Chronic Aseptic Meningitis Research Articles

Comparison of structure and immunogenicity of CVB1-VLP and inactivated CVB1 vaccine candidates.

Coxsackievirus B1 (CVB1) is a common cause of acute and chronic myocarditis, dilated cardiomyopathy and aseptic meningitis. However, no CVB-vaccines are available for human use. In this study, we investigated the immunogenicity of virus-like particle (VLP) and inactivated whole-virus vaccines for CVB1 when administrated to mice via either subcutaneous or intranasal routes formulated with and without commercial and experimental adjuvants. Here, the potential of utilizing epigallocatechin-3-gallate (EGCG) as a mucosal adjuvant synergistically with its ability to inactivate the virus were investigated. EGCG had promising adjuvant properties for CVB1-VLP when administered via the parenteral route but limited efficacy via intranasal administration. However, intranasal administration of the formalin-inactivated virus induced high CVB1-specific humoral, cellular, and mucosal immune responses. Also, based on CVB1-specific IgG-antibody responses, we conclude that CVB1-VLP can be taken up by immune cells when administrated intranasally and further structural engineering for the VLP may increase the mucosal immunogenicity. The preparations contained mixtures of compact and expanded A particles with 85% expanded in the formalin-inactivated virus, but only 52% in the VLP observed by cryogenic electron microscopy. To correlate the structure to immunogenicity, we solved the structures of the CVB1-VLP and the formalin-inactivated CVB1 virus at resolutions ranging from 2.15 A to 4.1 A for the expanded and compact VLP and virus particles by image reconstruction. These structures can be used in designing mutations increasing the stability and immunogenicity of CVB1-VLP in the future. Overall, our results highlight the potential of using formalin inactivated CVB1 vaccine in mucosal immunization programs and provide important information for future development of VLP-based vaccines against all enteroviruses.

Clinical spectrum of Cryopyrin-associated Periodic Syndrome associated with a single nucleotide variant of the NLRP3 gene in a Puerto Rican family

Cryopyrin-associated Periodic Syndromes (CAPS) are a group of autoinflammatory disorders of varying degrees of severity that include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID, or as Chronic Infantile Neurological, Cutaneous, and Articular (CINCA). There is one case per one million inhabitants in the United States. Cryopyrinopathies arise from mutations in the NOD-like receptor protein 3 (NLRP3) gene, which assembles with the cysteine protease caspase-1 to form the NLP3 and releases several proinflammatory cytokines, including IL-1β. An autosomal dominant GOF mutation of the NLRP3 gene causes the overproduction of IL-1β, inducing excessive inflammation and even permanent organ damage. We describe a Puerto Rican family of three with Cryopyrin-associated Periodic Syndrome and varying degrees of severity that received Canakinumab. A 40-year-old mother and her two sons, ages 26 and 20, presented for an evaluation of cold-induced maculopapular rash, arthralgia, and lower extremity swelling. Their symptoms initially presented at birth and continued into their adulthood. The episodes started briefly after exposure to cool temperatures and lasted hours to days. High fevers and chills often accompany episodes. They all presented with chronic leukocytosis and high inflammatory laboratory values. The oldest son showed the most intense, enduring flares and severe complications. At age 1, he was diagnosed with neuroblastoma of the right adrenal gland and achieved remission with a combination of surgical resection, chemotherapy, and radiotherapy. He subsequently required multiple hospitalizations due to episodes of high fevers as a child. He also developed severe leptomeningeal inflammation at age 12 and underwent an exploratory craniotomy that yielded normal findings. The three family members underwent genetic testing two decades after the children were born, revealing a heterozygous missense mutation. They had a single nucleotide variant of the NPL3 gene c.913G>A (p. Asp305Asn) that has been linked to CAPS. Severe inflammatory neurologic symptoms and familial cold urticaria were the clues for the diagnostic suspicion of CAPS. IL-1β antagonists have been demonstrated to be effective in substantially reducing inflammatory markers and thus decreasing inflammation-related signs and symptoms. Residence in the tropics could have contributed to delayed diagnosis.Table 1General characteristics of the Cryopyrin-associated Periodic SyndromesFCASMWSNOMID/CINCAGenes and pattern of inheritanceNLRP3 gene ADNLRP3 gene ADNLRP3 gene ADEpidemiology Age of onset1:1 million.1Infancy1:1 million1Infancy1:1 million1Neonatal/early infancyCutaneous NeurologicUrticaria-like rash Headaches with fever after cold exposureUrticaria-like rash Headaches with fever during flares. Uncommon to have other CNS symptoms. 3Urticaria-like rash Headaches, fever, chronic aseptic meningitis, and high CNS pressure. Many develop mental or cognitive impairment.AuditoryMild hearing lossSensorineural hearing loss starting in adolescenceSensorineural hearing loss from infancy/childhoodOphthalmicConjunctivitis during flaresConjunctivitis during flaresPapilledema, uveitis, iritis, conjunctivitis, and vision lossLymphaticNot notedMay be notedMay have enlarged lymph nodesJointsArthralgiaArthralgia, stiffness, and swelling during flaresArthralgia, stiffness, and swelling during flaresLaboratory valuesHigh ESR, CRP, SAA, and leukocytosis with flaresHigh ESR, CRP, SAA, and leukocytosis with flaresChronically elevated ESR, CRP, SAA, and leukocytosisFCAS, Familial cold autoinflammatory syndrome; MWS Muckle Wells Syndrome; CINCA/NOMID, chronic infantile neurologic, cutaneous, and articular syndrome/neonatal-onset multisystem inflammatory disease.

Lifting the Lid on CAPS: Uncovering Genetic Anticipation in Cryopyrin-Associated Periodic Syndrome

Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of autoinflammatory conditions comprising three subtypes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID).1 Symptoms include urticaria, fever, arthralgias, conjunctival injection, and headaches, which can occur spontaneously or during periods of cold/stress.2 Complications include permanent sensorineural hearing loss (SNHL), chronic aseptic meningitis, systemic amyloidosis, developmental delay, seizures, and chronic arthropathy.3 CAPS is treated with inhibition of interleukin (IL)-1 which can reduce symptoms and prevent progression of complications including hearing loss, CNS inflammation, and renal disease from amyloidosis.3,4.Here, we present a five-year-old boy who developed unexplained arthralgias, SNHL, increased intracranial pressure, atrophic retinal nerve fiber layer, and painful urticaria. Laboratory testing showed elevated inflammatory markers and neutrophil count. Genetic testing showed a heterozygous variant in the NLRP3 gene that was previously reported in a patient with NOMID. Interestingly, his mother had similar history of arthralgia, aseptic meningitis, SNHL, and recurrent aphthous ulcers, while his maternal grandmother had a history of SNHL and arthralgia. The mother and grandmother had similar elevations in inflammatory markers and neutrophils. Both were found to have the same variant in NLRP3 as the index patient and were diagnosed with CAPS/NOMID. The histories suggested a degree of genetic anticipation, for the child’s symptoms were most severe, while his mother had moderate symptoms and his grandmother was relatively mildly affected. Notably, neither the mother nor grandmother had signs of kidney disease to suggest amyloidosis. All three family members were started on canakinumab injections. The child’s arthralgias and mother’s symptoms improved, and flares have decreased in frequency. The grandmother has not yet received therapy long enough to assess for improved symptoms.CAPS is a group of autoinflammatory disorders with autosomal dominant inheritance, quality-of-life-limiting symptoms, and potential life-long complications. CAPS should be suspected and screened for in relatives of affected individuals. This familial case demonstrates a pattern of increased severity of CAPS symptoms with each subsequent generation from grandmother to grandchild suggestive of genetic anticipation. Early diagnosis and initiation of anti-IL-1 therapy is important to prevent progression and complications.

Chronic aseptic meningitis caused by enterovirus in a humorally immunosuppressed adult patient presenting with sensorineural hearing loss: a case report

BackgroundEnterovirus has been described as a cause of aseptic meningitis in humorally immunosuppressed patients.Case presentationA 67-year-old female with a history of mantle cell lymphoma on rituximab therapy presented with subacute hepatitis, myalgias, and sensorineural hearing loss several months after an initial febrile illness. She was diagnosed with enterovirus infection by CSF PCR as a unifying etiology of her presentation, representing an unusual presentation of disease.Discussion and conclusionsThis patient’s unique presentation and clinical course presents important implications in the care of similarly immunosuppressed patients with cryptic complaints.

Isolated Chronic Aseptic Meningitis Due to SARS-COV-2 Unresponsive to Ordinary Treatments

: Serious, and sometimes, deadly complications of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are devastating. Whereas most manifestations of COVID-19 are respiratory (fever, dry cough, fatigue, pneumonia), it is getting to be progressively recognized that numerous organ functions can be affected by this disease, and the nervous system is one of them as neurological complications can affect up to 36% of adult patients. However, the prevalence and pathophysiology of these complications have yet to be fully elucidated in children. Here, we discuss an infant with neurological symptoms manifested as chronic isolated aseptic meningitis associated with COVID-19, which was unresponsive to ordinary treatments and dramatically responsive to dexamethasone. Immune-mediated reactions may have had a major pathophysiologic role in this case.

Neurological manifestations of autoinflammatory diseases in Chinese adult patients

ObjectiveSystemic autoinflammatory diseases (SAIDs) are a group of disorders characterized by a dysregulation of innate immune system leading to multi-systemic inflammation. We aim to assess the neurological manifestations of Chinese adult patients with SAIDs. MethodsEighty adult patients (≥16 years) were diagnosed as SAIDs from April 2015 to June 2019, at the center of adult autoinflammatory diseases, Department of Rheumatology, Peking Union Medical College Hospital. Clinical and genetic features of these patients were collected. All patients underwent neurologic, ophthalmologic and otolaryngologic evaluation. ResultsTotally 31 out of 80 (38.8%) patients had neurological manifestations, including 14 familial Mediterranean fever (45.2%), 6 NLRP3-associated autoinflammatory disease (19.4%), 5 tumor necrosis factor receptor-associated periodic fever syndrome (16.1%), 5 NLRP12-associated autoinflammatory disease (16.1%), and 1 Yao syndrome (3.2%). Twenty patients (64.5%) were adult-onset. The median time of diagnosis delay was 11.7 years (0.5–50 years). The common neurological damage included headache (28 patients, 90.3%), sensorineural hearing loss (6, 19.4%), dizziness (4, 12.9%), cerebral infarction/hemorrhage (4, 12.9%), chronic aseptic meningitis (3, 9.7%), intracranial hypertension (3, 9.7%), papilledema (3, 9.7%), optic neuritis (2, 6.5%), and hydrocephalus (1, 3.2%). Severe neurological damage was observed in 8 patients (25.8%), including brain atrophy, hydrocephalus, complete hearing loss, chronic aseptic meningitis and optic neuritis. ConclusionNeurological damage was diverse in SAIDs patients. Neurological symptoms should be fully realized by physicians, in not only pediatric but also adult patients with SAIDs. CSF analysis and brain images should be performed promptly. Early diagnosis and appropriate treatment are essential to avoid irreversible neurological complications.

Formalin treatment increases the stability and immunogenicity of coxsackievirus B1 VLP vaccine

Type B Coxsackieviruses (CVBs) are a common cause of acute and chronic myocarditis, dilated cardiomyopathy and aseptic meningitis. However, no CVB-vaccines are available for human use. We have previously produced virus-like particles (VLPs) for CVB3 with a baculovirus-insect cell production system. Here we have explored the potential of a VLP-based vaccine targeting CVB1 and describe the production of CVB1-VLPs with a scalable VLP purification method. The developed purification method consisting of tangential flow filtration and ion exchange chromatography is compatible with industrial scale production. CVB1-VLP vaccine was treated with UV-C or formalin to study whether stability and immunogenicity was affected. Untreated, UV treated and formalin treated VLPs remained morphologically intact for 12 months at 4 °C. Formalin treatment increased, whereas UV treatment decreased the thermostability of the VLP-vaccine. High neutralising and total IgG antibody levels, the latter predominantly of a Th2 type (IgG1) phenotype, were detected in female BALB/c mice immunised with non-adjuvanted, untreated CVB1-VLP vaccine. The immunogenicity of the differently treated CVB1-VLPs (non-adjuvanted) were compared in C57BL/6 J mice and animals vaccinated with formalin treated CVB1-VLPs mounted the strongest neutralising and, CVB1-specific IgG and IgG1 antibody responses. This study demonstrates that formalin treatment increases the stability and immunogenicity of CVB1-VLP vaccine and may offer a universal tool for the stabilisation of VLPs in the production of more efficient vaccines.

Early canakinumab therapy for the sensorineural deafness in a family with Muckle-Wells syndrome due to a novel mutation of NLRP3 gene

Cryopyrin-associated periodic syndrome (CAPS) is one of the autoinflammatory disorders caused by mutations in NLRP3 gene. The over-production of interleukin (IL)-1β induced by NLRP3 gene mutations plays an important role in the pathophysiology of CAPS. We diagnosed 3 patients with CAPS, who were lineal family members having a novel mutation of NLRP3 gene. The objective of this report is to compare the characteristics of symptoms and differences in the therapeutic responses of them, who had the same mutation. In addition, we aimed to examine the usefulness of cytokine measurement for diagnosis or determination of treatment effect of CAPS. A 5-year-old Japanese boy (proband) came to our hospital because of short stature, reached the diagnosis of Muckle-Wells syndrome (MWS) due to a mutation in NLRP3 gene, which had not been reported so far (p.G328E, c.G983A). His mother and grandmother harbored the same mutation of NLRP3. We measured serum concentrations of cytokines in the proband assessed by flow-cytometric bead array. All of them had episodic skin eruptions with conjunctivitis, hearing loss, and arthralgia, but not periodic fever, cold-triggered episodes, and chronic aseptic meningitis. Only the proband had short stature. Canakinumab therapy led to a prompt relief of symptoms and normalized laboratory data in all patients. Audiograms demonstrated an improved hearing level in the proband, but not two others despite of the same mutation. All cytokines did not show any characteristic findings. Sensorineural hearing loss and itchless rash but not serum cytokine profile deserved attention to the diagnosis and treatment start of CAPS. The early intervention of IL-1β blockade may reduce the chance of complete deafness in patients with CAPS.

Atypical type of familial Mediterranean fever: An underdiagnosed cause of chronic aseptic meningitis.

We report an atypical case of familial Mediterranean fever (FMF) concomitant with chronic aseptic meningitis. The patient experienced fever, abdominal and back pain because of serositis, and headache because of aseptic meningitis for 4 weeks. Blood examinations revealed increased white blood cells and serum amyloid A level. Medications, including steroids, did not improve his symptoms. However, the patient experienced immediate relief after the administration of colchicine. We diagnosed him as having atypical FMF based on the symptoms, especially positive response to colchicine, and heterozygous mutations on exon2 and 5 (E148Q/S503C) in MEFV gene. Unlike typical FMF, a cause of recurrent aseptic meningitis, atypical FMF might be an underdiagnosed cause of chronic aseptic meningitis.

Chronic Infantile Neurological Cutaneous and Articular (CINCA) syndrome: a review.

IntroductionThe Chronic Infantile Neurological Cutaneous and Articular (CINCA, or Neonatal-onset multisystem inflammatory disease NOMID) is a rare autoinflammatory disease identified in 1987 by Prieur et al., typically characterized by the triad of skin rash, arthropathy and central nervous system manifestations. It represents the most severe phenotype of the cryopyrin-associated periodic syndrome (CAPS).Clinical description and etiologyThe syndrome is due to autosomal dominant gain of function mutations in NLRP3, which encodes a key component of the innate immunity that regulates the activation and secretion of interleukin (IL)-1β. From the first days of life, patients display an urticarial rash in association with chronic inflammation with a typical facies featured by frontal bossing and saddle back nose. The CNS manifestations include chronic aseptic meningitis leading to brain atrophy, mental delay and sensorineural hearing loss. Chronic polyarthritis and alteration of the growth cartilage also may be present. CINCA/NOMID diagnosis is made clinically, based on the presence of characteristic features. The detection of NLRP3 mutations is diagnostic in 65–70% of cases. Indeed, up to 40% of affected patients are negative for germline NLRP3 mutations and several subjects are carriers of somatic mosaicism. Due to the pivotal role of Cryopyrin in the control of Caspase-1 activation and the massive secretion of active IL-1β observed in cryopyrin-mutated individuals, anti-IL1 treatment represents the standard therapy.ConclusionPrognosis of CINCA/NOMID syndrome has been changed by the availability of anti-IL1 drugs. Nowadays, the use of anti-IL-1 drugs has sensibly reduced the risk of developing main complications such as severe intellectual disability, hearing-loss and amyloidosis, if treatment is started early on.

Neurosarcoidosis in a Tertiary Referral Center: A Cross-Sectional Cohort Study.

The aim of this study was to evaluate clinical characteristics, diagnostic strategy, and treatment in patients with neurosarcoidosis in a tertiary referral centre.In a cross-sectional study, we included all patients with neurosarcoidosis treated at our tertiary referral center between September 2014 and April 2015.We identified 52 patients, among them 1 patient was categorized as having definite neurosarcoidosis, 37 probable neurosarcoidosis, and 14 possible neurosarcoidosis. Neurologic symptoms were the first manifestation of sarcoidosis in 37 patients (71%). Chronic aseptic meningitis was the most common presentation (19/52 patients [37%]), followed by cranial neuropathy (16/52 patients [31%]). Serum angiotensin-converting enzyme and lysozyme levels were elevated in 18 of 41 (44%) and 12 of 26 cases (46%). Pulmonary or lymph node sarcoidosis was identified by chest X-ray in 21 of 39 cases (54%) and by computed tomography of the chest in 25 of 31 cases (81%); Fluorodeoxyglucose-Positron emission tomography showed signs of sarcoidosis in 15 of 19 cases (79%). Thirty-one of the 46 cases receiving treatment (67%) improved, 13 cases (28%) stabilized, and 2 cases (4%) deteriorated. First-line treatment with corticosteroids resulted in satisfactory reduction of symptoms in 21 of 43 patients (49%). Seventeen patients (33%) needed second-line cytostatic treatment, and 10 patients (19%) were treated with tumor necrosis factor-α inhibitors.The majority of patients with neurosarcoidosis present with chronic meningitis without a history of systemic sarcoidosis. The diagnosis can be difficult to make because of the poor sensitivity of most diagnostic tests. Half of patients had a satisfactory reduction of symptoms on first-line therapy.

Leptomeningeal carcinomatosis as primary manifestation of pancreatic cancer

Leptomeningeal carcinomatosis (LMC) is a rare complication of cancer that often presents at an advanced stage after obvious metastasis of a primary cancer or locally advanced disease. We present an uncommon case of LMC secondary to pancreatic carcinoma presenting with headache, unilateral VII nerve palsy, and lower extremity weakness. Initial cerebrospinal fluid (CSF) studies were concerning for chronic aseptic meningitis but negative for malignant cells; the diagnosis of tuberculous meningitis was erroneously evoked. Three lumbar punctures were required to capture malignant cells. The diagnosis of LMC was based on CSF examination with cytology/immunohistochemistry and leptomeningeal enhancement on MRI. Post mortem autopsy revealed advanced and diffusely metastatic pancreatic adenocarcinoma. This patient demonstrates that solid tumors can present with leptomeningeal spread that often confuses the treating physician. Fungal or tuberculous meningitis can mimic LMC in the absence of neoplastic signs and negative CSF cytology. This event is exceedingly rare in pancreatic cancer. If the index of suspicion is high, repeat CSF sampling can increase the sensitivity of detection of malignant cells and thus result in the correct diagnosis.

Neurocysticercosis Presenting as Chronic Relapsing Aseptic Meningitis

Distinguishing between recurrent and relapsing meningitis can be difficult, particularly in those instances when cerebrospinal fluid is not analyzed during resolved or asymptomatic periods. Relapsing meningitis is a rare clinical entity and implies a chronic condition characterized by spans of time void of any symptoms, during which time the etiology or stimulus for the chronic meningeal inflammatory process has been either partially responsive to treatment or has eluded a specific diagnosis altogether. We report a case of neurocysticercosis that presented in such a relapsing fashion that necessitated an open craniotomy to eventually make a diagnosis and allow for specific treatment.

A173: Cerebrospinal Fluid Cytokines Correlate With Innate Immune Cells in Neonatal Onset Multisystem Inflammatory Disease (NOMID) Patients in Clinical Remission Treated With Anakinra

Background/Purpose:Neonatal onset multisystem inflammatory disease (NOMID) is a rare autoinflammatory disease caused by NLRP3 mutations that lead to constitutive NLRP3 inflammasome activation and IL‐1β release. Patients present with neutrophilic urticaria, chronic aseptic meningitis, and papilledema. IL‐1β inhibitors improve the inflammatory manifestations, normalize acute phase reactants, decrease CSF WBC and protein, and proinflammatory cytokine levels. We found that cytokine levels decrease with anakinra treatment, but do not normalize during clinical remission. The higher IL‐6 and IP‐10 levels in CSF than in the blood suggest local production in the brain/CSF. Our objective is to examine whether CSF cytokines, particularly IL‐6 and IP‐10, correlate with CSF subpopulations of immune cells and CSF characteristics.Methods:Immunophenotyping and cytokine data were available on 2 baseline and 16 anakinra treated patients, 9/16, fulfilled clinical remission criteria (ESR ≤25 mm/hr, CRP ≤0.5 mg/dl, CSF WBC ≤5 cells/μl and protein ≤40 mg/dl) and control patients (n = 7). Cytokines levels (IL‐1β, IL‐6, IL‐10, IP‐10, IL‐12 (p70) and (p40), IFN‐γ, TNF‐α, and IL‐18) were correlated to CSF WBC, protein, albumin quotient (AQ), and opening pressure at baseline, post‐treatment, and clinical remission. Correlation was assessed with Pearson and Spearman tests.Results:At baseline, monocytes, granulocyte, and T cells were higher in NOMID patients versus controls. Post‐treatment monocytes and granulocyte counts decreased but remained higher even in clinical remission, relative to control. Only IL‐6 and IP‐10 correlated with monocytes (r = .66, p = .051; r = .86, p = .002) respectively. A correlation of IP‐10 but not IL‐6 with granulocytes was weaker than with monocytes (r = .66, p = .058). IL‐6, IP‐10, and IL‐18 correlated with CSF protein, AQ, and WBC (except IL‐18). At baseline, IL‐6 and IL‐18 significantly correlated with CSF protein (r = .68, p = .027; r = .80, p = .0065) and AQ (r = .82, p = .011; r = .78, p = .029) respectively. At post‐treatment, IL‐18 significantly correlated and IL‐6 trend towards significance with CSF protein (r = .53, p = .022; r = .40, p = .096) and AQ (r = .83, p = .0002; r = .47, p = .087) respectively.Conclusion:1) Inflammatory cells significantly decrease in NOMID patients, especially monocytes which remain elevated even in patients in clinical remission, suggesting residual inflammation. 2) The correlation of monocytes with IL‐6 and IP‐10 suggests their contribution to IL‐6 and IP‐10 production, which may contribute to the recruitment of other inflammatory cells including granulocytes. 3) IL‐6, IP‐10, and IL‐18 may be a marker for blood brain barrier dysfunction in NOMID and their use in long term monitoring should be explored. 4) These results are consistent with the notion that NOMID is caused by dysfunction in innate immune cells, particularly monocytes.

PReS-FINAL-2200: Phenotype of V198M and Q703K NLRP3 variants

The term CAPS (Cryopyrin-Associated Periodic Syndromes) identifies a spectrum of autoinflammatory diseases caused by heterozygous mutations of the CIAS1/NLRP3. Affected individuals may present three different phenotypes: Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) and CINCA syndrome, the most severe form of the clinical spectrum. Clinical manifestations include urticaria-like rash, recurrent fever, arthralgia, conjunctivitis; chronic aseptic meningitis, cerebral atrophy and bone malformations in the severe cases. The term CAPS (Cryopyrin-Associated Periodic Syndromes) identifies a spectrum of autoinflammatory diseases caused by heterozygous mutations of the CIAS1/NLRP3. Affected individuals may present three different phenotypes: Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) and CINCA syndrome, the most severe form of the clinical spectrum. Clinical manifestations include urticaria-like rash, recurrent fever, arthralgia, conjunctivitis; chronic aseptic meningitis, cerebral atrophy and bone malformations in the severe cases.

P02-031 - Phenotype of V198M and Q703K NLRP3 variants

The term CAPS (cryopyrin-associated periodic syndromes) identifies a spectrum of autoinflammatory diseases caused by heterozygous mutations of the CIAS1/NLRP3. Affected individuals may present three different phenotypes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and CINCA syndrome, the most severe form of the clinical spectrum. Clinical manifestations include urticaria-like rash, recurrent fever, arthralgia, conjunctivitis; chronic aseptic meningitis, cerebral atrophy and bone malformations in the severe cases.

A report of the natural history of leptomeningeal gliomatosis

Primary leptomeningeal gliomatosis (PLG) is a rare condition, with fewer than 50 patients reported. Our report illustrates the natural history of PLG in full, from the prodromal phase of subacute meningitis to the final stages characterised by extensive nerve root infiltration, cranial nerve palsies and widespread peripheral neurogenic muscle wasting. We provide correlative neuroimaging with serial MRI, and present the first published positron emission tomography imaging of this condition. We emphasise the importance of considering PLG in the differential diagnosis of chronic aseptic meningitis, the difficulties of making the diagnosis ante mortem, and the utility and potential limitations of early meningeal biopsy in this condition.

The Anesthetic Management of Children with Neonatal-Onset Multi-System Inflammatory Disease

Neonatal-onset multi-system inflammatory disease (NOMID), a rare autosomal dominantly inherited disease, belongs to a growing spectrum of autoinflammatory diseases, is characterized by urticarial rash, arthropathy, and chronic aseptic meningitis, and is associated with mutations in the cold-induced autoinflammatory gene, CIAS1, the gene that encodes the protein, cryopyrin. As little is known about the anesthetic considerations of the disease, we sought to identify the main features and respective anesthetic and perioperative implications of NOMID. We examined perianesthetic records of children with NOMID who were anesthetized for invasive diagnostic and therapeutic interventions between 2003 and 2006. In addition, we conducted an extensive literature review of the genetic, clinical, and biochemical abnormalities of the disease. Seventeen children with NOMID (median age 8 yr, range 9 mo to 11 yr) were anesthetized for diagnostic and therapeutic procedures. All patients had neurological involvement, including increased intracranial pressure, chronic aseptic meningitis, and developmental delay; 7 had bony overgrowth, 15 ocular, and 14 otological manifestations of NOMID. Despite the complexity of the disease, the perioperative course was uncomplicated, and no serious adverse events were observed. This study is the first to investigate the anesthetic implications of NOMID, an autoinflammatory disease associated with arthropathy, recurrent fevers, urticarial rash, and chronic aseptic meningitis. While for the pediatric anesthesiologist, the presence of fever and aseptic meningitis might make the conduct of anesthetics for elective procedures less desirable, our findings suggest that without evidence of active infection, even in the presence of fever and chronic aseptic meningitis, general and regional anesthesia may be conducted in patients with NOMID without untoward complications.

Disseminated primary diffuse leptomeningeal gliomatosis: a case report with liquid based and conventional smear cytology

BackgroundPrimary diffuse leptomeningeal gliomatosis is a rare neoplasm confined to the meninges without evidence of primary tumor in the brain or spinal cord parenchyma. Cerebrospinal fluid diversion via ventriculoperitoneal shunt may be used as a therapeutic modality. Herein, we describe the first report of cytologic findings of a case of this neoplasm with shunt-related peritoneal metastasis.Case presentationA 19-year-old male presented with a 6-month history of severe headaches. He had bilateral papilledema on physical exam. Cerebrospinal fluid examination was negative. Four months later a ventriculoperitoneal shunt was placed. Shortly thereafter, he was diagnosed with primary diffuse leptomeningeal gliomatosis based on the biopsy of an intradural extramedullary lesion adjacent to the lumbar spinal cord at a referral cancer center. The histology featured an infiltrating growth pattern of pleomorphic astrocytes with diffuse positivity for glial fibrillary acidic protein. A couple of months later he presented at our institution with ascites and an anterior peritoneal mass. Repeat cerebrospinal fluid cytology and fine needle aspiration of the mass confirmed disseminated gliomatosis. Cytologic characteristics included clusters of anaplastic cells of variable size, high nuclear to cytoplasm ratio and scant to moderate cytoplasm. Occasional single bizarre multinucleated cells were seen with eccentric "partial wreath-like" nuclei, clumped chromatin and prominent nucleoli. Patient expired 13 months after initial presentation.ConclusionDisseminated primary diffuse leptomeningeal gliomatosis should be considered in the differential diagnosis of chronic aseptic meningitis and in the presence of a peritoneal tumor in patients with ventriculoperitoneal shunts. Immunocytochemistry may be of diagnostic value.

Pneumocephalus and Cerebrospinal Fluid Fistula Following Removal of a Superior Sulcus Tumor (Pancoast Tumor)

Pneumocephalus resulting from a subarachnoid-pleural fistula following resection of a pulmonary neoplasm is a very rare postoperative complication: we have found only 17 cases in the literature. We report the case of a 65-year-old man diagnosed with a superior sulcus tumor who underwent a left upper lobectomy and costal resection following neoadjuvant radiation therapy. Soon after surgery, the patient developed a subarachnoid-pleural fistula and pneumocephalus that required reoperation and drainage. Recurrence was suspected when chronic aseptic meningitis developed. Another thoracotomy was required to resolve the complication.