A Case of Aseptic Meningitis Presenting With Widespread Non-Dermatomal Neuropathic Pain.

BackgroundThe spinal inflammatory signal often spreads to distant segments, accompanied by widespread pain symptom under neuropathological conditions. Multiple cytokines are released into the cerebrospinal fluid (CSF), potentially inducing the activation of an inflammatory cascade at remote segments through CSF flow. However, the detailed alteration of CSF in neuropathic pain and its specific role in widespread pain remain obscure.MethodsA chronic constriction injury of the infraorbital nerve (CCI-ION) model was constructed, and pain-related behavior was observed on the 7th, 14th, 21st, and 28th days post surgery, in both vibrissa pads and hind paws. CSF from CCI-ION rats was transplanted to naïve rats through intracisternal injection, and thermal and mechanical allodynia were measured in hind paws. The alteration of inflammatory cytokines in CCI-ION’s CSF was detected using an antibody array and bioinformatic analysis. Pharmacological intervention targeting the changed cytokine in the CSF and downstream signaling was performed to evaluate its role in widespread pain.ResultsCCI-ION induced local pain in vibrissa pads together with widespread pain in hind paws. CCI-ION’s CSF transplantation, compared with sham CSF, contributed to vibrissa pad pain and hind paw pain in recipient rats. Among the measured cytokines, interleukin-6 (IL-6) and leptin were increased in CCI-ION’s CSF, while interleukin-13 (IL-13) was significantly reduced. Furthermore, the concentration of CSF IL-6 was correlated with nerve injury extent, which gated the occurrence of widespread pain. Both astrocytes and microglia were increased in remote segments of the CCI-ION model, while the inhibition of astrocytes in remote segments, but not microglia, significantly alleviated widespread pain. Mechanically, astroglial signal transducer and activator of transcription 3 (STAT3) in remote segments were activated by CSF IL-6, the inhibition of which significantly mitigated widespread pain in CCI-ION.ConclusionIL-6 was induced in the CSF of the CCI-ION model, triggering widespread pain via activating astrocyte STAT3 signal in remote segments. Therapies targeting IL-6/STAT3 signaling might serve as a promising strategy for the widespread pain symptom under neuropathological conditions.Graphical abstract

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

We carefully read the article published in the European Journal of Neurology entitled “How to distinguish Guillain-Barré syndrome from nitrous oxide-induced neuropathy: a 2-year, multicenter, retrospective study” [1]. We aim to propose suggestions regarding the use of vitamin B12 as a biomarker of nitrous oxide (N2O) intoxication. Fortanier et al. established criteria to define the Guillain-Barré syndrome (GBS)-like group; however, clinical symptoms of N2O exposure vary. Clinical and cerebrospinal fluid analysis can be available rapidly and guide treatment decisions. In case of uncertainty between GBS and N2O-induced neuropathy, intravenous immunoglobulins must be initiated for critical patients, without waiting for biological laboratory test results. Clinical symptoms of N2O exposure are related to the functional inactivation of vitamin B12 by oxidation of its cobalt ion [2]. This oxidation prevents the formation of methylcobalamin, resulting in a decrease in methionine synthase activity which converts homocysteine into methionine. A similar action is suspected for MMA-CoA mutase, which converts methylmalonic acid (MMA) into succinyl-CoA (Figure 1). Fortanier et al. only focused on the significance of serum vitamin B12 measurement, a routine laboratory test providing results within a few hours. However, as N2O leads to functional inactivation of vitamin B12, quantitative deficiency is secondary and inconsistent [3]. In N2O abuse, vitamin B12 is neither specific (prevalence of about 25% in the general population) nor sensitive: only about 50% of N2O consumers exhibit vitamin B12 deficiency [1, 3]. Functional exploration of vitamin B12 with plasma homocysteine and MMA gives informative results. These measurements were conducted but not discussed by the authors. However, as vitamin B12, homocysteine can be measured rapidly [4]. Homocysteine increases rapidly, and it is a sensitive biomarker for recent N2O consumption [3]. As reported by Fortanier et al., the majority of patients (96.2%) have elevated plasma homocysteine levels [1]. However, homocysteine lacks specificity: it also rises in cases of vitamin B9 or B12 deficiency, renal or hepatic insufficiency, hypothyroidism, and in certain metabolic disorders. Plasma MMA is a reliable marker of functional vitamin B12 deficiency. Plasma MMA lacks sensitivity in N2O intoxication as its elevation is not consistent, but is correlated with the clinical severity [3]. Plasma MMA is more specific than homocysteine in the assessment of vitamin B12 deficiency as it is independent of vitamin B6 and B9 status, but rises in cases of renal insufficiency and in certain metabolic diseases. In the context of N2O abuse, high plasma homocysteine suggests recent consumption, and plasma MMA can aid evaluation of the clinical severity [5]. Vitamin assays (B6, B9, B12) may uncover nutritional deficiencies. Consequently, it is important to exclude other causes of homocysteine or MMA elevation. The European Federation of Laboratory Medicine is in the process of formulating guidelines concerning the use of biological parameters for initial evaluation and follow-up of N2O intoxication (https://www.eflm.eu/site/page/a/1832). Data sharing is not applicable to this article as no new data were created or analyzed in this study.

IntroductionPatients with Crohn’s Disease (CD) who frequently have ileal involvement are at increased risk of vitamin B12 deficiency. Vitamin B12 deficiency in patients with ulcerative colitis (UC) is not widely...

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

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.

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.

Small fiber neuropathy (SFN), due to loss of A-delta and unmyelinated C fibers, is a cause of neuropathic pain. Although the patients with vitamin B12 deficiency are included in SFN studies in the literature, there is no histopathological study investigating the small fiber loss solely in patients with vitamin B12 deficiency. In this pilot study, we aim to demonstrate the intraepidermal nerve fiber density (IENFD) in skin punch biopsy of patients with vitamin B12 deficiency. Ten patients with vitamin B12 deficiency suffering from neuropathic pain and as control group ten patients with vitamin B12 deficiency without neuropathic pain were included. Neurological examination, electrophysiological evaluation, and DN4 questionnaire were performed. Subsequently, skin punch biopsy 10cm above the lateral malleolus was done. The biopsy samples were stained with PGP9.5 antibody, and IENFD was determined. IENFD was low in two groups compared to their age normative values. The median of IENFD was 3.345 (1.12-5.32) in patients with neuropathic pain and 6. 20 (4.6-9.8) in controls (p<0.001). Our pilot study showed that vitamin B12 deficiency causes symptomatic as well as asymptomatic small fiber loss like diabetes mellitus.

Cetuximab induced aseptic meningitis

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

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&amp;gt;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.

Aseptic meningitis. A local experience

Aging is associated with increased incidence and prevalence of chronic diseases, and the role of micronutrient deficiencies in the development of diseases is important. Vitamin B12 and folic acid deficiency are often associated with increased homocysteine (Hcy) levels. In our study, we aimed to detect the relationship between Hcy levels by examining vitamin B12 and folate levels in the healthy elderly Turkish population. In our study, the levels of vitamin B12, folate, and Hcy were analyzed and examined in 657 elderly and 642 non-elderly healthy adults admitted to the Internal medicine outpatient clinic. Vitamin B12 &lt;200 pg/mL was considered to be deficient. Folic acid &lt;5 ng/mL was considered a deficiency, and Hcy&gt;15 µmol/L was considered a high concentration. Vitamin B12 levels were detected to be significantly decreased in the elderly group compared to the non-elderly group, while Hcy levels were marked to be increased (p&lt;0.05). Women had lower levels of Hcy and higher levels of vitamin B12 and folate (p&lt;0.05). There was a moderate negative correlation between Hcy and vitamin B12 levels in the elderly group (r=-0.576; p&lt;0.0001), and a moderate negative correlation between Hcy and folate (r=-0.510; p&lt;0.0001). In the elderly group, 21.5% had vitamin B12 deficiency and 21.6% had folate deficiency. An increase in Hcy level was detected in 54.8%. Those with Hcy levels &gt;15 µmol/L had vitamin B12 deficiency in 38.4%, folate deficiency in 36.0%, and both vitamin B12 and folate deficiency in 15.8%. Our results indicate that it is important to measure vitamin B12, folate, and Hcy in the elderly, given the significant growth in the elderly population. We predict that vitamin B12 and folate supplementation, when necessary, may be beneficial in preventing some common diseases in the elderly and increasing the standard of life of the elderly and their relatives.

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.

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.