Long-term nivolumab treatment possibly associated with aseptic meningitis.

Nivolumab is a programmed death-1 receptor blocker within the family of medications called immune checkpoint inhibitors (ICIs). Although generally well tolerated, cases of immune-related adverse events (irAEs) have been reported. We present a case of a man being treated with nivolumab for renal cell carcinoma who presented to the emergency department with problems of headache, fever and disorientation. After extensive evaluation, a diagnosis of immunotherapy-induced aseptic meningitis was considered more probable than infectious. Due to stable clinical status, no treatment was initiated, and the patient's condition improved spontaneously. The patient was discharged home. To date, only a handful of prior cases of nivolumab-induced meningitis have been reported. Our case demonstrates that irAEs can occur years after the initiation of ICIs. This was a milder presentation of a neurological irAE that resolved spontaneously with watchful waiting, showing that irAEs are likely an evolving spectrum of disease for which clinicians should be aware.

Fabry Disease with Aseptic Meningitis: A Case Series and Literature Review of an Underestimated Clinical Presentation.

OBJECTIVE: Fabry disease (FD) is an X-linked lysosomal storage disease caused by the mutation in the α-galactosidase A gene that leads to a consequently decreased α-galactosidase A enzyme activity and a series of clinical presentations. However, FD accompanied with aseptic meningitis can be relatively scarce and rarely reported, which leads to significant clinical misdiagnosis of this disease. METHODS: Sixteen patients diagnosed with FD based on a decreased activity of α-galactosidase A enzyme and/or genetic screening were identified through a 6-year retrospective chart review of a tertiary hospital. Clinical presentations, brain magnetic resonance imaging, cerebrospinal fluid analysis, treatment and outcome data were analyzed in cases of aseptic meningitis associated with FD. RESULTS: Three out of 16 cases exhibited aseptic meningitis associated with FD. There was one female and two male patients with a mean age of 33.3 years. A family history of renal failure or hypertrophic cardiomyopathy was found in 3 cases. All cases presented with a persistent or intermittent headache and recurrent ischemic stroke. The cerebrospinal fluid analyses showed mild pleocytosis in 2 patients and an elevated level of protein in all patients. Cerebrospinal fluid cytology revealed activated lymphocytes, suggesting the existence of aseptic meningitis. In the literature review, up to 9 cases presenting with FD and aseptic meningitis were found, which bore a resemblance to our patients in demographic and clinical characteristics. CONCLUSION: Our cases suggested that aseptic meningitis in FD might be under-detected and easily misdiagnosed, and should be more thoroughly examined in further cases.

Aseptic meningitis and hydrocephalus secondary to neurosarcoidosis.

A 53-year-old woman presented to hospital with gait instability, urinary incontinence and confusion. She had a 4-month history of headache, blurred vision, personality change and memory problems. Magnetic Resonance Imaging of the brain after contrast application showed tectal plate and occipital enhancement, as well as a known hydrocephalus. Cerebrospinal fluid showed aseptic meningitis with no evidence of clonal expansion. After further imaging that showed generalised lymphadenopathy and subsequent tissue biopsy that showed granulomatous lymphadenitis, she was diagnosed with neurosarcoidosis. She was treated with steroids which resulted in immediate cognitive and motor improvements as well as resolution of her urinary incontinence. We discuss the features of this case that pointed towards neoplastic, infective and other autoimmune aetiologies. We describe how they were excluded and provide the rationale for our treatment. This case demonstrates an important sequela sarcoidosis, and we conclude by recommending a multidisciplinary approach towards its diagnosis and management.

Aseptic Meningitis-retention Syndrome Associated with Tocilizumab in a Patient with Idiopathic Multicentric Castleman Disease.

This is the first report of tocilizumab-associated meningitis-retention syndrome in a patient with idiopathic multicentric Castleman disease. A 57-year-old man presented with headache, nuchal rigidity, impaired consciousness, pyramidal tract signs and urinary retention. A cerebrospinal fluid examination revealed increased cell counts and protein levels. These symptoms were improved by intravenous methylprednisolone. Tocilizumab-associated meningoencephalitis has been reported in patients with rheumatoid arthritis and juvenile idiopathic arthritis but not with multicentric Castleman disease. This case presents evidence of the increased probability of meningitis as a neurological complication of tocilizumab administration.

Meningitis aséptica secundaria a la administración de inmunoglobulina / Aseptic meningitis following immunoglobulin therapy

Introducción: la meningitis aséptica es una entidad infrecuente y multifactorial, siendo raros los efectos secundarios a la administración de inmunoglobulina. Objetivo: reportar el caso de una paciente hospitalizada en el servicio de pediatría en un hospital de Bogotá. Discusión: las principales causas de la entidad son virales. Aunque el uso de inmunoglobulina en pediatría es seguro, uno de sus efectos adversos menos comunes es la meningitis aséptica. Están descritas las posibles teorías fisiopatológicas que podrían explicar su desenlace. Conclusión: la meningitis aséptica puede corresponder a un efecto secundario al uso de inmunoglobulina en pediatría.

Introduction: aseptic meningitis is a rare and multifactorial entity and side effects of immunoglobulin therapy are rare. Objective: to report the case of a female patient hospitalized in the pediatrics service in a hospital in Bogotá. Discussion: the most common cause of aseptic meningitis is viral infection. Although the use of immunoglobulin therapy in pediatric patients is safe, one of its less common adverse effects is aseptic meningitis. The pathophysiological theories that could explain its outcome have been described. Conclusion: aseptic meningitis may be a side effect to the use of immunoglobulin in pediatric practice.

Meningite recorrente de Mollaret: uma revisão / Mollaret's recurrent meningitis: an overview

A meningite recorrente linfocítica benigna ou meningite de Mollaret, inicialmente descrita pelo neurologista francês Pierre Mollaret em 1944, é uma condição relativamente rara, benigna mas incapacitante durante os seus períodos de agudização. Trata-se de quadro inflamatório meníngeo recorrente devido a reativação de infecção pelo herpes simples vírus, particularmente o herpesvirus do tipo 2 (HSV-2). Pode ser reconhecida a partir do seu quadro clínico de meningismo agudo, perfil liquórico linfocítico e identificação do genoma viral por PCR no líquor. Aciclovir e seus derivados podem ser utilizado no seu tratamento ou na sua profilaxia. Sua identificação é importante no sentido de se excluir outras causas de quadros meníngeos recorrentes.

Benign recurrent lymphocytic meningitis or Mollaret's meningitis (MM) was frst described by the French neurologist Pierre Mollaret in 1944. MM is a relatively rare, benign but disabling condition. MM is a recurrent meningeal inflammatory illness due to reactivation of herpes simplex virus infection, particularly herpesvirus type 2 (HSV-2). It can be recognized from its clinical picture of acute meningism, lymphocytic CSF profle and by the identifcation of the viral genome in the CSF by PCR. Acyclovir and its derivatives may be used for its treatment or prophylaxis. The identifcation of MM is important in order to exclude other causes of recurrent meningeal conditions.

Mollaret Meningitis with a High Level of Cytokines in the Cerebrospinal Fluid Successfully Treated by Indomethacin.

A rare case of Mollaret meningitis characterized by four recurrent episodes of aseptic meningitis during a three-year period is reported. The patient showed a high fever and severe headache accompanied by a high level of cerebrospinal fluid (CSF) cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). The symptoms and high CSF cytokines were resolved immediately after introducing indomethacin treatment. Reactivation of the latent virus is considered to be the cause of this rare disease, and indomethacin is believed to inhibit the periodic abnormal generation of eicosanoid in the brain, resulting in a reduction in the fever and subsequent inflammation.

Aseptic and Bacterial Meningitis: Evaluation, Treatment, and Prevention.

The etiologies of meningitis range in severity from benign and self-limited to life-threatening with potentially severe morbidity. Bacterial meningitis is a medical emergency that requires prompt recognition and treatment. Mortality remains high despite the introduction of vaccinations for common pathogens that have reduced the incidence of meningitis worldwide. Aseptic meningitis is the most common form of meningitis with an annual incidence of 7.6 per 100,000 adults. Most cases of aseptic meningitis are viral and require supportive care. Viral meningitis is generally self-limited with a good prognosis. Examination maneuvers such as Kernig sign or Brudzinski sign may not be useful to differentiate bacterial from aseptic meningitis because of variable sensitivity and specificity. Because clinical findings are also unreliable, the diagnosis relies on the examination of cerebrospinal fluid obtained from lumbar puncture. Delayed initiation of antibiotics can worsen mortality. Treatment should be started promptly in cases where transfer, imaging, or lumbar puncture may slow a definitive diagnosis. Empiric antibiotics should be directed toward the most likely pathogens and should be adjusted by patient age and risk factors. Dexamethasone should be administered to children and adults with suspected bacterial meningitis before or at the time of initiation of antibiotics. Vaccination against the most common pathogens that cause bacterial meningitis is recommended. Chemoprophylaxis of close contacts is helpful in preventing additional infections.

Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood-Brain Barrier Function in Neonatal-Onset Multisystem Inflammatory Disease: Central Nervous System Biomarkers in Neonatal-Onset Multisystem Inflammatory Disease Correlate With Central Nervous System Inflammation.

OBJECTIVE: To evaluate proinflammatory cytokines and leukocyte subpopulations in the cerebrospinal fluid (CSF) and blood of patients with neonatal-onset multisystem inflammatory disease (NOMID) after treatment, and to compare inflammatory cytokines in the CSF and blood in 6 patients treated with 2 interleukin-1 (IL-1) blockers-anakinra and canakinumab. METHODS: During routine follow-up visits between December 2011 and October 2013, we immunophenotyped the CSF of 17 pediatric NOMID patients who were treated with anakinra, and analyzed CSF cytokine levels in samples obtained at baseline and at 3-5-year follow-up visits and compared them to samples from healthy controls. RESULTS: CSF levels of IL-6, interferon-γ-inducible 10-kd protein (IP-10/CXCL10), and IL-18 and monocyte and granulocyte counts significantly decreased with anakinra treatment but did not normalize to levels in the controls, even in patients fulfilling criteria for clinical remission. CSF IL-6 and IL-18 levels significantly correlated with measures of blood-brain barrier function, specifically CSF protein (r = 0.75 and r = 0.81, respectively) and albumin quotient (r = 0.79 and r = 0.68, respectively). When patients were treated with canakinumab versus anakinra, median CSF white blood cell counts and IL-6 levels were significantly higher with canakinumab treatment (10.2 cells/mm3 versus 3.7 cells/mm3 and 150.7 pg/ml versus 28.5 pg/ml, respectively) despite similar serum cytokine levels. CONCLUSION: CSF leukocyte subpopulations and cytokine levels significantly improve with optimized IL-1 blocking treatment, but do not normalize. The correlation of CSF IL-6, IP-10/CXCL10, and IL-18 levels with clinical laboratory measures of inflammation and blood-brain barrier function suggests that they may have a role as biomarkers in central nervous system (CNS) inflammation. The difference in inhibition of CSF biomarkers between 2 IL-1 blocking agents, anakinra and canakinumab, suggests differences in efficacy in the intrathecal compartment, with anakinra being more effective. Our data indicate that intrathecal immune responses shape CNS inflammation and should be assessed in addition to blood markers.

Cetuximab-induced aseptic meningitis: case report and review of a rare adverse event.

BACKGROUND: Cetuximab is a commonly used antibody agent in the treatment of colorectal or head and neck cancer. Although it is generally well tolerated in most patients, cetuximab has been associated with some rare but serious adverse events. Aseptic meningitis is one such distinctly uncommon adverse drug reaction. CASE PRESENTATION: We present the case of a middle-aged Caucasian patient, who presented with fever and headache within a few hours of starting cetuximab therapy and was diagnosed with cetuximab-induced aseptic meningitis after a complete workup. CONCLUSION: To our knowledge, this is the ninth case of cetuximab-induced aseptic meningitis reported in literature. Because of a nonspecific clinical presentation, this adverse drug reaction can be easily misdiagnosed. It is important to increase awareness of this potentially severe reaction among oncologists.

[Aseptic meningitis in a patient with cerebrospinal fluid anti-agalactosyl IgG antibody-positive preclinical rheumatoid arthritis: a case report].

A 69-year-old woman presented with non-fluent aphasia, ideomotor apraxia, right hemiparesis and convulsion. Her medical history was unremarkable, and she had not suffered from arthritis. DWI and FLAIR image of brain MRI showed hyperintensities in the subarachnoid space along the left frontal and both parietal lobes, and these lesions were associated with gadolinium enhancement. The levels of serum anti-cyclic citrullinated peptide antibody, anti-agalactosyl IgG antibody and matrix metalloproteinase-3 were elevated. The results of blood cultures were negative. Cerebrospinal fluid (CSF) analysis revealed monocytic pleocytosis and negative findings for infection or malignancy. The level of anti-agalactosyl IgG antibody in CSF was elevated. The antibody index (AI) of anti-agalactosyl IgG antibody (the ratio between the CSF/serum quotient for IgG antibodies, and the CSF/serum quotient for total IgG; normal value of AI < 1.3) showed considerably high value of 8.4, indicating the intrathecal-specific antibody synthesis. As a result, the pathogenesis of her disease was consistent with rheumatoid meningitis despite lack of arthritis. After intravenous administration of methylprednisolone, her symptoms, the level of anti-agalactosyl IgG antibody in CSF, and the MRI findings were ameliorated. Anti-agalactosyl IgG antibody in the CSF was a helpful biomarker in diagnosis and assessment of the severity of rheumatoid meningitis.

Aseptic arachnoiditis in a patient treated with intrathecal morphine infusion: symptom resolution on switch to ziconotide.

INTRODUCTION: Since 1980, about 95,000 intrathecal (IT) drug delivery pumps have been implanted for the administration of a variety of opioid and non-opioid agents for neuropathic and nociceptive pain patients. IT granuloma in chronic opioid infusion is becoming less rare as an adverse effect of IT therapy and has been associated with many analgesic infusion agents. MATERIALS AND METHODS: After thymectomy, upper left lobectomy, and pericardial resection, our patient developed a left hemithorax nociceptive pain. An IT catheter and infusion pump were implanted, providing adequate analgesia. After eight months, the patient developed pain in the lower extremities without neurological impairment and an urge to move the legs without meningeal signs (3.2 mg morphine/day). A lumbar puncture revealed an inflammatory reaction in the cerebrospinal fluid (CSF); neuroimaging results were negative for granuloma. Reduction in morphine dose and a switch to ziconotide infusion were carried out. Nine months after the switch, CSF test values were in normal ranges. The patient described ongoing benefit in terms of pain and walking ability. RESULTS: The patient reported restless legs and leg pain, causing insomnia and necessitating an increase in IT opioid dose. After the switch to ziconotide and morphine discontinuation, inflammatory reactions and symptoms in the CSF abated. CONCLUSIONS: CSF analysis should be performed in patients chronically treated by IT infusion who develop a rapid increase in pain with or without neurological deficits. A switch to ziconotide can be an option in patients without neurological signs. Further studies are needed to determine the relationship between granuloma formation and CSF reaction.

Successful long-term control of lymphomatous meningitis with intraventricular rituximab.

Most primary central nervous system lymphomas (PCNSL) are highly malignant B-cell non-Hodgkin lymphomas. First-line therapy consists of high-dose methotrexate-based chemotherapy with or without whole brain radiotherapy. However, no standard of care is defined for refractory or recurrent PCNSL. We report a patient with lymphomatous meningitis, which was refractory to standard treatment but was successfully controlled for more than 6 years with intraventricular rituximab. Apart from two infections of the Ommaya reservoir, no severe side effects of intraventricular long-term treatment could be detected. This report indicates that intraventricular administration of rituximab might be beneficial in select patients with refractory or recurrent lymphomatous meningitis.