Core Collection, and Google Scholar up to December 2020 was performed. Cases of MOG-AD were included if they met the following criteria: 1) Initial clinical presentation of aseptic meningitis; 2) positive leptomeningeal enhancement and 3) MOG-Ab seropositivity. Descriptive statistics were used. This analysis was limited to the cases available in the literature. RESULTS: 11 total cases of aseptic meningitis and leptomeningeal enhancement in setting of MOG-ab were identified. Demyelinating type T2 lesions were also present at time of presentation in 6/11; however, 5/11 of patients had leptomeningeal enhancement alone without demyelinating lesions. All 5 patients required immunotherapy for improvement, including one patient with symptoms for 28 days, with 4/5 receiving steroids and 1/5 receiving intravenous immunoglobulin (IVIG). CONCLUSIONS: Aseptic meningitis with leptomeningeal enhancement can be the initial presenting symptom of MOG-AD. MOG-ab testing should be considered in a patient presenting with aseptic meningitis and leptomeningeal enhancement of unknown etiology.

IgG4-related meningeal disease: clinico-pathological features and proposal for diagnostic criteria.

IgG4-related disease has evolved from originally being recognized as a form of pancreatitis to encompass diseases of numerous organs including the hypophysis and one reported case of dural involvement. A search of the University of Virginia, Division of Neuropathology files for 10 years identified ten cases of unexplained lymphoplasmacytic meningeal inflammation that we then evaluated using immunohistochemical stains for IgG4 and IgG. Ten control cases including sarcoidosis (4), tuberculosis (1), bacterial abscess (2), Langerhans cell histiocytosis (2), and foreign body reaction (1) were also examined. The number of IgG4-positive plasma cells was counted in five high power fields (HPFs) and an average per HPF was calculated. Cases that contained greater than ten IgG4-positive cells/HPF were considered to be IgG4-related. Five of the study cases met these criteria, including one case of leptomeningeal inflammation. All cases exhibited the typical histological features of IgG4-related disease including lymphoplasmacytic inflammation, fibrosis, and phlebitis. The dural-based lesions appear to represent a subset of the cases historically diagnosed as idiopathic hypertrophic pachymeningitis. While the leptomeningeal process most closely resembles non-vasculitic autoimmune inflammatory meningoencephalitis. Given these findings, IgG4-related meningitis should be considered in the differential diagnosis of meningeal inflammatory lesions after stringent clinical and histologic criteria are used to rule out other possible diagnoses.

Viral (aseptic) meningitis: A review.

Viral meningitis is an inflammation of the meninges associated with acute onset of meningeal symptoms and fever, pleocytosis of the cerebrospinal fluid, and no growth on routine bacterial culture. It is sometimes associated with viral encephalitis and meningoencephalitis. Viruses reach the central nervous system (CNS) hematogenously or in a retrograde manner from nerve endings. The viral etiology varies according to age and country. Molecular diagnostics technology has helped improve the rate of pathogen detection reducing unnecessary antibiotic use and length of hospitalization. Most of the viral infections detailed in this article have no specific treatment other than supportive care. Many of the viruses discussed are preventable by vaccination and proper skin protection against transmitting vectors.

MOG antibody seropositive aseptic meningitis: A new clinical phenotype.

The spectrum of myelin oligodendrocyte glycoprotein antibody (MOG-Ab) associated demyelination is evolving. Our case report describes a unique clinical presentation of aseptic meningitis with demyelinating lesions of the brain resembling acute disseminated encephalomyelitis and MOG-Ab seropositivity. A 22-year-old lady presented with history of fever of one week duration followed by headache, vomiting and neck stiffness. She had bilateral papilledema and signs of meningeal irritation. Neuroimaging revealed T2 and FLAIR hyperintense lesions in the right caudate, temporal lobe and left insula with enhancement on gadolinium contrast along with leptomeningeal enhancement. An extensive search for infectious and inflammatory etiology was negative while serum was positive for MOG-Abs tested twice at an interval of 12 days. She showed remarkable clinical-radiological resolution with steroids and has remained symptom free on follow up.

Encephalitis and aseptic meningitis: short-term and long-term outcome, quality of life and neuropsychological functioning.

For those surviving encephalitis, the influence on daily life of patients and their relatives may be substantial. In contrast, the prognosis after aseptic meningitis (ASM) is considered good. In this prospective study in patients with encephalitis (n = 20) and ASM (n = 46), we show that both groups experienced reduced Health Related Quality of Life (HRQoL) at two months after discharge, and that workability was reduced in 37% of the patients with ASM. However, 12 months after discharge no neuropsychological deficits were detected in the ASM group, whereas patients with encephalitis had lower scores on tests of fine motor and psychomotor skills as well as on learning and memory. We also found that for patients with encephalitis, neopterin, as a marker of Th1 cell induced macrophage activation, and a putatively neurotoxic ratio of the kynurenine pathway (KP) measured during the acute phase was associated with lower HRQoL. Our data show that not only encephalitis, but also ASM has substantial short-term influence on HRQoL and workability. For patients with encephalitis we suggest a link between immune activation and activation of the KP during the acute phase with impaired HRQoL.

Recurrent benign lymphocytic (mollaret) meningitis in systemic lupus erythematosus.

BACKGROUND: Aseptic meningitis is one of the most infrequent neuropsychiatric manifestations of systemic lupus erythematosus (SLE) with multifactorial etiologies including medications such as nonsteroidal anti-inflammatory drugs, azathioprine, and trimethoprim-sulfamethoxasole, as well as viruses and malignancy. Recurrent aseptic meningitis in SLE is rare, and remains a diagnostic challenge. METHODS: We report a unique SLE patient with recurrent (10 episodes), benign (self-limited) lymphocytic aseptic meningitis, which suggests the diagnosis of Mollaret meningitis. There was no prior use of medications known to provoke meningitis. No infectious etiology was identified and chronic meningitis was not observed. The patient had spontaneous resolution of symptoms with no neurologic sequelae. CONCLUSION: Recurrent benign lymphocytic aseptic meningitis is recognized in this SLE patient. We propose that noninfectious Mollaret meningitis be classified as a feature of neuropsychiatric SLE syndromes.

Description of six cases of child cauda equina leptomeningitis: an emerging disease.

Child cauda equina leptomeningitis (CCEL) is a typical clinical example of aseptic meningitis with patterns of an emerging disease, and it affects children aged 2-9. Here we will describe six cases of CCEL. After the prodromes, all children underwent an acute phase with hypoasthenia of the lower limbs, hyporeflexia, staggering and ataxia with steppage. Only in one case there were generalized fits and coma of grade 1-2 too. All children underwent a spinal magnetic resonance imaging (MRI), proving pathologic enhancement of cauda equina and conus medullaris leptomeningitis. At the same time, MRI made possible the differential diagnosis between cauda equina leptomeningitis and isolated minor forms of Guillain-Barre syndrome involving the lower limbs. Three hypotheses will be formulated for understanding the pathogen mechanism(s) of CCEL. The first one is based on the presence of an immediate viral damage on the meninges, the second one, the more likely, contemplates the occurrence of an immunomediated mechanism in a host genetically prone to react in an abnormal way from an immune viewpoint. The third hyphotesis consists in a two-time damage: an early immediate damage from the virus, and a later immunomediated reaction.

Prodromal headache in anti-NMDAR encephalitis: An epiphenomenon of NMDAR autoimmunity.

OBJECTIVE: To investigate the nature of prodromal headache in anti-NMDA receptor (NMDAR) encephalitis. METHODS: Retrospective review of the clinical information of 39 patients with anti-NMDAR encephalitis admitted between January 1999 and September 2017. Five patients with an atypical presentation were excluded. Thus, in 34 patients (median 27 years [range, 12-47 years]; 28 [82%] female), the clinical features were compared between patients who initially reported headache and those who did not report. RESULTS: Twenty-two patients (65%) reported headache either transiently (n = 5) or continuously (n = 17). Encephalitic symptoms (psychobehavioral memory alterations, seizure, dyskinesias, or altered level of consciousness) developed in 20 patients with median 5.5 days (range, 1-29 days) after headache onset. In one patient, NMDAR antibodies were detected in CSF 3 days after headache onset. Patients with headache had more frequently fever (14/22 [64%] vs. 2/12 [17%] p = 0.013) and higher CSF pleocytosis (median white blood cells 79/µl [range, 6-311/µl] vs. 30/µl [range, 2-69/µl], p = 0.035) than those without headache, but there was no difference in gender, age at onset, seizure, migraine, CSF oligoclonal band detection, elevated IgG index, tumor association, or brain MRI abnormalities between them. CONCLUSIONS: Headache often developed with fever and pleocytosis, but it was rapidly replaced by psychiatric symptoms. Based on current knowledge on the antibody-mediated mechanisms that cause a decrease of synaptic NMDAR through crosslinking and internalization leading to a state mimicking "dissociative anesthesia," we speculated that prodromal headache is not likely caused by direct effect of the autoantibodies but rather meningeal inflammation (noninfectious aseptic meningitis) that occurs in parallel to intrathecal antibody synthesis as an epiphenomenon of NMDAR autoimmunity. Psychobehavioral alterations following headache is an important clue to the diagnosis.

Sarcoidosis of the nervous system.

Although sarcoidosis is rarely confined to the nervous system, any neurological features that do occur frequently happen early in the course of the disease. The most common neurological presentation is with cranial neuropathies, but seizures, chronic meningitis and the effects of mass lesions are also frequent. The diagnostic process should first confirm nervous system involvement and then provide supportive evidence for the underlying disease; in the absence of any positive tissue biopsy, the most useful diagnostic tests are gadolinium enhanced MRI of the brain and CSF analysis, although both are non-specific. The mainstay of treatment is corticosteroids, but these often have to be combined with other immunosuppressants such as methotrexate, hydroxychloroquine or cyclophosphamide. There is increasing evidence that infliximab is a safe treatment with good steroid sparing capacity.

Human parechovirus and enterovirus initiate distinct CNS innate immune responses: Pathogenic and diagnostic implications.

BACKGROUND: Human parechovirus (HPeV) and enterovirus (EV) cause a range of human diseases including serious CNS infections. Little is known regarding the immune response to HPeV meningitis compared to EV meningitis or how the immune response to HPeV reflects its pathogenesis. OBJECTIVE: To characterize the innate immune response to HPeV CNS infection in order to increase our understanding of HPeV pathogenesis and possibly help identify HPeV in the clinical setting. STUDY DESIGN: CSF samples from 13 patients with HPeV meningitis, 7 patients with EV meningitis, and 11 patients negative for CNS infections were analyzed for chemokines/cytokines using multiplex ELISA assays. RESULTS: CSF levels of the majority of cytokines/chemokines analyzed were significantly higher in patients with EV meningitis (EV group) compared to patients with HPeV meningitis (HPeV group) and controls. In the HPeV group, a small number of cytokine/chemokine levels were higher than controls; however, these levels were either significantly lower or not significantly different compared to the EV group. IL-6 levels were lower in HPeV than in both EV and controls. CONCLUSIONS: The immune response to HPeV CNS infection differs from that of EV. Distinct patterns of cytokine/chemokine expression in HPeV infections suggest HPeV-mediated modulation of the immune response. HPeV disrupts the interferon cascade and seems to interfere with early inflammatory signaling. Although HPeV elicits a predominantly muted immune reaction, a partial, general infectious-type cytokine/chemokine response does occur. Beyond providing insight into HPeV pathogenesis, the identified cytokine/chemokine profile may aid in early detection of HPeV infection.