Spectrum of Sensory Conduction Abnormalities in Guillain Barre Syndrome.

Background: Sensory nerve conduction parameters in Guillain Barre Syndrome (GBS) are underemphasized. Objective: To describe abnormalities on sensory conduction studies in a large cohort of prospectively evaluated patients of GBS and to correlate with clinico-electrophysiological features. Methods and Materials: Sensory conduction parameters of three nerves (median, ulnar, and sural) were analyzed using standard protocols in 238 patients (M: F 163:75, mean age: 35.76 ± 15.9 years). Electrophysiological subtyping was based on criteria of Hadden et al., and Rajabally et al. Results: Among patients with "typical" GBS who underwent electrophysiological testing within 30 days of symptom-onset (n = 219), 183 (83.5%) had abnormal sensory potentials (one nerve = 52, two nerves = 77, all three nerves = 54). Frequency of abnormalities in sensory potentials increased with duration of illness. Commonest abnormality was reduced amplitude or in-excitable nerves. Mean amplitude and velocity of median and ulnar nerve sensory potentials were significantly lower among those with demyelinating electrophysiology (P < 0.05). Proportion of subjects with reduced amplitude and velocity of median and ulnar nerve sensory potentials was higher among those who required mechanical ventilation (P < 0.05). Frequency of "sural sparing" ranged from 10.5% to 84.5% depending on the criteria used and almost always was significantly associated with demyelinating neuropathy. Conclusion: This prospective study provides comprehensive data on sensory conduction parameters in GBS. Abnormalities are frequent and vary with duration of illness. While median nerve is most frequently and more severely affected, involvement of sural nerve may have prognostic value.

Impact of Antecedent Infections on the Antibodies against Gangliosides and Ganglioside Complexes in Guillain-Barré Syndrome: A Correlative Study.

Background and Aims: Guillain-Barré Syndrome (GBS), an immune-mediated neuropathy, is characterized by antibodies against gangliosides/ganglioside complexes (GSCs) of peripheral nerves. Antecedent infections have been reported to induce antibodies that cross-react with the host gangliosides and thereby have a pivotal role in conferring an increased risk for developing GBS. Data pertaining to the impact of various antecedent infections, particularly those prevalent in tropical countries like India on the ganglioside/GSC antibodies is sparse. We aimed at exploring the association between six antecedent infections and the profile of ganglioside/GSC antibodies in GBS. Methods: Patients with GBS (n = 150) and healthy controls (n = 50) were examined for the serum profile of antibodies against GM1, GM2, GD1a, GD1b, GT1b, and GQ1b and their GSCs by ELISA. These antibodies were correlated with immunoreactivities against Campylobacter jejuni, Japanese encephalitis (JE), dengue, influenza, zika, and chikungunya infections. Results: The frequencies of antibodies against six single gangliosides (P < 0.001) and their GSCs (P = 0.039) were significantly higher in patients as compared to controls. Except for GT1b-antibody which was more frequent in axonal GBS, none of the other ganglioside/GSC antibodies correlated with the electrophysiological subtypes of GBS. Antecedent JE infection was significantly associated with increased frequency of antibodies against GD1a, GD1b, GT1b, and GQ1b. Antibodies against GSCs were not influenced by the antecedent infections. Interpretation: This study for the first time shows an association between antecedent JE infection and ganglioside antibodies in GBS. This finding reinforces the determining role of antecedent infections on ganglioside antibody responses and the subsequent immunological processes in GBS.

Role of altered IL-33/ST2 immune axis in the immunobiology of Guillain-Barré syndrome.

BACKGROUND: The IL-33/ST2 immune axis plays crucial roles in infection and immunity. A dysregulated IL-33/ST2 axis can induce autoimmune reaction and inflammatory responses. Guillain-Barré syndrome (GBS) is an acute peripheral neuropathy, mostly caused by post-infection autoimmunity. The role of IL-33/ST2 axis is not known in GBS. This study aimed to explore the role of IL-33/ST2 axis in GBS. METHODS: Three single nucleotide polymorphisms (SNPs) of Il33 gene (rs16924159, rs7044343, rs1342336) and three SNPs of Il1rl1 gene (rs10192157, rs1041973, rs10206753) coding for suppressor of tumorigenicity 2 (ST2) were genotyped in 179 GBS patients and 186 healthy controls by TaqMan Allelic Discrimination Assay. Plasma levels of IL-33 and sST2 were measured in a subset of GBS patients (n = 80) and healthy controls (n = 80) by ELISA. RESULTS: The frequencies of CC genotype of rs10192157 (p = 0.043) and TT genotype of rs10206753 (p = 0.036) SNPs of Il1rl1 gene differed significantly between GBS patients and healthy controls. Gene-gene interaction between Il33 and Il1rl1 genes also conferred significant risk for GBS. In addition, the plasma sST2 levels were significantly elevated in GBS patients compared to healthy subjects (24,934.31 ± 1.81 pg/ml vs. 12,518.97 ± 1.51 pg/ml, p < 0.001). Plasma sST2 levels showed a significant correlation with the disability scores at the peak of neurological deficit in GBS patients. CONCLUSIONS: The IL-33/ST2 axis is suggested to influence the immunopathogenesis of GBS. Genetic variants of Il1rl1 gene might serve as a risk determinant of GBS and plasma sST2 levels might emerge as a biomarker of severity of GBS, if replicated further by other studies.

Variations within Toll-like receptor (TLR) and TLR signaling pathway-related genes and their synergistic effects on the risk of Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is the commonest post-infectious polyradiculopathy. Although genetic background of the host seems to play an important role in the susceptibility to GBS, genes conferring major risk are not yet known. Dysregulation of Toll-like receptor (TLR) molecules exacerbates immune-inflammatory responses and the genetic variations within TLR pathway-related genes contribute to differential risk to infection. The aim of this study was to delineate the impact of genetic variations within TLR2, TLR3, and TLR4 genes as well as TLR signaling pathway-related genes such as MyD88, TRIF, TRAF3, TRAF6, IRF3, NFκß1, and IκBα on risk of developing GBS. Fourteen polymorphisms located within TLR2 (rs3804099, rs111200466), TLR3 (rs3775290, rs3775291), TLR4 (rs1927911, rs11536891), MyD88 (rs7744, rs4988453), TRIF (rs8120), TRAF3 (rs12147254), TRAF6 (rs4755453), IRF3 (rs2304204), NFκß1 (rs28362491), and IκBα (rs696) genes were genotyped in 150 GBS patients and 150 healthy subjects either by PCR-RFLP or TaqMan Allelic Discrimination Assay. Genotypes of two polymorphic variants, Del/Del of rs111200466 insertion and deletion (INDEL) polymorphism of TLR2 gene and TT of rs3775290 single nucleotide polymorphism (SNP) of TLR3 gene had significantly higher frequencies among GBS patients, while the frequencies of TT genotype of rs3804099 SNP of TLR2 gene and TT genotype of rs11536891 SNP of TLR4 gene were significantly higher in controls. Gene-gene interaction study by Multifactor Dimensionality Reduction analysis also suggested a significant combined effect of TLR2, and NFκß1 genes on the risk of GBS. The SNPs in the IκBα and IRF3 genes correlated with severity of GBS. The genes encoding TLRs and TLR signaling pathway-related molecules could serve as crucial genetic markers of susceptibility and severity of GBS.

Antecedent infections in Guillain-Barré syndrome patients from south India.

Guillain-Barré syndrome (GBS) is the commonest post-infectious inflammatory peripheral neuropathy with undiscerned aetiology. The commonly reported antecedent infections implicated in India include Campylobacter jejuni, chikungunya, dengue, and Japanese encephalitis (JE). In this study from south India, we investigated the role of these four agents in triggering GBS. This case-control study was performed on 150 treatment-naive patients with GBS and 150 age and sex-matched controls from the same community. IgM immunoreactivity for C. jejuni, chikungunya, and dengue was detected by enzyme-linked immunosorbent assay (ELISA) in serum of patients with GBS and control subjects. Immunoreactivity against JE was detected in serum as well as cerebrospinal fluid (CSF) from patients (n = 150) and orthopaedic control (n = 45) subjects. The immunoreactivity against infections was compared between demyelinating and axonal subtypes of GBS. Overall, 119/150 patients with GBS had serological evidence of antecedent infection. Amongst those with evidence of antecedent infection, 24 (16%), 8 (5%), and 9 (6%) patients were exclusively immunoreactive to chikungunya, JE, and C. jejuni, respectively. In the remaining patients (78/119), immunoreactivity to multiple pathogens was noted. Immunoreactivity to C. jejuni infection was found in 32% of GBS patients compared to 2.7% controls (P < .001), whereas to chikungunya virus was reported in 66.7% of patients with GBS compared to 44.7% controls (P = .006). Anti-dengue immunoreactivity was significantly associated with the demyelinating subtype of GBS. Patients positive for JE IgM (CSF) manifested demyelinating electrophysiology. In this large case-control study, immunoreactivity against multiple infectious agents was observed in a subset of patients. Chikungunya was the commonest antecedent infection, followed by C. jejuni.

Ganglioside complex antibodies in an Indian cohort of Guillain-Barré syndrome.

BACKGROUND: Antibodies against ganglioside complexes (GSCs) are associated with various clinical features and subtypes of Guillain-Barré syndrome (GBS). METHODS: One-hundred patients were evaluated for antibodies to GSCs formed by combination of GM1, GM2, GD1a, GD1b, GT1b, and GQ1b using manual enzyme linked immuno-sorbent assay (ELISA). RESULTS: Twenty-six patients were GSC antibody-positive, most frequent being against GM1-containing GSC (76.9%). Gender distribution, mean age, symptom-duration, antecedent events, electrophysiological subtypes, requirement for mechanical ventilation, and median duration of hospital stay were comparable between the GSC antibody-positive and negative groups. There was no association between specific GSC antibody and electrophysiological subtypes or clinical variants. After controlling for false discovery rate (FDR) using the Benjamini-Hochberg method, the number of subjects who improved in overall disability sum score, modified Erasmus GBS outcome score, and neuropathy symptom score at discharge was significantly higher in the GSC antibody-positive group. Improvements in Medical Research Council sum scores and Hughes Disability Scale during the hospital stay between the GSC antibody-positive and negative groups were not significantly different after controlling for FDR. CONCLUSIONS: The GSC antibody-positive group had better outcome at hospital discharge in some of the disability scores. Pathophysiological pathways among patients without GSC antibodies may be different and this requires further evaluation.

Evidence of altered Th17 pathway signatures in the cerebrospinal fluid of patients with Guillain Barré Syndrome.

Data indexing the contribution of various immuno-inflammatory components in the cerebrospinal fluid (CSF) towards the pathophysiology of Guillain Barré Syndrome (GBS) are limited. Th17 pathway plays crucial role in many immune mediated disorders of the nervous system. This study was aimed at exploring the role of Th17 pathway related cytokines in the CSF of patients with GBS. Levels of multiple key cytokines of Th17 pathway in CSF of patients with GBS (N = 37) and controls (N = 37) were examined in this prospective study using Bio-plex Pro Human Th17 cytokine assays in a Multiplex Suspension Array platform. The findings were correlated with clinical features and electrophysiological subtypes. Three key cytokines of Th17 pathway (IL-6, IL-17A and IL-22) were significantly elevated in CSF of patients with GBS as compared to controls. There was a positive correlation between the levels of IL-6 and IL-17A as well as between the levels of IL-17A and IL-22 in the CSF of patients with GBS. The CSF levels of IL-6 and IL-22 were negatively correlated with the duration of symptoms of GBS. None of the studied cytokines correlated with functional disability scores at admission to hospital or with the electrophysiological subtypes. Identification of Th17 pathway signatures in CSF sheds more insights into the pathogenic role of Th17 cells in GBS. These findings complement the contemporary knowledge and tender further support towards the involvement of Th17 pathway in GBS.

Th17 pathway signatures in a large Indian cohort of Guillain Barré syndrome.

The etiopathogenesis of Guillain Barré Syndrome (GBS) is inadequately understood. The role of immuno-inflammatory Th17 pathway was examined in GBS patients by genetic, gene expression and biochemical studies. Genotyping of G197A single nucleotide polymorphism within IL17 gene was carried out by PCR-RFLP method in 220 GBS patients. Quantification of gene expression of STAT3 and RORC and estimation of plasma level of IL-17A were carried out in a subset of patients. Significantly increased STAT3 gene expression in lymphocytes and plasma IL-17A levels were observed in GBS patients. This study adds new dimension and reinforces important implications of Th17 pathway in GBS.

Comprehensive cytokine profiling provides evidence for a multi-lineage Th responses in Guillain Barré Syndrome.

Guillain Barré Syndrome (GBS) is one of the commonest acquired immune-mediated neuropathies, often preceded by infections. Although cellular immune responses are shown to substantially account for the pathophysiology of GBS, the precise mechanistic basis of risk and disease course remains enigmatic till date. Cytokines are best known for their abilities to drive cellular immunity and inflammation through their co-ordinated actions. Data obtained from clinical and animal model studies suggest important implications of some of the cytokines in the progression and recovery of GBS. However, these studies were performed on few cytokines and small set of GBS patients, thereby lacking a complete understanding of the patterns of association of cytokines representing Th1, Th2, and Th17 responses with GBS. We studied 65 well-characterized GBS patients and 73 age- and sex-matched healthy controls. A panel of 15 cytokines representing Th1, Th2 and Th17 pathways was assayed using Multiplex Suspension Array platform. Plasma levels of five cytokines were found to be altered in GBS patients compared to healthy control subjects: (i) IL-1ß exhibited reduced levels, and (ii) IFN-γ, IL-4, IL-21 and IL-33 were elevated in GBS patients. The most important finding of this study was up-regulated expression of IL-21 and IL-33 in patients with GBS. Given the role of IL-33 as an alarmin, the elevated level of this cytokine provides important indication about a much broader role of cytokines in GBS. This study also provides evidence towards a multi-lineage Th cells (Th1, Th2 and Th17) associated cytokine responses in the pathophysiology of GBS.

The Tale of the Storyteller and the Painter: The Paradoxes in Nature.

INTRODUCTION: Brain as the seat of behavior is acknowledged from the times of Charaka, however where neurology ends and philosophy begins remains an enigma. It is certainly every neurologist's observation that there is loss of function either region based or domain based in progressive diseases of the nervous system making it the seat of all useful activities. However, there are references to occurrence of new skills seen during various illnesses causing progressive cognitive dysfunction. This serves as a pharmaco-sparing agent in behavior management and therefore serves as a rehabilitatory tool. However, its pathomechanism is not clear. PATIENT AND METHODS: Two patients comprising one male and one female who were being evaluated for progressive cognitive dysfunction and were found to have interesting creative skills and are being described. RESULTS: The first patient is a case of young onset behavioral variant frontotemporal dementia and the second patient is a case of neurosarcoidosis. CONCLUSION: The emergence of these skills could be due to disinhibition of some of the innate skills of the patients during degeneration or establishment of new data linking circuits with creative potential during attempted repair.

Syndromes of Rapidly Progressive Cognitive Decline-Our Experience.

BACKGROUND: Dementias are fairly slowly progressive degenerative diseases of brain for which treatment options are very less and carry a lot of burden on family and society. A small percentage of them are rapidly progressive and mostly carry a different course outcome. However, there are no definite criteria other than the time line for these patients. AIMS: The aim of this was to identify and categorize the causes and course of rapidly progressive dementias seen in our center. SETTINGS AND DESIGN: Patients who presented with rapid deterioration of cognitive functions within weeks to 1 year between 2011 and December 2016 were evaluated. PATIENTS AND METHODS: All patients underwent all mandatory tests for dementia including brain imaging. Complete vasculitis workup, autoimmune encephalitis profile including Voltage Gated Potassium Channel, N-methyl-D-aspartic acid receptor, glutamic acid-decarboxylase, thyroid-peroxidase antibody, cerebrospinal fluid, and other special tests such as duodenal biopsy and paraneoplastic workup were done based on clinical indications. RESULTS AND CONCLUSIONS: Out of 144 patients 42 had immune-mediated encephalopathy, 18 had Creutzfeldt-Jakob disease, 3 had Vitamin B12 deficiency, 63 had infection with neurocysticercosis, 7 had tuberculosis, 2 had HIV, 1 had herpes simplex encephalitis, 1 had neurosyphilis, 1 Whipples disease, 1 had Subacute Sclerosing Panencephalitis, 1 had Mass lesion, 3 had Frontotemporal dementia, and 3 had small vessel disease. Good majority of these patients have infective and immune-mediated causes and less number belong to degenerative group. Therefore, caution is needed to look for treatable cause as it carries a different treatment options and outcome.