Neurological Manifestations of Glutamic Acid Decarboxylase Autoimmunity in Indian Patients.

Objective: To study the neurological manifestations of glutamic acid decarboxylase (GAD 65) autoimmunity in Indian patients. Methods: Retrospective study conducted in a tertiary care referral hospital in South India. Patients who tested positive for GAD 65 antibodies from February 2013 to July 2019 were included. Results: We identified 922 patients who underwent GAD 65 testing, of which 81 tested positive (8.78%) [mean age 55.42 years (SD 17.39, range 9-86 years, median age 57 years)]. Males (n = 47) outnumbered the females (n = 34). All the GAD values measured were <5000 IU/ml. There were 34 cases (42%) of atypical parkinsonism (16/34, 47% fulfilled the diagnostic criteria for autoimmune atypical parkinsonism) in our series forming the most common group with GAD 65 positivity, followed by autoimmune encephalitis (8 cases, 9.88%). Men were more affected with atypical parkinsonism (22/34; 64.70%), stiff person syndrome (2/3; 66.66%), and neuropathy (4/7; 57.1%) while women were more with autoimmune encephalitis (6/8; 75%). Eighteen (22.6%) had underlying autoimmunity (three had type 1 diabetes mellitus). Six (7.4%) had underlying neoplasm. Thirty-three out of 43 patients responded to immunotherapy (76.74%). Five had spontaneous improvement. Conclusion: Glutamic acid decarboxylase65 antibody values were much lower in our study population. Male-dominant autoimmunity was seen unlike that in Western literature. The most striking was the high preponderance of atypical parkinsonism in GAD 65-positive patients. We also found that GAD 65 positivity is a useful marker for a positive response to immunotherapy in suspected autoimmune neurological syndromes irrespective of their titers.

Cerebrospinal fluid indices as predictors of treatment response in autoimmune encephalitis.

BACKGROUND: Cerebrospinal fluid (CSF) indices reflecting intrathecal antibody production and blood-brain barrier impairment are not routinely assessed in patients with autoimmune encephalitis (AE). We aimed to study CSF indices and their association with the prognosis of AE. METHODS: This retrospective cohort study conducted at Amrita Institute of Medical Sciences (AIMS), Kochi, India, included 60 patients aged more than 18 years with definite/probable/possible AE admitted to the Department of Neurology from August 2016 to November 2021. We introduced a classification of treatment response based on modified Rankin Scale change over time and treatment modalities. RESULTS: In our cohort of 60 patients (six [10%] seropositive cases), a good rapid treatment response was associated with CSF white blood cell count of more than 4 cells/mm3 (OR, 4.57; 95% CI 1.31-15.96; P = .02) and positive immunoglobulin G (IgG) Local Synthesis (OR, 7.27; 95% CI 1.56-33.86; P = .01). Albumin Index had association with a poor Glasgow Coma Scale score at the nadir of the disease (OR, 1.17; 95% CI 1.01-1.34; P = .04). Similar results were yielded in the seronegative cohort. IgG Local Synthesis appeared to be a strong predictor for good rapid treatment response in both univariate and multivariate (adjusted OR, 28.71; 95% CI 2.12-389.22; P= .01) analysis. Time to immunotherapy was reversely correlated with good response overall (in the cohort with outliers removed [N = 49]: unadjusted OR 0.97, 95% CI 0.95-0.99; P= .01; adjusted OR 0.97; 95% CI 0.95-0.99; P= .008). CONCLUSION: CSF indices reflecting intrathecal antibody production and blood-brain barrier impairment appear to be promising predictors of disease severity and therapeutic response in patients with autoimmune encephalitis.

The prevalence and clinical phenotype of dual seropositive neuromyelitis optica spectrum disorders at a national reference center in South Asia.

BACKGROUND: Neuromyelitis Optica Spectrum Disorders (NMOSD) is an autoimmune syndrome that is frequently positive for Aquaporin 4 (AQP4) IgG or Myelin Oligodendrocyte Glycoproteins (MOG) IgG. However, dual positivity to both is rare. OBJECTIVE: To assess the prevalence of dual-positive NMOSD and outline its clinical phenotype. DESIGN/METHODS: This is a retrospective cross-sectional study conducted at a tertiary healthcare center in South Asia between August 2018 and November 2021. The serum and/or CSF samples of suspected cases of NMOSD were tested for both AQP4-IgG and MOG-IgG using an Indirect immunofluorescence test on transfected cells. RESULTS: During the study period, 1935 cases of NMOSD were tested for both antibodies- 65 patients (3.35%; 57 females and 8 males) tested positive for AQP4-IgG, 217 patients (11.21%; 122 females and 95 males) tested positive for MOG-IgG and 3 patients (0.15%; 2 females and 1 male) showed dual positivity. There was a strong female preponderance in all three groups (87.69%, 56.22%, and 66.66% respectively). This study identified 3 patients with dual positivity. The first patient (42 years, Male) presented with area postrema syndrome initially and subsequently relapsed by developing right-sided numbness of the temporal area and limbs during which he tested dual positive. The second patient (27 years, Female) presented with bilateral optic neuritis (left>right) initially and subsequently relapsed following an episode of a seizure with left-sided hemiplegia. The third patient (25 years, Female) initially presented with acute bilateral optic neuritis and later developed left-sided hemiplegia post-recovery at which point she tested dual positive. Management using methylprednisolone was ineffective for all three patients, however, plasmapheresis and/or periodic rituximab injections produced an excellent response. CONCLUSIONS: Our study reports that the prevalence of dual-positive NMOSD is 0.15% and its clinical phenotype is more similar to NMO rather than MOG- associated disease.

Determination of sensitivities and specificities of cerebrospinal fluid free light chains to diagnose multiple sclerosis- a multicentric case-control study.

BACKGROUND: CSF free light chains help diagnose multiple sclerosis, but no data is available on the Asian population. Our objective was to study the diagnostic utility of CSF free light chains for diagnosing multiple sclerosis in Indian patients. METHODS: Prospective multicentric case-control study. Cases included those who were tested for oligoclonal bands and fulfilled the modified McDonald criteria 2017 for multiple sclerosis and clinically isolated syndromes. Those tested for oligoclonal bands (OCB) but with other diagnoses- inflammatory and non-inflammatory were included as controls. Clinical details were collected from electronic medical records. CSF and serum kappa and lambda free light chains were measured, apart from oligoclonal bands, immunoglobulin, and albumin in paired serum and CSF samples. RESULTS: There were 70 patients (31 cases and 39 controls). The mean age was 43.41(SD 16.073) years, and 43(61.4%) were females. CSF kappa showed highest specificity 97.4%, at a cut off 2.06 mg/L (sensitivity 71%) and highest sensitivity 90.3%, at a cut off 0.47 mg/L (specificity 79.5%). Best balance of sensitivity and specificity for CSF kappa was seen at a cut-off of ≥ 0.63 mg/L {sensitivity 87·1 (CI - 70.17-96.37), and specificity 87·18 (CI -72.57-95.70)}. The ratio of Kappa/lambda showed highest specificity of 100%(similar to OCB) with a sensitivity of 71% at a cut off of 1.72. The ratio of sum of kappa and lambda light chains, and Qalb (∑CSF FLC/Qalb), showed the highest specificity (94.87%)among the blood brain barrier corrected ratios. CONCLUSION: This study showed that the diagnostic utility of CSF kappa was comparable to OCB to diagnose multiple sclerosis in sensitivity, but not specificity, so can be a screening test before testing for OCB in our population.

Autoimmune parkinsonism with faciobrachiocrural dystonic seizures: a new phenotype of leucine-rich glioma-inactivated 1 (LGI1) autoimmunity.

Extrapyramidal symptoms are seen in patients with leucine-rich glioma-inactivated 1 (LGI1) antibody-positive patients infrequently and this can be successfully treated with immunotherapy. This is a retrospective hospital-based study from 2013 to 2021 at a tertiary care referral hospital in South India. LGI1 antibody-positive cases with Faciobrachio-crural dystonic seizures [FBCDS] were identified by reviewing electronic medical records and Neuroimmunology laboratory register. Clinical and laboratory details and treatment outcomes were analysed. There was a total of 23 patients who were positive for LGI1 antibody. Of these, three cases had FBCDS (2 males, age range 30-76 years). Upon reviewing the records they had additional asymmetric parkinsonian features. All had similar presentations with progressive slowness of activities and gait and later went on to have paroxysmal events of sudden falls with vocalization. Prolonged VEEG monitoring captured the habitual event, which were confirmed to be FBCDS. MRI did not show significant structural abnormalities, CSF showed elevated proteins and normal cell in two and lymphocytic pleocytosis in one, PET scans ruled out malignancy. Of the three patients, two were completely relieved of FBCDS with immunosuppression and there was complete resolution of extrapyramidal features in all. Thus, the patients in our series of FBCDS showed additional features of parkinsonism which responded well to immunotherapy. Involvement of basal ganglia can explain all the manifestations of this phenotype. This series reveals a unique phenotype of the LGI1 antibody.

Prozone phenomenon observed in indirect immunofluorescence assay by antibodies against neuronal antigens.

A marked prozone effect was observed in indirect immunofluorescence with human sera and human cerebrospinal fluid in two clinical cases involving breast carcinoma with paraneoplastic neuronal antibodies, and anti- N-methyl-D-aspartic acid (NMDA) receptor antibodies. Anti-Yo antibodies and anti-NMDA antibodies were not detectable under high concentrations (1:10 serum dilution and neat CSF respectively) but showed a true effect when sufficiently diluted at 1:80 and 1:5 respectively. This paper demonstrates that prozone effects have their occurrences in indirect immunofluorescence, and clinicians and laboratory technicians should be wary of its implications during screening of autoantibody markers in neurological diseases.

Expanding spectrum of contactin-associated protein 2 (CASPR2) autoimmunity-syndrome of parkinsonism and ataxia.

Contactin-associated protein 2 (CASPR2) antibodies are originally associated with Morvan's syndrome and peripheral nerve hyper excitability. Our objective was to study retrospectively the clinical spectrum of CASPR2 antibody-positive patients in our hospital. This is a retrospective observational study. Patients treated at the Amrita Institute of Medical Sciences from May 2013 to April 2016, who were tested positive for CASPR2 antibodies, were included. A total of 1584 samples were tested in the neuroimmunology laboratory during the study period for voltage-gated potassium channel (VGKC) complex antibodies-leucine-rich glioma-inactivated protein 1 (LGI1) and CASPR2 antibodies. Thirty-four were positive for LGI1, 13 were positive for CASPR2, and 7 were for both (total 54-3.4% positivity). Of these 54 cases, 11 were treated in our hospital. Seven were positive for LGI1, three for CASPR2, and one for both. The patient who had both CASPR2 and LGI1 antibody positive had Morvan's syndrome. One patient with CASPR2 had neuromyotonia. The other patient was admitted with status epilepticus with a syndrome of parkinsonism and ataxia. The third patient had encephalopathy and myoclonus with a syndrome of parkinsonism and ataxia. Two of them underwent siddha treatment for other ailments prior to the onset of the disease for other ailments. Our short series shows the expanding spectrum of CASPR2 autoimmunity. Syndrome of parkinsonism and ataxia is an important manifestation of CASPR2 autoimmunity where we can offer a definitive treatment.

Autoimmune atypical parkinsonism - A group of treatable parkinsonism.

BACKGROUND: Immunological causes of atypical parkinsonism/Parkinson plus syndromes are rare. OBJECTIVE: To study the clinical and laboratory features and treatment outcome of autoimmune atypical parkinsonism. METHODS: Retrospective case series. Patients with atypical parkinsonism and positive antibodies were identified retrospectively. Those who received immunotherapy (intravenous methyl prednisolone 1g daily for five days followed by mycophenylate mofetil 2g daily or azathioprine 2-3mg/kg/day) and consented for publication of non-anonymized videos were included. RESULTS: There were ten cases (nine males, age range 49-75years, disease duration 2months to 13years, follow-up 1-7months) of atypical parkinsonism [probable multiple system atrophy (MSA)-2, possible progressive supranuclear palsy (PSP)-1, probable PSP-3]. Eight had new uncharacterized neuronal antibodies, leucine rich glioma associated protein 1 (LGI1) antibody in one, and the other had another uncharacterized neuronal antibody along with LGI1 antibody. Four had abnormal CSF. There was a prompt, dramatic improvement in terms of Unified Parkinson Disease Rating Scale motor scale and or modified Rankin Scale as well as improvement in eye movement, postural instability, cerebellar, autonomic and non-motor symptoms. Two had reappearance of symptoms on discontinuing steroids and improvement on restarting. One died of infection despite good recovery of encephalopathy and parkinsonism. CONCLUSION: Autoimmune atypical parkinsonism is characterized by atypical parkinsonism with neuronal specific antibodies, sometimes associated with abnormal CSF and significant response to immunotherapy.

Autoimmune encephalitis: Clinical diagnosis versus antibody confirmation.

CONTEXT: Autoimmune encephalitis is a heterogeneous disorder which is being diagnosed with increasing frequency. The diagnosis of these disorders is based on the detection of autoantibodies and characteristic clinical profiles. AIMS: We aimed to study the antibody profile in encephalitis patients with suspected autoimmune etiology presenting to a tertiary care center. SETTINGS AND DESIGN: The subjects were selected by screening all patients with clinical profile suggesting autoimmune encephalitis admitted in the neuromedical intensive care unit (ICU) of a tertiary care center in South India. MATERIALS AND METHODS: Patients who fulfilled modified Zuliani et al.'s, criteria for autoimmune encephalitis were identified during the period December 2009-June 2013. Blood samples from these subjects were screened for six neuronal antibodies. STATISTICAL ANALYSIS USED: Chi-square test was applied to compare the antibody positive and negative patients. RESULTS: Out of 1,227 patients screened, 39 subjects (14 males: 25 females) were identified with a mean age of 15.95 years and 19 cases were assessed in the acute and 20 in the convalescent phase of the illness. Seizure (87.8 %) was the most common presenting symptom; status epilepticus occurred in 23 (60.5%) patients during the course of the illness. Fourteen (35.9%) patients were N-methyl-D-aspartate receptor (NMDAR) antibody-positive and all were negative for the other antibodies tested. CONCLUSIONS: One-third of patients presenting with acute noninfective encephalitis would be positive for NMDAR antibodies with the remaining two-thirds with clinically suspected autoimmune encephalitis being antibody-negative. There are few markers in the clinical and investigative profiles to distinguish antibody-positive and -negative patients.

Dot-immunobinding assay (Dot-Iba).

Dot-immunobinding assay (Dot-Iba) is a simple and highly reproducible immunodiagnostic method. Antibody or antigen is dotted directly onto nitrocellulose membrane (NCM) discs. The diagnostic material to be checked can be incubated on this disc. Presence of antigen-antibody complex in NCM discs can be directly demonstrated with enzyme-conjugated antiglobulins and substrate. Development of a purple-pink colored, insoluble substrate product in the nitrocellulose membrane will be considered a positive result in the assay. This assay allows the processing of multiple specimens at a time and the entire operational procedures required only 4-6 h. Dot-IBA is rapid and the technical steps involved in the assay are much simpler than the other immunoassays such as enzyme-linked immunosorbent assay in detecting circulating antigen and antibody in clinical samples. The Dot-Iba showed an overall sensitivity of 60 % for tuberculous meningitis diagnosis and no false positive results were encountered. Hence this assay is highly specific for the diagnosis of paucibacillary diseases like extrapulmonary tuberculosis. Dot-Iba is best suited to laboratories in developing world where there are constraints in laboratory resources.

Women with epilepsy and infertility have different reproductive hormone profile than others.

PURPOSE: One-third of women with epilepsy (WWE) may experience infertility (failure to conceive after 12 months of regular unprotected intercourse). We aimed to compare the hormone profile of WWE and infertility (WWE-I) with that of WWE who had conceived earlier (WWE-F). MATERIALS AND METHODS: In the Kerala Registry of Epilepsy and Pregnancy, we compared the clinical and hormone profile of 50 WWE-I and 40 age-matched WWE-F. Subjects were examined and blood samples were drawn in follicular phase (1-14 days) for 21 WWE-I and 18 WWE-F, in luteal phase (15-30 days) for 23 WWE-I and 15 WWE-F and beyond 30 days for 6 WWE-I and WWE-F who had irregular cycles. RESULTS: The two groups were comparable regarding physical, epilepsy syndrome, duration of epilepsy, body mass index, and serum cholesterol levels. Menstrual periods were irregular for 6 WWE-I and 5 WWE-F. The WWE-I group (compared to the WWE-F group) had significantly (P < 0.01) higher levels of dehydroepiandrostenedione (2.0 ± 1.7 ug/mL vs. 1.0 ± 0.7 ug/mL) and luteinizing hormone-LH (26.4 ± 37.3 mIU/mL vs. 9.9 ± 14.5 mIU/mL) and lower levels of progesterone (5.2 ± 9.2 ng/mL vs. 10.4 ± 13.4 ng/mL). There was no significant difference in the levels of FT3, FT4, thyroid stimulating hormone, prolactin, follicle-stimulating hormone (FSH), progesterone, testosterone, or androstenedione levels. The WWE-I had 8.5 times higher risk (95% confidence interval 1.2-59.9) of abnormal LH/FSH ratio. WWE who were on antiepileptic drugs (AEDs) (compared to WWE who were not on AEDs) had higher risk of elevated LH/FSH ratio. CONCLUSION: The hormone profile of WWE-I is significantly different from that of WWE-F. These variations need to be interpreted with caution as a causal relationship to epilepsy or use of antiepileptic drugs need to be established through further studies.

Serum tumor necrosis factor-alpha in Guillain-Barré syndrome and its relation to plasma exchange.

BACKGROUND: To correlate the serum tumor necrosis factor-alpha (TNFalpha) concentrations before, during and following plasma exchange in patients with Guillain-Barré syndrome (GBS). In this prospective study, 21 GBS patients were selected. Patients in clinical stages III to V were subjected to plasma exchange. The control group included equal numbers of age-matched patients with other neurological diseases and healthy voluntary blood donors. A sandwich ELISA method was applied to estimate serum TNFalpha concentrations in test and control groups. REVIEW SUMMARY: Twelve GBS patients had elevated serum TNFalpha levels that ranged between 74 and 182 pg/mL. All 12 GBS patients showed a steady decrease in the TNFalpha concentration following plasma exchange and also showed a positive correlation with neurological recovery. CONCLUSIONS: We conclude that serum TNFalpha concentrations are elevated in 57.1% of GBS patients and TNFalpha level decreases following plasma exchange.