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.

Clinical Characteristics of Double Seropositive Myasthenia Gravis.

Double seropositive myasthenia gravis (DSP-MG) has antibodies positive to both acetylcholine receptor (AChR) antibody and muscle-specific tyrosine kinase (MuSK) antibody. This study aims to delineate the clinical phenotype of DSP-MG and assess the histopathological correlation with thymoma. This is a retrospective case series conducted at a tertiary care hospital in South India between February 2018 and October 2021. We had 13 DSP-MG patients (seven females, mean age 60.77+/-14.24). The presentation was generalized in nine patients, bulbar in three, and ocular in one patient. Multi-detector computed tomography done in 11 patients showed thymoma in five and thymic hyperplasia in one. Four patients underwent thymectomy; histopathology showed Type A, B2 (n = 2), and AB thymomas. All 13 patients improved with anticholinesterases. Nine patients were administered immunosuppressants, three patients were given intravenous immunoglobulin, and a single patient underwent plasmapheresis. Our study shows that DSP-MG is more similar to the clinical phenotype of AChR-MG.

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.

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.

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.

Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis.

The concept of substrate inhibition to prevent its phosphorylation has potential in drug discovery and is envisioned to treat the autoimmune disorder multiple sclerosis (MS). Glia maturation factor-ß (GMF-ß) Ser83 phosphorylation by protein kinase A (PKA) is pivotal in the activation of GMF-ß-p38MAPK-NFκB biochemical pathway towards proinflammatory response induction in experimental autoimmune encephalomyelitis (EAE). Using structure-based drug design, we identified the small molecule inhibitor 1-H-indazole-4yl methanol (GMFBI.1) that specifically blocked Ser83 phosphorylation site on GMF-ß substrate. Using in vitro and in vivo techniques, molecular mechanism of action of GMFBI.1's direct interaction with GMF-ß substrate and prevention of its Ser83 phosphorylation was established. GMFBI.1 down regulated p38MAPK phosphorylation and NFκB expression essential for proinflammatory response. Further, GMFBI.1 administration at peak of EAE reversed clinical symptoms, immunopathology, proinflammatory cytokine response and up regulated the anti-inflammatory cytokines. Present strategy of substrate inhibition against the key immunomodulatory target has immense therapeutic potential in MS.

A combined approach of bedside clinical examination and flexible endoscopic evaluation of swallowing in poststroke dysphagia: A pilot study.

BACKGROUND: As with most neurologic conditions, stroke involves impairment of the swallowing mechanism. This could be a spectrum of issues, the worst of which is aspiration. At the same time, the prolonged presence of a naso-gastric tube (NGT) has its own morbidity. Flexible endoscopic evaluation of swallowing (FEES) is one reliable method to assess the structural and functional status of the oropharynx and larynx, during the swallowing process. OBJECTIVE: To study the utility of FEES in decision-making with respect to resumption of oral intake in stroke patients. To document the findings of FEES in stroke patients, and to look for correlations between these and the site of stroke. MATERIALS AND METHODS: Protocol insertion of naso-gastric tube in all stroke patients, at presentation. Initial assessment by a neurologist and swallowing therapist, depending on cognitive status of the patient. All patients underwent MRI Brain with diffusion weighted sequences. After detailed clinical examination, they underwent swallow exercises under the supervision of a trained swallowing therapist. The decision to remove NGT was taken clinically by the combined decision of neurologist and swallowing therapist. Then all patients underwent FEES by the ENT surgeon. The final decision for NGT removal was taken as per the FEES findings. RESULT: Sixteen stroke patients underwent the FEES procedure during a period of six months. The oropharyngeal and laryngeal findings varied depending on the area of stroke involvement. Of these, change in decision regarding swallowing rehabilitation or NGT removal was needed in four patients, following the FEES findings. CONCLUSIONS: FEES is an easy, efficient and reliable method to evaluate the swallowing status in stroke patients. In combination with good bedside clinical examination and swallow exercises, it can be a good tool in assessing patients with post- stroke dysphagia. Post-stroke rehabilitation and prevention of aspiration pneumonia can be effectively done with the help of FEES.