Cetuximab induced aseptic meningitis

Sirs: Sjogren’s syndrome (SjS) is one of the major autoimmune disorders and is characterized by dry eyes and a dry mouth. A wide variety of extraglandular manifestations has been reported in SjS. Aseptic meningitis is a well-known manifestation of SjS; however, little is known about its pathomechanism [1, 3]. We detected a unique autoantibody in the serum and cerebrospinal fluid (CSF) of an SjS patient with recurrent aseptic meningitis. A 19-year-old female was readmitted to our hospital after the third recurrence of aseptic meningitis. Nine months and five months before this admission, she had experienced the same symptoms, i.e., headache, nausea, and fever. She was diagnosed with aseptic meningitis because of the presence of mononuclear pleocytosis in the CSF. The symptoms subsided spontaneously within a few days. On examination, there were no subjective symptoms of sicca syndrome, and Schirmer’s test was negative. Neurological examination revealed no abnormalities, except stiffness of the neck. Laboratory tests revealed elevated amylase (268 IU/dl) and serum IgG (2920 mg/dl) concentrations; positive rheumatoid factor (2+); accelerated erythrocyte sedimentation rate (30 mm/h); and positive serum antinuclear antibody (ANA) as well as the anti-SS-A and anti-SS-B antibodies at titers of 1:2560, 1:256, and 1:8, respectively. The CSF contained 153 mg/dl protein and 85 mm of cells (81% mononuclear cells); the anti-SS-A and anti-SS-B antibodies were absent. These findings led us to suspect SjS. A sialogram revealed the destruction of the sialoducts, and a salivary gland biopsy revealed abundant lymphocytic infiltration. The patient was diagnosed with SjS and recurrent aseptic meningitis, and she was treated with 50 mg of daily oral prednisolone. Based on the results of the physical and serological examinations, we inferred that the overlapping of other systemic autoimmune diseases with SjS is unlikely. The clinical symptoms resolved immediately without subsequent recurrence. The patient’s serum and CSF were analyzed by using western blotting (WB) and immunohistochemistry as reported previously [4]. WB of bovine tissue samples showed that the CSF reacted with two bands with apparent molecular weights of 56 kD and 44 kD in the cerebral cortex, meningeal tissue, and liver (Fig. 1a). Immunohistochemical analysis by the avidin-biotin-peroxidase method using rat cerebral slices showed that the CSF labeled the nuclei of the neurons and meningeal cells (Fig. 1b). We detected an identical autoantibody in the patient’s serum (data not shown). Mauch et al. reported that approximately 70% SjS patients had neurological complications; of these, one-sixth had aseptic meningitis [3]. Alexander et al reported that from a group of 25 consecutive SjS patients with CNS involvements, 5 (20%) had recurrent aseptic meningitis or meningoencephalitis [1]. Although aseptic meningitis is common in SjS, recurrent aseptic meningitis without other CNS involvements is rare, and its pathoetiology has not been elucidated thus far. Some autoantibodies may be related to the pathogenesis of the CNS involvement in SjS, for example, the possible association of the anti-SS-A antibody with cerebral angiitis [2]. However, the relationship between these autoantibodies and CNS involvement remains unknown. We demonstrated the presence of an autoantibody in the patient’s CSF and serum; this autoantibody recognizes 56and 44-kD nuclear antigens of the CNS neurons, meningeal cells, and cells of other systemic organs. The presence of this autoantibody in the patient’s CSF may imply its causative association with recurrent aseptic meningitis in SjS. We already reported some other autoantibodies in SjS patients with CNS involvements, but this is the first report K. Ishida, MD, PhD T. Uchihara, MD, PhD H. Mizusawa, MD, PhD Dept. of Neurology and Neurological Science, Tokyo Medical and Dental University Graduate School 1-5-45 Yushima, Bunkyo-ku Tokyo 113-8519, Japan

The differentiation of bacterial from aseptic meningitis in postoperative neurosurgical patients has traditionally been based on the clinical setting, a recent history of steroid administration, and cerebrospinal fluid (CSF) studies, including the total and differential leukocyte counts, Gram stain, glucose, and total protein. Recent reports questioning both the validity of a relative CSF lymphocytosis in excluding bacterial meningitis and the usefulness of standard CSF testing prompted the authors to reevaluate these standard criteria. The type of operation, the presence of a foreign body, use of steroids, postoperative day on which symptoms developed, altered mental status, neck stiffness, headache, and nausea were not helpful in the differential diagnosis. High fever, new neurological deficits, an active CSF leak, and elevated leukocyte counts in the CSF and peripheral blood favored a bacterial etiology. The CSF glucose level and the differential leukocyte count were less helpful. No criterion or combination of criteria was sensitive and specific enough to reliably differentiate aseptic from bacterial meningitis in the majority of patients. The possibility of improving diagnostic accuracy with newer tests, such as CSF lactate, ferritin, total amino acids, C-reactive protein, and amyloid-A, should be assessed.

Aseptic meningitis. A local experience

Abstract: Background: Non-polio enteroviruses (EVs) are emerged as the most common pathogens of aseptic meningitis in children. In this study we aimed to evaluate clinical, laboratory, cerebrospinal fluid (CSF) findings and the usefulness of CSF EV polymerase chain reaction on management of pediatric patients diagnosed as EV aseptic meningitis. Material-methods:This study included the pediatric patients with aseptic meningitis between January 2014 and January 2016. Results: A total of 23 patients (69.5% boys) diagnosed with EV aseptic meningitis with a median age of 57 months old (range; 1-168 months) were included. The most common months of the patients' admission to hospital were July and May. The most common clinical complaints were womiting (77.2%), fever (73.9%), headache (59%), neck stiffness (36.3%), seizure (22.7%) and altered consciousness (22.7%). CSF pleocytosis was observed in 16 (69.5%) patients and the median CSF white blood cell (WBC) count was 50 cells/mm3 ranged from 0 to 500 cells/mm3. It was found that, CSF cell count was significantly increased with age (p=0.02), whereas acute phase reactant levels and CSF biochemical components were statistically similar according to age (p>0.05). Median duration for hospitalization was 6 days (range: 1-28 days). Eight patients (34.7%) did not receive any antibiotics. Conclusion: Absence of pleocytosis may be a diagnostic challange in very young infants with aseptic meningitis and CSF cell count significantly increases with age. By using rapid EV-PCR assays in the initial diagnosis of aseptic meningitis, the unnecessary usage of antibiotics in viral meningitis can be reduced and also the duration of hospitalization can be shortened.

ObjectiveTo assess the distinguishing features of aseptic meningitis (AM) in patients with Kawasaki disease (KD) compared with bacterial meningitis (BM) patients.MethodsThirty-eight patients with KD and 126 patients with BM were retrospectively investigated. The following clinical manifestations and laboratory parameters were compared between the two groups: duration of fever before lumbar puncture, conjunctival injection, oral cavity changes, rash, cervical lymphadenopathy and extremity changes, vomiting, front fontanel bulging, neck stiffness, leukocyte number, hemoglobin level, platelet number, C-reactive protein level, cerebrospinal fluid (CSF) content, liver enzyme level, and urinalysis.ResultsVomiting and neck stiffness were more prevalent in patients with BM. KD patients with AM showed elevated blood leukocyte numbers and C-reactive protein levels in the early febrile stage. CSF glucose was significantly lower in patients with BM compared with KD patients with AM. Receiver operating characteristic curve analysis showed that the optimal cutoff value of CSF glucose for discrimination of BM and AM/KD was 2.945 mmol/L, with a sensitivity of 84.2% and a specificity of 71.4%.ConclusionsDetailed investigations of clinical manifestation and laboratory parameters are necessary to distinguish AM and BM in patients with KD. Decreased CSF glucose is a potential indicator of BM.

Detection of enteroviruses by polymerase chain reaction in urine samples of patients with aseptic meningitis.

We report a 29-year-old man with subacute necrotizing lymphadenitis (SNL) associated with recurrent aseptic meningitis following an 11-year remission period. In both episodes, headache and fever were followed by lymphadenopathy, with increased serum IgE level. Although pleocytosis in cerebrospinal fluid was confirmed at admission in the first episode, it appeared at one week after admission in the second episode. Administration of glucocorticoid was effective for treating meningitis. The present case suggests a pathomechanism for SNL that involves both an immunological background and an acute viral infection as triggers of exacerbation of aseptic meningitis.

Pituitary abscess is a rare condition. In the setting of multiple surgical interventions, the risk of its development increases. A 49-year-old man presented with episodes of altered mental status. He...

To the Editor: Sandfly fever Naples virus, Sandfly fever Sicilian virus, and Toscana virus (family Bunyaviridae, genus Phlebovirus) have been recognized as etiologic agents of human illnesses in European countries bordering the Mediterranean Sea. These viruses are responsible for rapidly resolving diseases with nonspecific symptoms such as fever and myalgia. However, infection with Toscana virus may involve the central nervous system; severity may range from aseptic meningitis to meningoencephalitis (1). In most cases, illnesses caused by Toscana virus mimics a flulike syndrome with fever, photophobia, headache, red eyes, and stiff neck. Recently, 2 cases of Toscana virus meningoencephalitis in patients with unusual symptoms and life-threatening complications were described in Italy (2). However, sequelae have never been reported. Toscana virus infection is now epidemic in Italy and Spain (1,3). Furthermore, sporadic cases have been reported in travelers returning from Italy, Spain, Greece, Portugal, and the South of France (4–6). The epidemiology of Toscana virus in France is still unknown. Although infections with this virus have been diagnosed by serologic tests in French patients and in tourists residing in southeastern France, this pathogen has reportedly never been isolated in France (7,8). Here we describe the clinical and biologic features of autochthonous meningitis due to Toscana virus. On July 9, 2004, a 57-year-old woman who had never left the southeastern coast of France reported malaise and vomiting. On hospital admission, her body temperature was 38.5°C, and clinical examination showed photophobia and stiff neck. Skin and abdomen were normal. Cardiopulmonary and neurologic functions were also normal. Analysis of hematologic and biochemical blood tests revealed mild hyperglycemia (6.88 mmol/L) and elevated γ-glutamyltransferase (104 IU/L) and C-reactive protein levels (57 mg/L). Cerebrospinal fluid (CSF) analysis showed 3,500 leukocytes/μL (70% lymphocytes, 30% neutrophils), and glucose and protein levels of 2.5 mmol/L and 2.749 mg/L, respectively. Blood and CSF cultures were bacteriologically sterile. Polymerase chain reaction (PCR) assays of CSF for herpes simplex virus were also negative. The patient received intravenous amoxicillin and acyclovir for 3 days. The patient recovered after 6 days without sequelae. Serum and CSF samples collected during the acute phase were tested for immunoglobulin (Ig)M and IgG antibodies to a battery of arboviruses. These samples contained no antibodies (optical density [OD] ratio 3 for both IgM and IgG (Table). Table Arbovirus antibody investigation of samples* Virus isolation was attempted by incubation of peripheral blood mononuclear cells and CSF collected on the day of onset with C6/36 (Aedes albopictus) and Vero (E6 clone) monolayers. Toscana virus was found only on Vero cells by indirect immunofluorescence by using mouse hyperimmune ascitic fluid against Toscana virus. In contrast, no fluorescence was found by using mouse hyperimmune ascitic fluids against Rift Valley fever and Sandfly fever Sicilian virus. S segment of Toscana virus genome was partly amplified from culture supernatants by reverse-transcription PCR and sequenced (9). Nucleotide and peptide sequences obtained (GenBank accession no. {type:entrez-nucleotide,attrs:{text:AY766034,term_id:59859084}}AY766034) displayed 87% and 100% identity, respectively, with Toscana virus sequences available on GenBank database, thus confirming the infection by Toscana virus. Toscana virus, transmitted to humans by Phlebotomus vectors, has been recognized as a major cause of aseptic meningitis in Italy and Spain. P. perniciosus, proven to be a vector of Toscana virus (10), is abundant along the French Mediterranean coast. The isolation of an autochthonous Toscana virus strain shows that the conditions of an efficient transmission cycle were combined in southern France. Until now, human infection by Toscana virus was fortuitously detected by serologic means, suggesting that subclinical infection may also occur (8). Thus, Toscana virus infection in France likely has been underestimated. Moreover, meningitis caused by Toscana virus has been underestimated and other diseases caused by Toscana virus may have also been underestimated. The requirement for virus growth in cell culture delays a diagnosis based on viral isolation, which is limited by the transitory presence of the virus in blood or CSF. As reported here, Toscana virus infection was only confirmed after the patient relapsed. Considering that signs and symptoms of Toscana virus meningitis are not pathognomic, this case highlights the need for rapid and specific diagnostic tools, such as PCR assays, to identify infections caused by Toscana virus and other neurotropic viral agents. Moreover, a systematic serologic study of recovered meningitis patients may help to better characterize viral meningitis of unknown etiology. Finally, this work suggests that, in addition to West Nile virus, Toscana virus should now be considered as a potential etiologic agent of acute meningitis in the southeastern part of France. Entomologic and epidemiologic surveys, however, will have to be conducted in the near future to determine the risk for the people living in that area.

A variety of microorganisms have been shown to cause peripheral facial nerve palsy (PFNP) and/or aseptic meningitis in children. Clinical findings and history may help to predict the specific etiology of these entities. Children > or =12 months old hospitalized at the University Children's Hospital Basel, Switzerland, from 2000 to 2005 with clinical signs of PFNP and/or aseptic meningitis were studied retrospectively. History, clinical, and laboratory findings were evaluated using analysis of variance with Bonferroni (Dunn) correction. Of 181 patients, 123 (68%) had aseptic meningitis, 28 (15%) had PFNP, and 30 (17%) had a combination of both. PFNP with aseptic meningitis was associated with Borrelia burgdorferi (Bb) infection in the majority of patients (73%) compared with 11% and 9% of patients with PFNP or aseptic meningitis, respectively. The majority of patients with aseptic meningitis without PFNP had enterovirus infection (63%). In patients with aseptic meningitis, mean leukocyte counts in cerebrospinal fluid (CSF) were higher with enterovirus (565/microL) compared with Bb infection (191/microL; P < 0.01) or unknown causes (258/microL; P < 0.01). Further, CSF mean mononuclear cell proportion was higher in patients with Bb (89%) than in those with enterovirus infection (51%; P < 0.01) or unknown causes (60%; P < 0.01). Mean time interval between onset of disease and admission to hospital showed significant differences between Bb (7.6 days) and enterovirus infection (2.8 days; P < 0.01) or unknown causes (2.0 days; P < 0.01). Time interval between onset of disease and hospital admission and CSF characteristics can contribute to distinguishing the etiology of aseptic meningitis with or without PFNP. As expected, the most common etiology for aseptic meningitis with PFNP was Bb infection whereas enterovirus infection was the predominant cause for aseptic meningitis alone.

Facial herpes zoster complicated by varicella zoster virus (VZV) encephalitis: The diagnostic significance of atypical lymphocytes in cerebrospinal fluid (CSF)

Aseptic meningitis is a frequent diagnosis in emergency departments. Nevertheless, viral investigations are not carried out currently and the viral etiology in adult population has not been studied extensively. We conducted a prospective study including all consecutive patients undergoing lumbar puncture during a 15 months period in an adult emergency department. Bloody and purulent cerebrospinal fluid (CSF) were excluded. The main tests undertaken were: CSF genomic amplification by the polymerase chain reaction (PCR) for neurotropic viruses and serum and CSF interferon-alpha (IFN-alpha) measurements. Among 194 patients included, 45 had and 149 did not have aseptic meningitis. Of 45 patients with aseptic meningitis, 10 had alternative non-virological final diagnosis, and 35/45 were presumed to have neurological disorders of viral origin. Patients (27/35) completed virological analysis: 21/27 (78%) had either positive viral PCR (enterovirus: 8 patients, Varicella zoster virus (VZV): 5, Epstein-Barr virus (EBV): 2, herpes simplex virus (HSV): 1, human herpes virus 6: 1) or only raised serum or CSF IFN-alpha (4 patients). Overall, 59% of patients with a positive viral PCR had either CSF or serum raised IFN-alpha. Twentyone patients without meningitis had either positive viral PCR (enterovirus: 3 patients) or only high serum IFN-alpha level (18 patients). In the setting of aseptic meningitis diagnosed in an adult emergency department, viruses are the most common agents encountered, with enterovirus and VZV as the two main etiological agents. Current CSF viral genome amplification and IFN-alpha measurement are informative and could be useful to confirm the viral origin of various neurological disorders, although the sensitivity and specificity of IFN-alpha measurement for the diagnosis of viral infection need further confirmation.

Cerebrospinal fluid and peripheral blood leukocyte subsets in acute inflammation of the CNS

Background: Data on the utility of cerebrospinal fluid (CSF) lactate and serum lactate as prognostic markers for bacterial and viral meningitis remain scarce in the Indian setting. This study aimed to assess their effectiveness in differentiating bacterial from aseptic meningitis and in evaluating disease prognosis. Materials and Methods: A total of 60 patients diagnosed with meningitis were enrolled. Lumbar puncture was performed immediately upon admission, and patients were categorized into two groups: bacterial meningitis and aseptic meningitis. CSF and serum lactate levels were measured on Day 1 and Day 5. These values were compared across groups to determine their diagnostic utility and to assess their predictive value for outcomes such as recovery or death. Results: Mean CSF lactate levels were markedly higher in bacterial meningitis (12.0 mmol/L on Day 1 and 6.7 mmol/L on Day 5) than in viral meningitis (2.3 mmol/L on Day 1 and 1.7 mmol/L on Day 5). Among patients with bacterial meningitis, those who died had significantly higher CSF lactate levels (13.3 mmol/L) compared to survivors (5.8 mmol/L) ( P &lt; 0.05). Mean serum lactate was also significantly elevated in bacterial meningitis (5.1 mmol/L vs. 2.2 mmol/L). Furthermore, serum lactate levels were higher in non-survivors (8.9 mmol/L) than in those who recovered (2.4 mmol/L) ( P &lt; 0.05). Conclusion: Despite limited prior research, our findings indicate that both CSF and serum lactate are valuable markers for differentiating bacterial from aseptic meningitis and for predicting clinical outcomes.

Despite the fact that the prognosis of bacterial meningitis has been improved by the influence of antibiotics, this disease is still one of the significant causes of morbidity and mortality in children. Rapid differentiation between bacterial and aseptic meningitis, and the need for immediate antibiotic treatment in the former, is crucial in the prognosis of these patients. Ferritin is one of the most sensitive biochemical markers investigated in cerebrospinal fluid (CSF) for the early diagnosis of bacterial meningitis. The present study aims to evaluate the diagnostic capability of CSF ferritin in differentiating bacterial and viral meningitis in the paediatric setting. A cross-sectional study was carried out in the referral Children’s Medical Center Hospital, Tehran, during 2008 and 2009. According to the inclusion criteria, CSF samples from 42 patients with suspected meningitis were obtained and divided into two meningitis groups, bacterial (n=18) and viral (n=24). Ferritin and other routine determinants (i.e., leucocytes, protein and glucose) were compared between the two groups. Ferritin concentration in the bacterial meningitis group was 106.39±86.96 ng/dL, which was considerably higher than in the viral meningitis group (10.17±14.09, P<0.001). Mean CSF protein concentration and cell count were significantly higher in the bacterial meningitis group and showed a positive correlation with CSF ferritin. In conclusion, this study suggests that CSF ferritin concentration is an accurate test for the early differentiation of bacterial and aseptic meningitis; however, further investigation on a larger cohort of patients is required to confirm this finding.