Gastrointestinal dysfunction in Parkinson's disease: molecular pathology and implications of gut microbiome, probiotics, and fecal microbiota transplantation.

Gastrointestinal symptoms and gut dysbiosis may occur before the onset of motor symptoms in Parkinson's disease (PD). Prediagnostic and prodromal features, such as constipation and α-synuclein pathology, can be detected several years before the clinical diagnosis of PD and have the potential to develop as early PD biomarkers. Environmental toxins and gut dysbiosis may trigger oxidative stress and mucosal inflammation, and initiate α-synuclein accumulation in the enteric nervous system, early in PD. Chronic gut inflammation can lead to a leaky gut and systemic inflammation, neuro inflammation, and neuro degeneration via gut-vagus-brain signaling or through blood-brain barrier permeability. Concepts regarding the gut-brain signaling in PD pathogenesis are changing rapidly and more investigation is required. The gut microbiota interacts with the human body by modulating the enteric and central nervous systems, and immune activity. Understanding the immune responses between gut microbiota and human body might help in elucidating the PD pathogenesis. As changes in gut microbiota composition might be associated with different clinical phenotypes of PD, gut microbiota-modulating interventions, such as probiotics and fecal microbiota transplantation (FMT), have the potential to restore the gut dysbiosis, reduce inflammation, and possibly modulate the clinical PD phenotype.

Cross-sectional analysis of the Parkinson's disease Non-motor International Longitudinal Study baseline non-motor characteristics, geographical distribution and impact on quality of life.

Growing evidence suggests that non-motor symptoms (NMS) in Parkinson's disease (PD) have differential progression patterns that have a different natural history from motor progression and may be geographically influenced. We conducted a cross-sectional analysis of 1607 PD patients of whom 1327 were from Europe, 208 from the Americas, and 72 from Asia. The primary objective was to assess baseline non-motor burden, defined by Non-Motor Symptoms Scale (NMSS) total scores. Other aims included identifying the factors predicting quality of life, differences in non-motor burden between drug-naïve and non-drug-naïve treated patients, and non-motor phenotypes across different geographical locations. Mean age was 65.9 ± 10.8 years, mean disease duration 6.3 ± 5.6 years, median Hoehn and Yahr stage was 2 (2-3), and 64.2% were male. In this cohort, mean NMSS scores were 46.7 ± 37.2. Differences in non-motor burden and patterns differed significantly between drug-naïve participants, those with a disease duration of less than five years, and those with a duration of five years or over (p ≤ 0.018). Significant differences were observed in geographical distribution (NMSS Europe: 46.4 ± 36.3; Americas: 55.3 ± 42.8; Asia: 26.6 ± 25.1; p < 0.001), with differences in sleep/fatigue, urinary, sexual, and miscellaneous domains (p ≤ 0.020). The best predictor of quality of life was the mood/apathy domain (ß = 0.308, p < 0.001). This global study reveals that while non-motor symptoms are globally present with severe NMS burden impacting quality of life in PD, there appear to be differences depending on disease duration and geographical distribution.

The Spectrum of Movement Disorders in Tertiary Care Centers in India: A Tale of Three Cities.

BACKGROUND: Movement disorders constitute a major burden among the neurological disorders. Overall prevalence and distribution of disorders requiring medical resources remain unknown. OBJECTIVE: To understand the pattern of movement disorders burden in India. MATERIALS AND METHODS: Retrospective electronic database review of new patients attending movement disorders clinics in three cities from 2012 to 2018 was done. RESULTS: 14,561 patients (M:F-9,578:4,983) with mean age at assessment of 60.5 ± 14.9 years (Range: 1-98 years) were analyzed. The major broad syndromic diagnosis included: Parkinsonism (n = 9560, 64.9%), Dystonia (n = 2159, 14.8%), Tremors (n = 1129, 7.7%), Ataxia (n = 475, 3.3%), Chorea (n = 402, 2.7%), Peripheral induced movement disorders (n = 400, 2.7%), Gait Disorders (n = 156, 1.1%), Tics (n = 112, 0.8%), Restless Leg Syndrome (n = 89, 0.6%), and Myoclonus (n = 58, 0.4%). The syndromic diagnosis also included the functional disorders (0.6%). CONCLUSION: This large database from India show the burden of different movement disorders in tertiary clinics. In addition, it also gives insight into disorders requiring more resources for evaluation and management.

Impact of home confinement during COVID-19 pandemic on sleep parameters in Parkinson's disease.

BACKGROUND: Literature shows that home confinement during coronavirus disease 2019 (COVID-19) pandemic has significantly affected sleep. However, such information regarding subjects having Parkinson's disease (PD) is unavailable. METHODS: This cross-sectional study was conducted using a questionnaire, developed and validated by experts. PD subjects from nine centers across India were included. Questionnaire assessed presence as well as change in sleep-related parameters and PD symptoms during home confinement. Restless legs syndrome (RLS) and REM sleep behavior disorder (REMBD) was diagnosed using validated questionnaire. Additionally, changes in physical activity, adoption of new hobbies during home confinement and perceived quality of life were assessed. RESULTS: Of 832 subjects, 35.4% reported sleep disturbances. New-onset/worsening of sleep disturbances (NOWS) was reported by 23.9% subjects. Among those with sleep disturbances (n = 295), insomnia symptoms worsened in half (51.5%) and nearly one-fourth reported worsening of RLS (24.7%) and REMBD (22.7%) each. NOWS was common in subjects lacking adequate family support during home confinement (P = 0.03); home confinement > 60 days (P = 0.05) and duration of PD > 7 years (P = 0.008). Contrarily, physical activity >1 h/day and engagement in new hobbies during home confinement were associated with better sleep. NOWS was associated with worsening of motor as well as non-motor symptoms of PD (P < 0.001) and poorer life quality (P < 0.001). CONCLUSION: Home confinement during COVID-19 pandemic was significantly associated with NOWS among PD subjects. NOWS was associated with global worsening of PD symptoms and poorer life quality. Physical activity >1 h/day and adoption of new hobbies during home confinement were associated with better sleep.

Genetic Architecture of Parkinson's Disease in the Indian Population: Harnessing Genetic Diversity to Address Critical Gaps in Parkinson's Disease Research.

Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our "hub-spoke" model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.

Apomorphine: The Initial Indian Experience in Relation to Response Tests and Pumps.

BACKGROUND: Apomorphine is an option for continuous dopaminergic therapy in Parkinson's disease (PD). However, its effects in varied populations are limited due to its availability. OBJECTIVE: To assess the efficacy and outcomes of apomorphine in Indian patients. MATERIALS AND METHODS: Retrospective analysis of PD patients who underwent apomorphine response test (ART), along with the subset, who went on to apomorphine pumps. RESULTS: Twenty-nine confirmed PD patients underwent ART and all PD patients showed good clinical response. 19 subjects developed adverse events which included: nausea (n-15, 51.7%), vomiting (n-10, 34.4%), sleepiness (n-08; 27.5%), yawning (n-07, 24.1%), postural hypotension (n-03, 10.3%), dizziness (n-03, 10.3%), and profuse sweating (n-01, 3.4%). Apomorphine pumps were initiated in six subjects, with significant clinical improvement. Adverse events on pump included subcutaneous nodules, nausea, hypersexuality. Two among them subsequently discontinued the pump primarily due to financial constraints. CONCLUSIONS: Apomorphine adds up to the armamentarium for treatment of PD patients in India with good clinical responses.

Cervical Dystonia Mimics: A Case Series and Review of the Literature.

Background: Cervical dystonia is mostly idiopathic in nature. However, a small subset of cases are mimics, leading to diagnostic pitfalls. There is paucity of literature on pseudodystonias affecting the cervical region. Method: We performed a retrospective review of patients attending a movement disorders clinic over a period of 7 years (2012-2018). Among them, those who were considered to have mimics of cervical dystonia based upon clinical and supportive investigations were included. Results: Six out of 2,412 patients (0.24%) were diagnosed as cervical dystonia mimics and the causes included isolated neck extensor myopathy (2), craniovertebral junction anomalies (2), sternocleidomastoid fibrosis (1) and post traumatic sequelae (1). Among these patients, three patients had received various treatments for cervical dystonia, including botulinum toxin injections. Discussion: Mimics of isolated cervical dystonia are rare. A high degree of suspicion and proper diligent clinical assessment assists management and prognostication.

Minimal change multiple system atrophy: an aggressive variant?

BACKGROUND: Glial cytoplasmic inclusions containing α-synuclein are the pathological hallmark of multiple system atrophy (MSA). Minimal change (MC-MSA) is an unusual MSA subtype with neuronal loss largely restricted to the substantia nigra and locus coeruleus. METHODS: Immunohistochemistry on selected brain regions and semiquantitative assessment were performed on six MC-MSA and eight MSA control cases. RESULTS: More neuronal cytoplasmic inclusions were seen in the caudate and substantia nigra in MC-MSA than in MSA controls (P = 0.002), without any statistical difference in glial cytoplasmic inclusion load in any region. Severe glial cytoplasmic inclusion load was found in the ventrolateral medulla (P = 1.0) and nucleus raphe obscurus (P = 0.4) in both groups. When compared with MSA controls, the three MC-MSA cases who had died of sudden unexpected death had an earlier age of onset (mean: 38 vs. 57.6 y, P = 0.02), a numerically shorter disease duration (mean: 5.3 vs. 8 y, P = 0.2) and a more rapid clinical progression with most of the clinical milestones reached within 3 y of presentation, suggesting an aggressive variant of MSA. Another three MC-MSA cases, who had died of unrelated concurrent diseases, had an age of onset (mean: 57.7 y) and temporal course similar to controls, had less severe neuronal loss and gliosis in the medial and dorsolateral substantia nigra subregions (P < 0.05) than in MSA controls, and could be considered as a unique group with interrupted pathological progression. Significant respiratory dysfunction and early orthostatic hypotension were observed in all MC-MSA cases. CONCLUSIONS: Our findings could suggest that α-synuclein-associated oligodendroglial pathology may lead to neuronal dysfunction sufficient to cause clinical symptoms before overt neuronal loss in MSA. © 2015 International Parkinson and Movement Disorder Society.

Over-the-counter self-medication leading to intracranial hypertension in a young lady.

Intracranial hypertension (idiopathic-IIH and secondary) is a potentially treatable condition. Although various factors such as female gender and obesity, certain drugs have been implicated as risk factors for IIH, there remains a lack of clarity in the exact causal-effect relationship. In India, self-medication by obtaining drugs over the counter due to lack of adequate drug regulation and ignorance of the public is a very common practice with a potential for severe adverse effects. We present a case of a young lady who has developed intracranial hypertension possibly due to self-medication with steroids and cyproheptadine, obtained over the counter.

Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic.

BACKGROUND: Recently, symptoms similar to addictive drug withdrawal have been reported in a structured longitudinal study of patients with idiopathic Parkinson's Disease (PD) withdrawing from dopamine agonists (DA): the dopamine agonist withdrawal syndrome (DAWS). OBJECTIVES: The objective of this study was to establish the frequency, predictors, and outcomes of DAWS in a movement disorders clinic. METHODS: We conducted a retrospective chart review of a sample of patients with a clinical diagnosis of PD treated with DA in whom withdrawal or attempted withdrawal of DA was carried out because of adverse effects, or for any other reason. Out of 487 PD patient charts reviewed, 84 were withdrawn from the agonists and were evaluable. RESULTS: Thirteen patients (15.5%) met criteria for DAWS (DAWS+) and 71 did not (DAWS-). DAWS developed upon withdrawal from pergolide, pramipexole and ropinirole, and did not respond to levodopa. DAWS outcomes included recovery in less than 6 months in 61%, in more than a year in 23%, and an inability to discontinue DA in 15% of patients. Development of impulse control disorders was the reason for DA withdrawal in all DAWS+, but only in 41% of DAWS- patients (p<0.0001). DAWS+ and DAWS- patients did not differ in other variables. CONCLUSION: DAWS is a disabling complication of DA use. Critical features of the syndrome are the strong link with impulse control disorders, possibly the independence of DA dosage and type, and the resistance to treatment, including levodopa. Further studies are required to characterise those at risk as well as to define an effective treatment.

Psychogenic facial movement disorders: clinical features and associated conditions.

The facial phenotype of psychogenic movement disorders has not been fully characterized. Seven tertiary-referral movement disorders centers using a standardized data collection on a computerized database performed a retrospective chart review of psychogenic movement disorders involving the face. Patients with organic forms of facial dystonia or any medical or neurological disorder known to affect facial muscles were excluded. Sixty-one patients fulfilled the inclusion criteria for psychogenic facial movement disorders (91.8% females; age: 37.0 ± 11.3 years). Phasic or tonic muscular spasms resembling dystonia were documented in all patients most commonly involving the lips (60.7%), followed by eyelids (50.8%), perinasal region (16.4%), and forehead (9.8%). The most common pattern consisted of tonic, sustained, lateral, and/or downward protrusion of one side of the lower lip with ipsilateral jaw deviation (84.3%). Ipsi- or contralateral blepharospasm and excessive platysma contraction occurred in isolation or combined with fixed lip dystonia (60.7%). Spasms were reported as painful in 24.6% of cases. Symptom onset was abrupt in most cases (80.3%), with at least 1 precipitating psychological stress or trauma identified in 57.4%. Associated body regions involved included upper limbs (29.5%), neck (16.4%), lower limbs (16.4%), and trunk (4.9%). There were fluctuations in severity and spontaneous exacerbations and remissions (60%). Prevalent comorbidities included depression (38.0%) and tension headache (26.4%). Fixed jaw and/or lip deviation is a characteristic pattern of psychogenic facial movement disorders, occurring in isolation or in combination with other psychogenic movement disorders or other psychogenic features.

l-Dopa-induced dyskinesia-clinical presentation, genetics, and treatment.

Levodopa-induced dyskinesia (LID) has been recognized since the introduction of levodopa for the management of Parkinson's disease (PD) and continues to be one of the most clinically challenging factors in long-term management of patients with PD. Most patients develop LID within 10 years of PD onset and the cause has been attributed to various factors including disease demographics, pharmacological, and possibly genetic causes. The clinical pattern of LID varies and shows intra and inter-patient variability and has been classified based upon phenomenology and relation to timing of levodopa. The potential armamentarium to address and manage LID has significantly increased in the last decade. This chapter addresses the current understanding of various clinical aspects and available therapeutics for LID.

Do MRI features distinguish Wilson's disease from other early onset extrapyramidal disorders? An analysis of 100 cases.

Magnetic resonance imaging (MRI) is frequently used in the evaluation of various extrapyramidal disorders. Among the plethora of MRI features in Wilson's disease (WD), only "face of the giant panda" sign has been recognized to distinguish WD from other early onset extrapyramidal disorders (EOEPD). To ascertain the value of various MRI features in differentiating neuropsychiatric form of WD from other EOEPD. This retrospective analysis included 100 patients (M:F = 56:44) of EOEPD (5-40 years), who had undergone MRI during Jan'03 to Nov'08. Their clinical features were recorded and the following MR sequences were analyzed: T1WI, T2WI, FLAIR. Fifty-six patients had WD (M:F = 28:30, age at onset: 14 +/- 6.8 years) and 44 had other EOEPD (M:F = 27:17, age at onset: 19 +/- 9.8 years) that included Huntington's disease--4, young-onset Parkinson's disease--7, mitochondrial disorders--2, Hallervorden-Spatz disease--8, non-Wilsonian hepatolenticular degeneration--2, toxic/metabolic disorder--1, and others--20. The duration of illness at the time of MRI was comparable (WD: 3.1 +/- 4.9 years; Other EOEPD: 2.8 +/- 2.4 years). MR signal characteristics varied in topography and severity in both the groups. All the patients of WD had signal abnormalities in MRI, as against 16/44 of the other EOEPD group. The following MR observations were noted exclusively in WD: "Face of giant panda" sign (14.3%), tectal plate hyperintensity (75%), central pontine myelinolysis (CPM)-like abnormalities (62.5%), and concurrent signal changes in basal ganglia, thalamus, and brainstem (55.3%). Besides "Face of giant panda" sign, hyperintensities in tectal-plate and central pons (CPM-like), and simultaneous involvement of basal ganglia, thalamus, and brainstem are virtually pathognomonic of WD.

Spectrum of epilepsy in Wilson's disease with electroencephalographic, MR imaging and pathological correlates.

BACKGROUND: Seizures are uncommon in Wilson's disease. OBJECTIVE: To analyze profile of seizures in WD and to correlate with EEG and MR imaging observations. SUBJECTS AND METHODS: 41/490 patients (8.3%) of WD were documented to have seizures. Autopsy observations were available in 3 cases. RESULTS: The age at onset of seizures was 12.8+/-5.7years. Seizure - preceded the onset of characteristic features of WD (19.5%); occurred concurrently (46.3%); or, followed de-coppering therapy (29.2%) and occurred as terminal event (4.8%). The types of seizures were: generalized tonic-clonic - 29, simple partial - 8, complex partial - 6, partial seizures with secondary generalization - 2 and periodic myoclonus - 1. Six patients had multiple seizure types and 4 had status epilepticus. EEG abnormalities were frequent (19/24) consisting of background slowing and epileptiform discharges. MRI (n=20) revealed varying degree of atrophy and signal changes involving basal ganglia, brainstem and white matter. The duration of follow-up was 8.1+/-9.2years. The outcome of seizure was: no recurrence - 68.3%, breakthrough seizures - 17.1%, poor control - 9.7% and no follow-up - 4.9%. Two of them succumbed following cluster attacks. Autopsy revealed cavitatory lesions in white matter in frontal, temporal and parietal areas with varying involvement of cortical ribbon. Patients with seizures had more often white matter changes than those without. It was also noted that patients whose seizures were not controlled had MRI suggestive of cavitation of white matter, though the reverse was not true. CONCLUSIONS: This is the largest series regarding epilepsy in WD. Seizures are not uncommon and could occur at any stage. Deafferentation of white matter tracts from cortex may contribute for seizure in WD.

Wilson's disease: (31)P and (1)H MR spectroscopy and clinical correlation.

INTRODUCTION: Proton ((1)H) magnetic resonance spectroscopy (MRS) changes are noted in Wilson's disease (WD). However, there are no studies regarding membrane phospholipid abnormality using (31)P MRS in these patients. We aimed to analyze the striatal spectroscopic abnormalities using (31)P and (1)H MRS in WD. METHODS: Forty patients of WD (treated, 29; untreated,11) and 30 controls underwent routine MR image sequences and in vivo 2-D (31)P and (1)H MRS of basal ganglia using an image-selected technique on a 1.5-T MRI scanner. Statistical analysis was done using Student's t test. RESULTS: The mean durations of illness and treatment were 6.2 ± 7.4 and 4.8 ± 5.9 years, respectively. MRI images were abnormal in all the patients. (1)H MRS revealed statistically significant reduction of N-acetyl aspartate (NAA)/choline (Cho) and NAA/creatine ratios in striatum ((1)H MRS) of treated patients compared to controls. The mean values of phosphomonoesters (PME) (p < 0.0001), phosphodiesters (PDE) (p < 0.0001), and total phosphorus (TPh) (p < 0.0001) were elevated in patients compared to controls. Statistically significant elevated levels of ratio of PME/PDE (p = 0.05) observed in the striatum were noted in treated patients as compared to controls in the (31)P MRS study. The duration of illness correlated well with increased PME/PDE [p < 0.001], PME/TPh [p < 0.05], and PDE/TPh [p < 0.05] and decreased NAA/Cho [p < 0.05] ratios. There was correlation of MRI score and reduced NAA/Cho ratio with disease severity. The PME/PDE ratio (right) was elevated in the treated group [p < 0.001] compared to untreated group. CONCLUSIONS: There is reduced breakdown and/or increased synthesis of membrane phospholipids and increased neuronal damage in basal ganglia in patients with WD.

Wilson's disease: An Indian perspective.

Wilson's disease (WD) is an autosomal recessive disease involving a defect of copper transport by the hepatic lysosomes. It leads to excess copper deposition in the liver, the brain, the kidneys and the skeletal system, affecting most commonly children or young adults and running an invariably fatal course if not adequately treated by de-coppering therapy. The last century has witnessed several changes, notable among these are: Increased awareness, improved diagnostic facilities leading to earlier recognition even in the pre-symptomatic phase, clear distinction from its mimics, aggressive therapeutic approaches owing to availability of effective treatment and an overall reduction in the morbidity and mortality. It is widely acknowledged that the disease is not as rare as once believed. Sir SAK Wilson published his landmark article in 1912, but it was only in 1968 that the first patient of WD was reported from our country. Publications from India on WD have focused on phenotypic characterization, documentations of lesser recognized aspects of the disease e.g. seizures, behavior abnormality, speech and cognitive impairment, sub-clinical affection of visual pathway, heart and autonomic function and pre-symptomatic detection. Attempts have been made to understand the clinical heterogeneity of the disease through identification of biochemical and immunological markers, magnetic resonance imaging, neuropathological study and genetic analysis for novel and/or known mutations. Assessment of impairment and severity and effect of various therapeutic interventions namely zinc sulphate on the long-term outcome and quality of life have also been studied. Nevertheless, clinicians often face difficulties in long-term care of these patients. Diagnostic errors leading to delay in diagnosis and initiation of treatment are common, even in patients with positive family history. There is no consensus regarding therapeutic protocols since the use of penicillamine, once a 'gold standard' for treatment, has been debated by experts. Mortality and morbidity of this potentially treatable disease and nonavailability of medications to the poor patients remain a major area of concern.