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.

Translational Significance of GMF-ß Inhibition by Indazole-4-yl-methanol in Enteric Glial Cells for Treating Multiple Sclerosis.

In the emerging context of gut-brain control of multiple sclerosis (MS), developing therapeutics targeting proinflammatory proteins controlling the gut-brain immunomodulation is welcoming. One such immunomodulator is glia maturation factor-ß (GMF-ß). GMF-ß activation following GMF-ß-ser-83 phosphorylation upregulates proinflammatory responses and exacerbates experimental autoimmune encephalomyelitis (EAE). Notably, GMF-ß-/- mice exhibited no EAE symptoms. Thus, we identified 1H-indazole-4-yl-methanol (GMFBI.1) inhibitor which blocked GMF-ß-ser-83 phosphorylation critical in EAE suppression. To establish gut GMF-ß's role in EAE in the context of gut-brain involvement in neurodegenerative diseases, we altered gut GMFBI.1 bioavailability as an index of EAE suppression. At first, we identified Miglyol 812N as a suitable biocompatible GMFBI.1 carrier compared to other FDA-approved carriers using in silico molecular docking analysis. GMFBI.1 administration in Miglyol 812N enhanced its retention/brain permeability. Subsequently, we administered GMFBI.1-Miglyol 812N by subcutaneous/oral routes at different doses with differential GMFBI.1 bioavailability in gut and brain to assess the role of local GMFBI.1 bioavailability in EAE reversal by a pharmacokinetic approach. Deprival of gut GMFBI.1 bioavailability led to partial EAE suppression despite having sufficient GMFBI.1 in circulation to inhibit brain GMF-ß activity. Restoration of gut GMFBI.1 bioavailability led to complete EAE reversal. Molecular pathology behind partial/full EAE reversal was associated with differential GMF-ß-Ser-83 phosphorylation/GM-CSF expression levels in enteric glial cells owing to GMFBI.1 bioavailability. In addition, we observed leaky gut reversal, tight junction protein ZO-1 restoration, beneficial gut microbiome repopulation, recovery from gut dysbiosis, and upregulation of Treg cells. GMFBI.1's dual gut/brain targeting of GMF-ß has therapeutical/translational potential in controlling autoimmunity in MS.

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.

New Onset Focal Seizure Clusters in Children: Expanding the Spectrum of Anti NMDAR Encephalitis.

INTRODUCTION: Anti-N-methyl-d-aspartate receptor (Anti-NMDAR) Encephalitis classically presents with polysymptomatic presentation of behavioral or cognitive changes, seizures, and focal deficits. Large series in adults and children have described the above features. Monosymptomatic presentation of Anti NMDAR encephalitis is rare and in literature single case reports in adults and children are available. Here we report a series of 6 children presenting with seizure alone and thus expanding the clinical spectrum of Anti NMDAR encephalitis. MATERIALS AND METHODS: This is a a retrospective case series of 6 cases of anti NMDAR encephalitis treated in our institute, which is a tertiary referral center between 2010 and 2014. All the patients with NMDA encephalitis were initially included. The baseline demographics, clinical presentations, investigations (CSF, MRI and EEG), course in the hospital, details of treatment, short and long term outcomes were documented from the available medical records. Children presenting with monosymptomatic seizure clusters were only included in the final analysis. RESULTS: Twenty eight children were diagnosed with ant NMDA R encephalitis during the study period. 22 children had classical polysymptomatic presentations and were not included in this analysis. The remaining 6 children (5 girls and one boy), who presented with only acute seizure clusters were included in the study. All children presented with acute cluster of focal seizures. Four out of six had focal status epilepticus while 2 out of six had recurrent focal seizures. Commonest semiology was clonic seizure in 4/6 and one child had dystonic seizure and one had tonic seizure. All patients were started on steroids and antiepileptic drugs. No other immunomodulators or immunosuppressants were used. On discharge all patients where seizure free and with no focal deficits. CONCLUSION: This is the first series of Anti NMDAR encephalitis presenting as new onset seizure clusters in children. Unlike the existing literature, these children did not develop any other symptoms. We propose that focal encephalitis could be the reason for this monosymptomatic presentation.

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.

Coexistent MOG, NMDAR, CASPR2 antibody positivity: Triumph over the triumvirate.

Myelin oligodendrocyte glycoprotein (MOG) antibody (MOG -Ab) positive cases can have a focal encephalitis like presentation. Many reports of anti N-methyl-D-aspartate receptor (NMDAR) encephalitis have documented simultaneous coexistence of MOG-Ab which is explained by the coexpression of NMDA receptors and MOG on oligodendrocytic processes. Contactin-associated protein-like 2 (CASPR2) is expressed in central and peripheral nervous system (PNS) axons and there are no case reports of coexistent NMDAR, CASPR2 and MOG antibodies. We describe a young adult male who had neuropsychiatric, cognitive symptoms and long tract signs with a strong positivity for all three antibodies. Bilateral cingulate gyri involvement, especially with contrast enhancement may be an imaging clue suggesting coexistent MOG and NMDAR antibodies. Bilateral T2 hyperintensities affecting hippocampi, have been described in both CASPR2 and anti NMDAR encephalitis. Our patient had both, bilateral cingulate and hippocampal lesions, which may be an imaging clue favouring the presence of all three antibodies.

Persistent extreme delta brush in anti-NMDA-receptor encephalitis: Does it portend a poor prognosis?

We describe an adolescent girl with non-paraneoplastic anti-NMDA-receptor encephalitis (ANMDARE), who despite persistence of the extreme delta brush (EDB) pattern for nearly 2 years in her serial EEGs, she exhibited a speedy and sustained response to immunotherapy. To the best of our knowledge, our patient had the longest persistence of the EDB pattern on EEG reported to date. Our patient illustrates that, although presence of EDB supports the diagnosis of ANMDARE, its presence and persistence may not be a reliable predictor of response to immunotherapy and overall clinical prognosis.

Clinical-radiological-pathological correlation in an unusual case of refractory epilepsy: a two-year journey of whodunit!

New-onset refractory focal epilepsy poses significant challenges to the clinician in the absence of specific diagnostic biomarkers. Differential diagnoses based on imaging may be expanded by a veritable spectrum of peri-ictal imaging findings that may mask the underlying substrate. We report a 13-year-old girl who presented with refractory focal seizures of left parieto-occipital origin with cytotoxic gyral oedema noted over the same region on imaging. Despite an initial negative autoantibody profile, the patient was treated with immunosuppression, followed by serial relapses requiring immune-modulation. Over the next year, her syndrome persisted as focal left posterior cortex epilepsy that necessitated occipital lobectomy, following a relapsing-remitting radiological profile, consistent with peri-ictal MRI changes. Histopathology was inconclusive for any definitive substrate. After a period of quiescence, she developed focal motor seizures of right hemispheric origin with progressive encephalopathy, at which point a repeat cerebrospinal fluid anti-N-methyl-D-aspartate receptor antibody profile returned positive. The patient was managed with steroids and rituximab with a good clinical outcome. We hypothesise that persistent or relapsing-remitting focal gyral oedema in unexplained refractory focal epilepsy mandates consideration of focal encephalitis secondary to autoimmunity, and late appearance of intrathecal auto-antibody synthesis correlates with evolution into a more diffuse disease.

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.

A case of post-leptospirosis autoimmune epilepsy presenting with sleep-related hypermotor seizures.

This video-illustrated case report concerns a 49-year-old woman who presented with sleep-related hypermotor seizures. The antecedent history of leptospirosis, high frequency of new-onset seizures, presence of an unclassified anti-neuronal antibody, and dramatic response to steroids strongly supported post-infectious immune-mediated pathogenesis in our patient. To the best of our knowledge, post-leptospirosis autoimmune epilepsy presenting as sleep-related hypermotor seizures has not hitherto been reported. [Published with video sequence on www.epilepticdisorders.com].

Delayed Orthostatic Hypotension: A Pilot Study from India.

INTRODUCTION: Orthostatic hypotension is defined as a sustained decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within three minutes of standing compared with blood pressure from the sitting or supine position or by head-up tilt-table testing (1). When sustained blood pressure (BP) drop is after three minutes of upright posture it is called delayed orthostatic hypotension (delayed OH) (2). AIM OF THE STUDY: To detect the incidence of delayed orthostatic hypotension in patients referred to our autonomic lab. MATERIALS AND METHOD: BP was measured noninvasively at 1-minute intervals with an automated cuff sphygmomanometer over the right brachial artery for 45 minutes. The onset and duration of falls in blood pressure either systolic or diastolic or both were documented, and any associated symptoms were recorded. Only patients with sustained falls in BP were included. Drugs causing OH was stopped 48 hours before testing as per protocol followed in lab. We also looked into other autonomic function test abnormalities in patients with delayed OH. INCLUSION CRITERIA: Patients above age of 18 years referred for evaluation of autonomic function tests. EXCLUSION CRITERIA: Patients with severe cardiac failure and cardiac arrhythmias were excluded and patients with rapid fall in BP and bradycardia (Neurally mediated syncope) were excluded. RESULTS: Total 170 patients underwent tilt table testing. Orthostatic hypotension was seen within 3 minutes in seventy patients, fifty patients had delayed OH (BP fall after 3 minutes). There were twenty seven males and twenty three females in this group. Twenty nine of the 50 patients with delayed orthostatic hypotension, had symptoms during the tilt table procedure. Asymptomatic OH was more common in patients who developed OH after 10 minutes. CONCLUSION: This is a pilot study, first in India where we looked into the incidence of delayed orthostatic hypotension in patients undergoing tilt table testing in our autonomic lab. We found that fifty patients had delayed orthostatic hypotension which could have been missed on clinical evaluation. High clinical suspicion is needed to detect this disorder and tilt table testing should be done in suspicious cases since orthostatic hypotension is cause of high morbidity.

Clinical Characteristics and Follow-up of South Indian Children with Autoimmune Encephalopathy.

OBJECTIVE: To describe the clinical characteristics of a cohort of south Indian children with probable autoimmune encephalopathy from a tertiary care academic hospital and to compare this data with the existing literature. METHODS: Patients with encephalopathy plus one or more of neuropsychiatric symptoms, seizures, movement disorder or cognitive dysfunction were identified. Common infectious causes were excluded. Clinical characteristics, investigations, management and outcome were analyzed. RESULTS: Thirteen patients were included in the study; 12 were females (92.3 %) and mean age was 9.6 y. Most common presentation was behavior change (13 patients) followed by seizures (11 patients). Three patients showed lymphocytic pleocytosis in CSF and one patient had oligoclonal bands. Initial MRI was normal in all patients except in one. Most common EEG abnormality was mild background slowing. Only one child had ovarian tumor. S.NMDA receptor antibody was positive in 10 patients (83 %), and all of them received immunotherapy. Six out of 13 children were followed up for more than 1 y (mean - 21 mo). Recurrence was noted in 4 out of 6 patients (66 %). On last follow-up, good recovery was seen in 2 children (33 %), moderate disability in 3 (50 %) and severe disability in 1 (16 %). CONCLUSIONS: The clinical characteristics and outcome of one of the largest single center cohort of Indian children with autoimmune encephalopathy is reported. Autoimmune encephalopathy should be considered as a differential diagnosis in the acute and subacute encephalopathies of childhood and treating pediatrician should be aware of this entity.

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.