Metabolic scoring in autoimmune epilepsy-Should APE scores be modified?

OBJECTIVE: We evaluate the potential utility of F-18 FDG-PET in addition to MRI in the diagnostic work-up of patients with autoimmune epilepsy (AE) and propose the inclusion of functional imaging in the antibody prevalence in epilepsy (APE) scoring system. METHODS: This was a retrospective analysis in 60 patients, diagnosed and treated for AE, of whom 40 were antibody negative (presumed AE) and 20 were antibody positive (definitive AE). All patients had undergone a dedicated brain and whole body FDG-PET in the department of Nuclear Medicine. RESULTS: In the antibody negative group, MRI supported a diagnosis of AE in 23 patients. Both MRI and PET were indicative in 12 cases, and standalone PET was positive in 8. While MRI alone was diagnostic in 57% (23/40), the combined yield of both modalities was 77% (31/40). When PET scores were added to assign the APE score in MRI negative cases, average APE score was 5.4. In the antibody positive group, MRI supported the diagnosis of AE in 7 patients. Both MRI and PET were positive in 4 patients and standalone PET was positive in 5 patients. While MRI alone was diagnostic in 35% (7/20), the combined yield of both modalities was 60% (12/20). When PET scores were added to assign the APE score in MRI negative cases, average APE score was 6.1. CONCLUSION: The inclusion of metabolic information from PET distinctly improved (the sensitivity of) APE scores to predict autoimmune origin even in antibody negative cases. A larger prospective study of similar type could justify adoption of FDG-PET into the standard diagnostic procedure.

Association of cutaneous adverse drug reactions due to antiepileptic drugs with HLA alleles in a North Indian population.

PURPOSE: Aromatic antiepileptic drugs (AEDs) are frequently implicated in cutaneous adverse drug reactions (cADRs), a few of which are associated with certain human leukocyte antigen (HLA) alleles in some populations. We aimed to find HLA-associations with AED-related cADRs among North Indians. METHODS: North Indian subjects with cADR due to an AED, and those who were AED-tolerant were recruited as cases and controls, respectively. Genotyping for HLA-A, B and DRB1 were performed. Statistical analysis to compare carrier-rates and allele-frequencies between cases and controls (and healthy population, where necessary), was done for HLA-alleles occurring more than twice in either group. RESULTS: 120 cases {11 - Lamotrigine (LTG), 14 -Valproic acid (VPA), 8 -Levetiracetam (LEV), 35 -Carbamazepine (CBZ) and 52 - Phenytoin (PHT)}, and 250 controls were recruited. Presence of HLA-A*31:01 and HLA-B*51:01 were found to increase the risk of Maculopapular exanthema (MPE) due to CBZ and PHT (OR = 6.38; 95% CI: 1.46-27.75; OR = 4.60; 95% CI: 1.54-13.72, respectively). Among the severe cADRs, HLA-B*57:01(OR = 11.00 95% CI: 1.41-85.81) and HLA-DRB1*07:01 (OR = 7.25; 95% CI: 1.09-48.18) were noted to be significantly associated with CBZ-induced Stevens Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN); HLA-B *51:01 was associated with drug reaction eosinophilia and systemic symptoms (DRESS) caused by PHT (OR = 6.90; 95% CI: 1.38-34.29). CONCLUSIONS: We found significant associations of some HLA alleles with specific cADRs to CBZ and PHT in North Indians, which may need to be tested before AED-initiation; only screening for HLA-B*15:02 may not help in this population.

Proportion and spectrum of movement disorders in adolescent and adult patients of autoimmune encephalitis of non-neoplastic aetiology.

We aimed to study the proportion of patients with movement disorders in seropositive autoimmune encephalitis of non-neoplastic aetiology and also to describe the spectrum of movement disorders in them. We prospectively screened 362 patients of age >12 years with encephalitis of unknown aetiology for a panel of antibodies for autoimmune encephalitis. Demographic and clinical characteristics with focus on the movement disorders were recorded. We also evaluated the differences in the spectrum of movement disorder based on various age groups and antibody positivity. Patients were treated with immune modulating drugs and were followed up for 6 months. Out of the 41 patients, 21 (51.2%) patients presented with movement disorder as a part of their clinical presentation. The commonest movement disorder encountered in our cohort was orofaciolingual dyskinesia (OFLD) 57.1% followed by tremor (38.1%), choreoathetosis (33.3%), paroxysmal dyskinesia (23.8%) stereotypies (14.3%), bradykinesia (13.1%), followed by dystonia (13.1%), catatonia (4.7%), neuromyotonia (4.7%) ballism (4.7%), ataxia (4.7%) and stiff person phenotype (4.7%). The hyperkinetic movement disorders were more commonly seen compared to hypokinetic disorders. All patients received immunomodulatory therapy. On follow, 17 (80.1%) patients had good response with total remission of the movement disorder. Four patients did not have total remission but significant improvement in the symptoms after 6 months of follow up. Our study shows that >50% of patients with antibody positive autoimmune encephalitis have movement disorder as a part of their clinical feature. Timely institution of immunotherapy leads to good outcome in majority of patients.

Metabolic topography of autoimmune non-paraneoplastic encephalitis.

PURPOSE: F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) is emerging to be a useful tool in supporting the diagnosis of AIE. In this study, we describe the metabolic patterns on F-18 FDG PET imaging in AIE. METHODS: Twenty-four antibody-positive patients (anti-NMDA-15, anti-VGKC/LGI1-6, and anti-GAD-3), 14 females and 10 males, with an age range of 2-83 years were included in this study. Each PET study was evaluated visually for the presence of hypometabolism or hypermetabolism and semiquantitatively using Cortex ID (GE) and Scenium (Siemens) by measuring regional Z-scores. These patterns were correlated with corresponding antibody positivity once available. RESULTS: Visually, a pattern of hypometabolism, hypermetabolism, or both in various spatial distributions was appreciated in all 24 patients. On quantitative analysis using scenium parietal and occipital lobes showed significant hypometabolism with median Z-score of -3.8 (R) and -3.7 (L) and -2.2 (R) and -2.5 (L) respectively. Two-thirds (16/24) showed significant hypermetabolism involving the basal ganglia with median Z-score of 2.4 (R) and 3.0 (L). Similarly on Cortex ID, the median Z-score for hypometabolism in parietal and occipital lobes was -2.2 (R) and -2.4 (L) and -2.6 (R) and -2.4 (L) respectively, while subcortical regions were not evaluated. MRI showed signal alterations in only 11 of these patients. CONCLUSION: There is heterogeneity in metabolic topography of AIE which is characterized by hypometabolism most commonly involving the parietal and occipital cortices and hypermetabolism most commonly involving the basal ganglia. Scenium analysis using regional Z-scores can complement visual evaluation for demonstration of these metabolic patterns on FDG PET.

Cutaneous Adverse Drug Reactions to Lamotrigine and Human Leukocyte Antigen Typing in North Indian Patients: A Case Series.

Cutaneous adverse drug reaction (cADR) has limited epidemiological data in India. The older antiepileptic drugs, i.e., carbamazepine, phenytoin, valproic acid, phenobarbitone, etc., induce severe cADRs that have a strong associated with human leukocyte antigen (HLA)-related genetic risk factors. There is also evidence of association of certain HLA alleles with lamotrigine (LTG)-induced cADRs, but this has not been reported in the Indian population. Here, we report case series of three patients with LTG-induced "Stevens-Johnson syndrome (SJS)." Their HLA-B typing was also performed which showed the presence of HLA-B*15:02 in one case with SJS.

LGI1 encephalitis: a disease of jerks and confusion.

Limbic encephalitis is a group of immune-mediated disorders that includes the classic paraneoplastic encephalitic syndrome and the recently described non-paraneoplastic autoimmune encephalitis most of which target the extracellular antigens. We present a case of 70-year-old man who presented with rapidly progressive cognitive decline and refractory faciobrachial dystonic seizures and demonstrated seropositivity for leucine-rich, glioma-inactivated protein 1 antibodies. After immunomodulation, the patient had dramatic improvement in the cognitive functioning and in seizure control.

Spectrum of Cutaneous Adverse Reactions to Levetiracetam and Human Leukocyte Antigen Typing in North-Indian Patients.

BACKGROUND AND PURPOSE: Aromatic antiepileptic drugs are frequently implicated for cutaneous adverse drug reactions (cADRs); there are case-reports of even severe reactions like drug reaction eosinophilia and systemic symptoms (DRESS) and Stevens Johnson syndrome (SJS)-toxic epidermal necrolysis with Levetiracetam (LEV). Certain human leukocyte antigen (HLA)-alleles have strong association with cADRs due to specific drugs - HLA-B*15:02 and HLA-A*31:01 in Carbamazepine (CBZ)-related SJS in Han-Chinese and European populations, respectively. Here, the spectrum of cADRs to LEV was studied, and HLA-typing in patients with cADRs due to LEV and some who were LEV-tolerant was performed, in an attempt to find an association between HLA and such reactions. METHODS: 589 patients taking LEV were screened for skin reactions, and eight patients with LEV-related cADRs and 25 LEV-tolerant controls were recruited - all 33 of North Indian ethnicity, their HLA-A, B, DRB1 genotyping done. Statistical analysis was done to compare carrier-rates and allele-frequencies of HLA-alleles between cases and controls (and healthy population, where necessary) for alleles occurring more than two times in either group. RESULTS: Out of 589 patients on LEV screened, there were 8 cases of cADR: 5 with maculopapular exanthema (MPE), 2 of SJS, and 1 with DRESS. Although HLA-A*33:01 was seen to occur more in MPE cases as compared to tolerant controls, the difference was not statistically significant (odds ratio [OR] 6.00, 95% confidence interval [CI] 0.30-116.6; p = 0.31). HLA A*11:01 and 24:02 were found to occur more in LEV-tolerant controls than in cases (OR 0.23 [95% CI 0.02-2.36, p = 0.33] and 1.00 [95% CI 0.09-11.02, p = 1.00] respectively). CONCLUSIONS: Cutaneous reactions to LEV are very unusual, and their association with HLA in North-Indian population was not statistically significant.

Autoimmune encephalitis: A potentially reversible cause of status epilepticus, epilepsy, and cognitive decline.

OBJECTIVES: To review clinical characteristics and response to immunomodulation therapy in autoimmune encephalitis presenting with status epilepticus (SE), epilepsy, and cognitive decline. DESIGN: Observational, prospective case series. SETTING: All India Institute of Medical Sciences, New Delhi, India. MATERIALS AND METHODS: Prospective analysis of 15 patients, who presented with SE, epilepsy, cognitive decline, and other neurological symptoms with positive autoantibodies. Demographic and clinical characteristics were recorded. Brain magnetic resonance imaging (MRI), cerebrospinal-fluid analysis (CSF), and tumor screening were done periodically. Treatment received and responses (categorized as per patients and treating doctor's information) were noted. RESULTS: There were 15 (males = 10) patients of autoimmune encephalitis. The mean age of presentation was 24 years (range: 2-64 years). The most common onset was subacute (64%) and four (29%) patients presented as SE. Predominant clinical presentations were seizures (100%) almost of every semiology. CSF was done in 10 patients; it was normal in 60%. Brain MRI was done in all patients, in six (40%) it was normal, six (40%) showed T2W and FLAIR hyperintensities in bilateral limbic areas. Antibodies found were the N-methyl-D-aspartate receptor antibody in seven (50%), voltage-gated potassium channel antibody in five (36%), two of antiglutamic acid decarboxylase, and one patient with double stranded DNA (dsDNA) antibodies. None showed evidence of malignancy. Patients received immunotherapy, either steroids, intravenous immunoglobulin, or both. Follow-up showed significant improvement in majority of cases, neither further seizures nor relapse in nine (67%) cases. One death occurred, due to delayed presentation. CONCLUSIONS: Uncommon but potentially reversible causes of SE, epilepsy, and cognitive decline may be immune-related and high index of suspicion will prevent missing the diagnosis.