Case Report: Clinical features and management of anti-mGluR1 encephalitis: case illustration and review of the literature

Nonculture infection tests of cerebrospinal fluid (CSF) samples using polymerase chain reaction and antigen or antibody assays are frequently ordered on lumbar puncture specimens concurrently with routine CSF cell counts, but the value of CSF infection testing in otherwise healthy children is unknown. To determine the value of nonculture CSF infection testing in immune-competent children with normal CSF cell counts. This cross-sectional study reviewed screening and diagnostic tests in the electronic medical record system of a large academic tertiary care children's hospital. Records of children aged 0.5 to 18.9 years (n = 4083) who underwent lumbar puncture (n = 4811 procedures) in an inpatient or outpatient facility of Children's Hospital of Philadelphia between July 1, 2007, and December 31, 2016, were reviewed. Those with indwelling CSF shunts or catheters; those with active or past oncologic, immunologic, or rheumatologic conditions; or those taking immune-suppressing medications were excluded from analysis. This study was conducted from July 20, 2017, to March 13, 2019. Outcome variables included frequency of nonculture CSF infection testing and frequency of positive results in the entire cohort, and among those with normal cell counts. Normal cell counts were defined as CSF white blood cell counts lower than 5 cells/μL and CSF red blood cell counts lower than 500 cells/μL. In total, 4811 lumbar puncture procedures were performed on 4083 unique children, with a median (range) age of 7.4 (0.5-18.9) years, 2537 boys (52.7%), and 3331 (69.2%) with normal CSF cell counts. At least 1 nonculture CSF infection test was performed on 1270 lumbar puncture specimens with normal cell counts (38.1%; 95% CI, 36%-40%), and more tests were performed in the summer months. Only 18 (1.4%; 95% CI, 0.9%-2.2%) of 1270 lumbar puncture specimens with normal cell counts had at least 1 nonculture infection test with a positive result; 2 of these 18 children required clinical intervention for their positive results, but each also had other clear clinical signs of infection. Nonculture CSF infection testing appeared to be common in immune-competent children with normal CSF cell counts, but positive results were uncommon and were not independently associated with clinical care; delaying the decision to send nonculture infection tests until CSF cell counts are available could reduce unnecessary diagnostic testing and medical costs, which may improve value-based care.

Index of suspicion. Case 2. Guillain-Barre Syndrome.

BackgroundThe objective of the study was to assess the cerebrospinal fluid (CSF) findings in COVID-19 patients.AimsThis was an observational retrospective cohort from electronic medical records of hospitalized patients (n = 2655) with confirmed COVID-19 between February 15, 2020, and April 15, 2020, in 182 hospitals from a large health system in the USA. The review of data yielded to a total of 79 patients in 20 hospitals who had CSF analysis.MethodsOutcomes during hospitalization, including hospital length of stay, disease severity, ventilator time, and in-hospital death were recorded. Independent variables collected included patient demographics, diagnoses, laboratory values, and procedures.ResultsA total of 79 patients underwent CSF analysis. Of these, antigen testing was performed in 73 patients. Ten patients had CSF analysis for general markers such as total protein, cell count, glucose, clarity, and color. Seven of the 10 cases (70%) had normal total cell count and normal white blood cell count in CSF. Sixty-three percent (5/8) had elevated total protein. Two patients had normal levels of lactate dehydrogenase (LDH) and 1 patient had significantly elevated (fourfold) neuron-specific enolase (NSE) level in CSF.ConclusionUnlike bacterial infections, viral infections are less likely to cause remarkable changes in CSF glucose, cell count, or protein. Our observations showed no pleocytosis, but mild increase in protein in the CSF of the COVID-19 patients. The fourfold elevation of NSE may have diagnostic/prognostic value as a biomarker in CSF for COVID-19 patients who have altered mental status.Graphical abstract

Evaluation of an internally controlled real-time PCR targeting the ospA gene for detection of Borrelia burgdorferi sensu lato DNA in cerebrospinal fluid

Relevance of nucleic acid amplification techniques for the diagnosis of respiratory tract infections in the clinical laboratory

Despite multiple studies showing that a normal white blood cell (WBC) count does not exclude serious disease, physicians in all specialties continue to behave as if it did. To assess whether a normal WBC count or absence of fever reliably excludes bacteremia in patients with suspected infection, investigators …

The aims of this study were to investigate the frequency of HIV-1 RNA level discordance between the cerebrospinal fluid (CSF) and plasma and of CSF viral escape (CVE) in patients with HIV-1 subtype C on antiretroviral therapy, and evaluate the CSF white blood cell (WBC) performance characteristics in predicting CSF discordance in HIV+ group and the frequency of cognitive impairment in individuals with CSF HIV discordance or escape. HIV-1 RNA levels were assessed in plasma and CSF samples from 68 HIV+ participants without opportunistic infection. CSF discordance was found in 7.4% and CVE in 10%, with comparable frequencies between HIV-1B and C. Twenty samples (29%) showed increased CSF WBC counts. This group had higher CSF and plasma HIV-1 RNA levels than the group with normal WBC counts (p < 0.0001 and 0.006, respectively). The odds of CSF discordance were 18 times higher for a person with CSF WBC count of > 5cells/mm3 than the group with normal CSF WBC count. CSF WBC counts (cut-off of 15cells/mm3) showed high-performance characteristics as a predictive biomarker of CSF discordance (AUC the ROC curve 0.98). The frequency of cognitive impairment for CSF escape or discordance was 83% and 80%. The odds of cognitive impairment in these groups were 19 and 15 times higher than those for an HIV(-) person. Viral discordance or escape in the CNS occurs at a comparable frequency for HIV-1C and HIV-1B. The CSF WBC count was effective as a predictive biomarker of CSF and plasma discordance.

Background. Although CSF cytology and MRI are standard methods to diagnose neoplastic meningitis (NM), this complication of neoplastic disease remains difficult to detect. We therefore reevaluated the sensitivity of gadolinium (GD)-enhanced MRI and cerebrospinal-fluid (CSF)-cytology and the relevance of tumor type and CSF cell count. Methods. We retrospectively identified 111 cases of NM diagnosed in our CSF laboratory since 1990 with complete documentation of both MRI and CSF cytology. 37 had haematological and 74 solid neoplasms. CSF cell counts were increased in 74 and normal in 37 patients. Results. In hematological neoplasms, MRI was positive in 49% and CSF cytology in 97%. In solid tumors, the sensitivity of MRI was 80% and of cytology 78%. With normal CSF cell counts, MRI was positive in 59% (50% hematological, 72% solid malignancies) and CSF cytology in 76% (92% in hematological, 68% in solid neoplasms). In cases of elevated cell counts, the sensitivity of MRI was 72% (50% for hematological, 83% for solid malignancies) and of CSF cytology 91% (100% for haematological and 85% for solid neoplasms). 91% of cytologically positive cases were diagnosed at first and another 7% at second lumbar puncture. Routine protein analyses had a low sensitivity in detecting NM. Conclusions. The high overall sensitivity of MRI was only confirmed for NM from solid tumors and for elevated CSF cell counts. With normal cell counts and haematological neoplasms, CSF-cytology was superior to MRI. None of the analysed routine CSF proteins had an acceptable sensitivity and specificity in detecting leptomeningeal disease.

Enteroviruses are among the most common causes of viral meningitis. Enteroviral meningitis continues to represent diagnostic challenges, as cerebrospinal fluid (CSF) cell numbers (a well validated diagnostic screening tool) may be normal in up to 15% of patients. We aimed to identify potential CSF biomarkers for enteroviral meningitis, particularly for cases with normal CSF cell count. Using targeted liquid chromatography-mass spectrometry, we determined metabolite profiles from patients with enteroviral meningitis (n = 10) and subdivided them into those with elevated (n = 5) and normal (n = 5) CSF leukocyte counts. Non-inflamed CSF samples from patients with Bell’s palsy and normal pressure hydrocephalus (n = 19) were used as controls. Analysis of 91 metabolites revealed considerable metabolic reprogramming in the meningitis samples. It identified phosphatidylcholine PC.ae.C36.3, asparagine, and glycine as an accurate (AUC, 0.92) combined classifier for enterovirus meningitis overall, and kynurenine as a perfect biomarker for enteroviral meningitis with an increased CSF cell count (AUC, 1.0). Remarkably, PC.ae.C36.3 alone emerged as a single accurate (AUC, 0.87) biomarker for enteroviral meningitis with normal cell count, and a combined classifier comprising PC.ae.C36.3, PC.ae.C36.5, and PC.ae.C38.5 achieved nearly perfect classification (AUC, 0.99). Taken together, this analysis reveals the potential of CSF metabolites as additional diagnostic tools for enteroviral meningitis, and likely other central nervous system (CNS) infections.

Background. Although CSF cytology and MRI are standard methods to diagnose neoplastic meningitis (NM), this complication of neoplastic disease remains difficult to detect. We therefore reevaluated the sensitivity of gadolinium (GD)-enhanced MRI and cerebrospinal-fluid (CSF)-cytology and the relevance of tumor type and CSF cell count. Methods.We retrospectively identified 111 cases of NM diagnosed in our CSF laboratory since 1990 with complete documentation of both MRI and CSF cytology. 37 had haematological and 74 solid neoplasms. CSF cell counts were increased in 74 and normal in 37 patients. Results. In hematological neoplasms, MRI was positive in 49% and CSF cytology in 97%. In solid tumors, the sensitivity of MRI was 78% and of cytology 80%. With normal CSF cell counts, MRI was positive in 59% (50% hematological, 72% solid malignancies) and CSF cytology in 76% (92% in hematological, 68% in solid neoplasms). In cases of elevated cell counts, the sensitivity of MRI was 72% (50% for hematological, 83% for solid malignancies) and of CSF cytology 91% (100% for haematological and 85% for solid neoplasms). 91% of cytologically positive cases were diagnosed at first and another 7% at second lumbar puncture. Routine protein analyses had a low sensitivity in detecting NM. Conclusions. The high overall sensitivity of MRI was only confirmed for NM from solid tumors and for elevated CSF cell counts.With normal cell counts and haematological neoplasms, CSF-cytology was superior to MRI. None of the analysed routine CSF proteins had an acceptable sensitivity and specificity in detecting leptomeningeal disease.

Background:The coronavirus disease 2019 pandemic was caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the predominant clinical presentation is a respiratory disease, neurologic manifestations are being recognized increasingly.Case Report:We report 2 children 9 years of age who developed acute disseminated encephalomyelitis-like disease associated with SARS-CoV-2. Seizures and encephalopathy were the main central nervous system symptoms. The cerebrospinal fluid analysis performed within the first week of disease onset showed elevated protein in both children with normal cell count and no evidence of infection including negative SARS-CoV-2 by antibody and polymerase chain reaction. Brain magnetic resonance imaging revealed T2A, fluid-attenuated inversion recovery cortical and subcortical hyperintensity without restricted diffusion consistent with acute disseminated encephalomyelitis–like disease. They received methylprednisolone followed by therapeutic plasma exchange. One of them showed complete clinical improvement and resolution in magnetic resonance imaging findings. The other developed laminar necrosis in brain magnetic resonance imaging and showed significant clinical improvement after therapeutic plasma exchange. He was positive for positive SARS-CoV-2 antibody in cerebrospinal fluid on day 55 of admission. They were both positive for SARS-CoV-2 antibodies in serum after 2 weeks.Conclusions:Our two cases highlight the occurrence of acute disseminated encephalomyelitis–like disease as a postinfectious/immune-mediated complication of SARS-CoV-2 infection.

Clinical and Diagnostic Features of Delayed Hypoxic Leukoencephalopathy

9566 Background: Although CSF cytology and MRI are standard methods for the diagnosis of neoplastic meningitis (NM), this complication of neoplastic disease still remains to be difficult to detect in some cases. We therefore re-evaluated the sensitivity of gadolinium(GD)-enhanced MRI and cerebrospinal-fluid (CSF)-cytology for the diagnosis of LM differentially for solid and haematological malignancies and for normal or elevated cell counts. Methods: We identified retrospectively 101 cases of NM diagnosed in our CSF laboratory since 1990 with complete data of both MRI and CSF-cytology. 34 had haematological, 67 solid neoplasms. CSF-cell counts were increased in 63 and normal in 35 patients. Results: For haematological neoplasms, MRI was positive in 53%. CSF cytology was positive in 97%. In solid tumours, we found MRI-sensitivity of 0.81 and cytological sensitivity of 0.76. With normal CSF-cell-counts, MRI was positive in 63%, (0.57 haematological, 0.75 solid malignancies), CSF-cytology in 78%, (0.9 in haematological, 0,64 in solid neoplasms). In cases of increased cell-counts, MRI-sensitivity was 0.75 (0.52 for haematological, 0.87 for solid malignancies), and sensitivity of CSF-cytology was 0.89 (1.0 for haematological and 0.82 for solid neoplasms). 23 patients were treated with intrathecal MTX or Ara-C, 16 patients with liposomal Ara-C. 62 patients were not treated intrathecally. Conclusions: We confirmed here the high overall sensitivity of MRI for the diagnosis of neoplastic meningitis. The best sensitivity, however, was seen in solid tumours and elevated cell counts. In haematological malignancies, a markedly lower sensitivity of MRI was seen. Of note, we consider the very high sensitivity of cytology in haematological malignancies to be artificial due to methodological reasons of this retrospective study. We conclude that MRI is a very sensitive method to detect NM especially in solid tumours and elevated cell counts. With normal cell counts and haematological neoplasms, CSF-cytology remains to be superior to radiological methods. [Table: see text]

The intrathecal immune response in 114 patients with clinically diagnosed acute poliomyelitis was studied by measuring poliovirus-specific immunoglobulin M (IgM) antibodies in cerebrospinal fluid (CSF) by a mu-capture immunoassay and by assessing the ratio between levels of poliovirus-neutralizing antibodies in serum and CSF. Fecal specimens were used for attempts to isolate the causative agents. Eighty-five percent of CSF specimens collected during the first 15 days of disease contained virus-specific IgM antibodies. Forty-five of 48 tested children (94%) also showed virus-specific IgM responses in their sera. Later on, the antibody levels decreased, and positive results after 30 days of onset of paralytic symptoms were rare. If the presence of poliovirus-specific IgM antibodies in the CSF was considered diagnostic, more cases were confirmed by this test than by virus isolation. A relative increase in poliovirus-neutralizing antibodies in the CSF was observed in about one-third of the cases; in all but three cases the increase was observed together with the presence of virus-specific IgM antibodies. A systemic virus-specific response can be seen and poliovirus can be isolated from a subclinically infected individual suffering from a concomitant poliomyelitis-like disease, while positive results by the two methods demonstrating an intrathecal immune response are likely to indicate a true causal relationship between infection and disease. Demonstration of poliovirus-specific IgM antibodies in the CSF thus appears to be a sensitive and specific method for laboratory confirmation of clinically diagnosed poliomyelitis.

IntroductionSubacute cerebellar ataxia combined with cerebrospinal fluid (CSF) pleocytosis is the result of an immune response that can occur due to viral infections, paraneoplastic diseases or autoimmune-mediated mechanisms. In the following we present the first description of a patient with anti-Homer-3 antibodies in serum and CSF who has been diagnosed with paraneoplastic subacute cerebellar degeneration due to a papillary adenocarcinoma of the breast.Case presentationA 58-year-old female was admitted to our clinical department because of increasing gait and visual disturbances starting nine months ago. The neurological examination revealed a downbeat nystagmus, oscillopsia, a severe standing and gait ataxia and a slight dysarthria. Cranial MRI showed no pathological findings. Examination of CSF showed a lymphocytic pleocytosis of 11 cells/µl and an intrathecal IgG synthesis of 26%. Initially, standard serological testing in serum and CSF did not indicate any autoimmune or paraneoplastic aetiology. However, an antigen-specific indirect immunofluorescence test (IIFT) revealed the presence of anti-Homer-3 antibodies (IgG) with a serum titer of 1: 32,000 and a titer of 1: 100 in CSF. Subsequent histological examination of a right axillary lymph node mass showed papillary adenocarcinoma cells. Breast MRI detected multiple bilateral lesions as a diffuse tumour manifestation indicative of adenocarcinoma of the breast. Treatment with high-dose methylprednisolone followed by five plasmaphereses and treatment with 4-aminopyridine resulted in a moderate decrease of the downbeat nystagmus and she was able to move independently with a wheeled walker after 3 weeks. The patient was subsequently treated with chemotherapy (epirubicin, cyclophosphamide) and two series of immunoglobulins (5 × 30 g each). This resulted in a moderate improvement of the cerebellar symptoms with a decrease of ataxia and disappearance of the downbeat nystagmus.ConclusionThe presented case of anti-Homer-3 antibody-associated cerebellar degeneration is the first that is clearly associated with the detection of a tumour. Interestingly, the Homer-3 protein interaction partner metabotropic glutamate receptor subtype 1A (mGluR1A) is predominantly expressed in Purkinje cells where its function is essential for motor coordination and motor learning. Based on our findings, in subacute cerebellar degeneration, we recommend considering serological testing for anti-Homer-3 antibodies in serum and cerebrospinal fluid together with tumor screening.