Application of the 2017 Revised McDonald Criteria for Multiple Sclerosis to Patients With a Typical Clinically Isolated Syndrome.

Importance: In 2017, the International Panel on Diagnosis of Multiple Sclerosis revised the McDonald 2010 criteria for the diagnosis of multiple sclerosis (MS). The new criteria are easier to apply and could lead to more and earlier diagnoses. It is important to validate these criteria globally for their accuracy in clinical practice. Objective: To evaluate the diagnostic accuracy of the 2017 criteria vs the 2010 criteria in prediction of clinically definite MS in patients with a typical clinically isolated syndrome (CIS). Design, Setting and Patients: A total of 251 patients at Erasmus MC, Rotterdam, the Netherlands, in collaboration with several regional hospitals, fulfilled the inclusion criteria. Thirteen patients received another diagnosis early in the diagnostic process and therefore were excluded from the analyses. Nine patients with CIS declined to participate in the study. This left 229 patients who were included between March 2006 and August 2016 in this prospective CIS cohort. Patients underwent a baseline magnetic resonance imaging scan within 3 months after onset of symptoms and, if clinically required, a lumbar puncture was performed. Data were analyzed between December 2017 and January 2018. Main Outcomes and Measures: Sensitivity, specificity, accuracy, and positive and negative predictive value were calculated after 1, 3, and 5 years for the 2017 vs the 2010 criteria. Results: Among the 229 patients with CIS, 167 were women (73%), and the mean (SD) age was 33.5 (8.2) years. One hundred thirteen patients (49%) were diagnosed as having CDMS during a mean (SD) follow-up time of 65.3 (30.9) months. Sensitivity for the 2017 criteria was higher than for the 2010 criteria (68%; 95% CI, 57%-77% vs 36%; 95% CI, 27%-47%; P < .001), but specificity was lower (61%; 95% CI, 50%-71% vs 85%; 95% CI, 76%-92%; P < .001). Using the 2017 criteria, more MS diagnoses could be made at baseline (n = 97 [54%]; 95% CI, 47%-61% vs n = 46 [26%]; 95% CI, 20%-32%; P < .001). In the group with at least 5 years of follow-up, 33% of patients who were diagnosed as having MS using the 2017 criteria did not experience a second attack during follow-up vs 23% when using the 2010 criteria. Conclusions and Relevance: The 2017 revised McDonald criteria are associated with greater sensitivity but less specificity for a second attack than the previous 2010 criteria. The tradeoff is that it leads to a higher number of MS diagnoses in patients with a less active disease course.

Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease.

OBJECTIVE: To determine the clinical features and presence in CSF of antineuronal antibodies in patients with pathologically proven autoimmune encephalitis derived from a cohort of patients with suspected Creutzfeldt-Jakob disease (CJD). METHODS: The Dutch Surveillance Centre for Prion Diseases performed 384 autopsies on patients with suspected CJD over a 14-year period (1998-2011). Clinical information was collected from treating physicians. Antineuronal antibodies were tested in CSF obtained postmortem by immunohistochemistry on fresh frozen rat brain sections, by Luminex assay for the presence of well-characterized onconeural antibodies, and by cell-based assays for antibodies against NMDAR, GABABR1/2, GABAAR GLUR1/2, LGI1, Caspr2, and DPPX. RESULTS: In 203 patients, a diagnosis of definite CJD was made, while in 181 a variety of other conditions were diagnosed, mainly neurodegenerative. In 22 of these 181, the neuropathologist diagnosed autoimmune encephalitis. One patient was excluded because of lack of clinical information. Inflammatory infiltrates were predominantly perivascular and consisted mainly of T cells. The predominant locations were basal ganglia and thalamus (90%) and temporal lobes and hippocampus (81%). In 6 patients (29%), antineuronal antibodies were detected in postmortem CSF, directed against Hu, NMDAR, GABABR1/2, Caspr2, and an unidentified synaptic antigen in 2. The most frequent symptoms were dementia (90%), gait disturbance (86%), cerebellar signs (67%), and neuropsychiatric symptoms (67%). Immunopathologic and clinical findings did not differ between autoantibody-negative patients and patients with antineuronal antibodies. CONCLUSIONS: It is important to consider immune-mediated disorders in the differential diagnosis of rapidly progressive neurologic deficits.

[Juxta facet cyst of the lumbar spine: an uncommon cause of lumbar radiculopathy]. / De juxta-articulaire facetcyste: een bijzondere oorzaak van het lumbosacraal radiculair syndroom.

Lumbar juxta facet cysts (JFC) are an uncommon cause of radiculopathy. Spontaneous regression of symptomatic JFC has not often been reported. We describe 2 patients, a 59-year-old man and a 55-year-old man, with radiculopathy of the 5th lumbar nerve root due to a JFC at L4-5. The first patient recovered spontaneously. After 8 months, the JFC had clearly reduced on MRI. In the second patient the JFC was surgically resected due to progressive pain, after which the patient remained without symptoms. In the literature it is suggested that surgical removal of the JFC should be the treatment of choice. However, of the 5 patients who were diagnosed with a JFC in our department, 3 recovered spontaneously and 2 after surgery. In our opinion further studies on the course and management of symptomatic lumbar JFC are warranted.

HLA-DQ2+ individuals are susceptible to Hu-Ab associated paraneoplastic neurological syndromes.

BACKGROUND: Hypothetically, T cells are involved in the pathogenesis of paraneoplastic neurological syndromes associated with Hu-antibodies (Hu-PNS). OBJECTIVE: To identify genetic risk factors for Hu-PNS and investigate the role of T cells. METHODS: HLA-A, B, DRB1 and DQB1 alleles were compared in 53 Hu-PNS patients with 24 small-cell lung-cancer (SCLC) patients and 2440 healthy controls (HC). RESULTS: The frequency of both HLA-DQ2 and HLA-DR3 was significantly higher in Hu-PNS patients than in HC. CONCLUSIONS: This study indicates an association between Hu-PNS and presence of HLA-DQ2 and HLA-DR3, which supports a role for CD4(+) T cells in the pathogenesis of Hu-PNS.

Contamination of synthetic HuD protein spanning peptide pools with a CMV-encoded peptide.

To detect HuD-specific T cells in patients with Hu-antibody associated paraneoplastic neurological syndromes (Hu-PNS), we used short-term stimulation assays with HuD protein spanning peptide pools (PSPP) with purities of at least 70% and found reproducible false-positive CD8+ T-cell responses in three of 127 individuals (two healthy controls and one Hu-PNS patient), which all shared HLA-A*2402 and HLA-B*1801. After testing the 15-mer peptides of the HuD antigen separately, we discovered that the same three 15-mers yielded the CD8+ T cell response in those three individuals. This highly unusual result could not be reproduced when using new batches of peptides with a higher level of purity (>82% and >95%). Therefore, we assumed this response was not directed against the HuD peptides and analyzed the HuD 15-mers by Fourier transform ion cyclotron resonance (FT-ICR) tandem mass spectrometry (MS/MS), which showed the presence of a cytomegalovirus (CMV)-encoded peptide (AIAEESDEEEAIVAY) as a contaminant. The three responding individuals all were CMV-seropositive and the contaminating peptide appeared to fit in the binding groove of HLA-B*18. Our data reveal that synthetic PSPP may contain immunogenic contaminations which may cause false positive results in T-cell stimulation assays.

No evidence for circulating HuD-specific CD8+ T cells in patients with paraneoplastic neurological syndromes and Hu antibodies.

AIM: In paraneoplastic neurological syndromes (PNS) associated with small cell lung cancer (SCLC) and Hu antibodies (Hu-PNS), Hu antigens expressed by the tumour hypothetically trigger an immune response that also reacts with Hu antigens in the nervous system, resulting in tumour suppression and neuronal damage. To gain more insight into the hypothesized CD8(+ )T cell-mediated immune pathogenesis of these syndromes, we searched for circulating HuD-specific CD8(+) T cells in a large cohort of Hu-PNS patients and controls. PATIENTS AND METHODS: Blood was tested from 43 Hu-PNS patients, 31 Hu antibody negative SCLC patients without PNS and 54 healthy controls. Peripheral blood mononuclear cells (PBMC) were stimulated with HuD protein-spanning peptide pools (15-mers) and individual HuD-derived peptides (9-mers) and analysed by cytokine flow cytometry and interferon-gamma ELISPOT-assays. Additionally, HuD-based Class I HLA multimers were used to visualize HuD-specific CD8(+) T cells. RESULTS: No HuD-specific CD8(+ )T cells could be detected in the blood of Hu-PNS patients or controls. CONCLUSIONS: Our results do not support a role for HuD-specific CD8(+) T cells in Hu-PNS. Further studies should focus on the detection of circulating HuD-specific CD4(+ )T cells and examine the antigen specificity of T cells in affected tissues.

The impact of impurities in synthetic peptides on the outcome of T-cell stimulation assays.

Protein-spanning peptide pools have proven valuable as a screening tool for detecting T-lymphocyte responses against a wide range of proteins. We have used this approach in our search for T cells reactive to the onconeural protein HuD. We found positive responses in only 3 of 127 individuals; however, these were highly unusual in that the same class I HLA alleles and peptides were involved. These T-cell responses were not confirmed when peptides re-synthesized by the same manufacturer with similar and with higher purity levels were used. Our observations indicated that these T-cell responses were not directed against the designed HuD peptides. Here, we report on (i) comparisons of the peptide batches analyzed by matrix-assisted laser desorption/ionization Fourier transform mass spectrometry (MALDI-FTMS) that did--and did not--elicit T-cell responses and (ii) a detailed analysis of the various by-products of peptides, irrespective of T-cell assay outcome. We found numerous differences between the peptide batches, such as omissions of amino acids in the primary structure of the peptides. Furthermore, some batches revealed strong interactions with calcium ions or contained sulfated peptides. Our data reveal that different batches from the same peptide may contain artefacts that influence the outcome of HLA-restricted T-cell response assays.

Managing paraneoplastic neurological disorders.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer that are not caused by invasion of the tumor or its metastases. Immunologic factors appear important in the pathogenesis of PNS because antineuronal autoantibodies and T-cell responses against nervous system antigens have been defined for many of these disorders. The immunologic response is elicited by the ectopic expression of neuronal antigens by the tumor. Expression of these so-called "onconeural" antigens is limited to the tumor and the nervous system and sometimes also the testis. At the time of presentation of the neurological symptoms, most patients have not yet been diagnosed with cancer. Detection of paraneoplastic antibodies is extremely helpful in diagnosing an otherwise unexplained and often rapidly progressive neurological syndrome as paraneoplastic. In addition, the paraneoplastic antibodies may also direct the search for an underlying neoplasm. On the other hand, in patients known to have cancer, the presentation of a PNS may herald recurrence of the tumor or a second tumor. The number of paraneoplastic antibodies is still growing, and at least seven of these can now be considered well characterized. Based on the clinical syndrome, the type of antibody, and the presence or absence of cancer, patients are classified as having a "definite" or "possible" PNS. Despite the presumed autoimmune etiology of PNS, the results of various forms of immunotherapy have been disappointing, with some exceptions. Rapid detection and immediate treatment of the underlying tumor appears to offer the best chance of stabilizing the patient and preventing further neurological deterioration.

Resolution of EBV(+) CNS lymphoma with appearance of CSF EBV-specific T cells.

Current knowledge of Epstein-Barr virus (EBV)-specific T-cell responses in the cerebrospinal fluid (CSF) of patients with EBV-related lymphoproliferative disease (EBV-LPD) in the central nervous system (CNS) is very limited. Here, we present two recipients of hematopoietic stem cell transplants with EBV-LPD in the CNS. EBV-specific CD8(+) T lymphocytes were detected in CSF and peripheral blood using major histocompatibility complex (MHC) class I multimers loaded with EBV-derived peptides. The appearance of EBV-specific CD8(+) T cells in CSF and blood correlated with neurological improvement and disappearance of EBV-LPD. These observations suggest a role for EBV-specific CD8(+) T cells in the control of EBV-LPD in the CNS.