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.
Abstract
Advanced Parkinson’s Disease (APD) is complicated by the emergence of motor and non-motor fluctuations, which are initially predictable and eventually become unpredictable, in part due to ...erratic gastric absorption and short half of oral levodopa. Attempts to manage such fluctuations with oral dopaminergic drugs often lead to disabling dyskinesias. Continuous Subcutaneous Apomorphine Infusion (CSAI), despite being approved for the treatment of APD since 1993, was approved in India only in 2019. We studied the safety, tolerability and efficacy of CSAI in Indian patients with APD in a registry design to raise local awareness of this important treatment. We conducted a prospective registry-based observational audit at 10 centers across different states of India. Patients with APD, not responding to or with significant side effects from oral dopaminergic therapy, were assessed at baseline and at month 6 and 12 following CSAI infusion. Fifty-one patients completed the study, CSAI significantly reduced the functional impact of dyskinesia (p < 0.01 at 6 months and p < 0.001 at 12 months). There was a significant improvement in the OFF-state from baseline (p < 0.01 at 6 months and p < 0.001 at 12 months) No discernible side effects were observed apart from mild site reaction (n = 7), nausea (n = 7) skin nodules (n = 2). CSAI demonstrated safety, efficacy, tolerability and improved quality of life in patients with APD, as shown in previous studies. Our study highlighted current existing inequalities in treatment availability, lack of awareness, knowledge gap, affordability and cost remains a concern regarding apomorphine use in Indian PD population.
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 (β = 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.
We have recently published the notion of the "vitals" of Parkinson's, a conglomeration of signs and symptoms, largely nonmotor, that must not be missed and yet often not considered in neurological ...consultations, with considerable societal and personal detrimental consequences. This "dashboard," termed the Chaudhuri's vitals of Parkinson's, are summarized as 5 key vital symptoms or signs and comprise of (a) motor, (b) nonmotor, (c) visual, gut, and oral health, (d) bone health and falls, and finally (e) comorbidities, comedication, and dopamine agonist side effects, such as impulse control disorders. Additionally, not addressing the vitals also may reflect inadequate management strategies, leading to worsening quality of life and diminished wellness, a new concept for people with Parkinson's. In this paper, we discuss possible, simple to use, and clinically relevant tests that can be used to monitor the status of these vitals, so that these can be incorporated into clinical practice. We also use the term Parkinson's syndrome to describe Parkinson's disease, as the term "disease" is now abandoned in many countries, such as the U.K., reflecting the heterogeneity of Parkinson's, which is now considered by many as a syndrome.
Background
Progressive supranuclear palsy (PSP) is a progressive neurodegenerative condition presenting with different clinical endophenotypes. The parkinsonian variant of PSP (PSP‐P) is ...characterised by early but fading responsiveness to high‐dose levodopa therapy; however, high‐dose oral therapy is often associated with intolerance due to dopaminergic side effects and so doses may have to be capped despite clinical benefits. Evidence from animal models and real‐life registries suggest far higher doses of levodopa can be tolerated if given in a continuous drug delivery (CDD) manner. We investigated tolerance and possible clinical benefits in patients with PSP‐P still responsive to levodopa after initiating CDD in the form of intrajejunal levodopa infusion (IJLI) therapy as part of a compassionate usage program (CU).
Methods
This is an observational clinical data report from the IJLI implementation program undertaken in regional tertiary referral Parkinson's centres in India and at King's College Hospital London, Dubai as part of a CU. Four patients with PSP‐P receiving IJLI as a part of a CU underwent evaluations of liver and renal function, motor and nonmotor function, quality of life, sleep dysfunction, fatigue, anxiety and depression, and cognitive impairment at baseline and 6 and 12 months post‐IJLI initiation.
Results
In total, three out of four patients successfully completed 12 months of treatment (6 months in one patient). All four patients showed good tolerability to IJLI even at higher doses (1400 and 1960 mg at 6 and 12 months, respectively) when compared to oral levodopa (812.5 ± 103 levodopa equivalent daily dose LEDD) and presented with overall persistent improvements in motor and nonmotor scores and quality‐of‐life scores at 6 and 12 months post‐IJLI. All patients showed improvement in estimated glomerular filtration rate (43.50 ml/min/1.73 m2 to 67.5 ml/min/1.73 m2 and 79.5 ml/min/1.73 m2 at 6 and 12 months, respectively).
Conclusions
IJLI led to persistent beneficial effects on motor and some nonmotor aspects in patients with PSP‐P at up to 12 months after treatment with associated improvement in overall renal function.
Intrajeujunal levodopa infusion for patients with Progressive supranuclear palsy‐Parkinson's variant
Device-aided therapies, including levodopa-carbidopa intestinal gel infusion, apomorphine subcutaneous infusion, and deep brain stimulation, are available in many countries for the management of the ...advanced stage of Parkinson’s disease (PD). Currently, selection of device-aided therapies is mainly focused on patients’ motor profile while non-motor symptoms play a role limited to being regarded as possible exclusion criteria in the decision-making process for the delivery and sustenance of a successful treatment. Differential beneficial effects on specific non-motor symptoms of the currently available device-aided therapies for PD are emerging and these could hold relevant clinical implications. In this viewpoint, we suggest that specific non-motor symptoms could be used as an additional anchor to motor symptoms and not merely as exclusion criteria to deliver bespoke and patient-specific personalised therapy for advanced PD.
Parkinson's disease (PD) is a chronic, progressive neurological disorder and the second most common neurodegenerative condition. We report three common but overlooked symptoms in PD-hiccups, ...hypersalivation, and hallucinations-in terms of their prevalence, pathophysiology, and up-to-date evidence-based treatment strategies. Whilst all these three symptoms do occur in many other neurological and non-neurological conditions, early recognition and treatment are paramount. Whilst hiccups affect 3% of healthy people, their rate of occurrence is higher (20%) in patients with PD. Hypersalivation (Sialorrhea) is another common neurological manifestation of many neurological and other neurodegenerative conditions such as motor neuron disease (MND), with a median prevalence rate of 56% (range: 32-74%). A 42% prevalence of sialorrhea is also reported in sub-optimally treated patients with PD. Hallucinations, especially visual hallucinations, are commonly reported, with a prevalence of 32-63% in PD, and a 55-78% prevalence is noted in patients with dementia with Lewy bodies (DLB), followed by tactile hallucinations, which are indicated by a sensation of crawling bugs or imaginary creatures across the skin surface. Whilst mainstay and primary management strategies for all these three symptoms are carried out through history taking, it is also essential to identify and treat possible potential triggers such as infection, minimise or avoid causative (such as drug-induced) factors, and especially carry out patient education before considering more definitive treatment strategies, such as botulinum toxin therapies for hypersalivation, to improve the quality of life of patients. This original review paper aims to provide a comprehensive overview of the disease mechanisms, pathophysiology, and management of hiccups, hypersalivation, and hallucinations in Parkinson's disease.
Parkinson’s disease (PD) is a chronic, progressive neurological disorder and the second most common neurodegenerative condition. Advanced PD is complicated by erratic gastric absorption, delayed ...gastric emptying in turn causing medication overload, and hence the emergence of motor and non-motor fluctuations and dyskinesia, which is initially predictable and then becomes unpredictable. As the patient progresses to the advanced stage, advanced Parkinson’s disease (APD) is characterized by refractory motor and non motor fluctuations, unpredictable OFF periods, and troublesome dyskinesias. The management of APD is a complex affair. There is growing recognition that GI dysfunction is common in PD, with virtually the entire GI system (the upper and lower GI tracts) causing problems from dribbling to defecation. The management of PD should focus on personalized care addressing both motor and non-motor symptoms, ideally including not only dopamine replacement but also associated non-dopaminergic circuits, particularly focusing on noradrenergic, serotonergic, and cholinergic therapies bypassing the gastrointestinal tract (GIT) by infusion or device-aided therapies (DAT), including levodopa–carbidopa intestinal gel infusion, apomorphine subcutaneous infusion, and deep brain stimulation, which are available in many countries for the management of the advanced stage of Parkinson’s disease (APD). The PKG (KinetiGrap) can be used as a continuous objective monitoring (COM) aid, as a screening tool to help to identify advanced PD (APD) patients suitable for DAT, and can thus improve clinical outcomes.
Although subcutaneously administered apomorphine is widely used as an effective adjunct therapy for Parkinson’s disease (PD), it was approved for use in India only in 2019. This review summarizes the ...history, pharmacology, clinical spectrum, indications, efficacy, and side effects of subcutaneous apomorphine use in patients with PD along with clinical recommendations for its use in Indian context. Intermittent subcutaneous apomorphine injection or continuous subcutaneous apomorphine infusion is effective adjunctive treatments for patients with advanced PD with levodopa-related refractory motor complications and some specific nonmotor symptoms (NMS) as growing evidence shows apomorphine also improves aspects of NMS of PD. Common side effects of subcutaneous apomorphine are skin nodules, nausea, and somnolence with incidence being higher with infusion than that with injection. Impulse control disorders and neuropsychiatric complications common to most dopamine agonists can also occur. As per National Institute for Health and Care Excellence (NICE), United Kingdom, apomorphine, as intermittent injection or continuous subcutaneous infusion, is one of the best medical therapies and may be considered before using deep brain stimulation (DBS) or levodopa/carbidopa intestinal gel (LCIG). Head-to-head open-label comparative multicenter data suggest that apomorphine is at least as effective as DBS or LCIG in relation to nonmotor and motor benefit. More studies are needed to reduce the paucity of apomorphine data in Indian population. We also discuss criteria to select one device therapy over another and newer apomorphine delivery strategies in the pipeline.
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