parkinson

Parkinson’s disease

Parkinson’s disease

James Parkinson was the first to describe Parkinson’s disease (PD) in 1817; he described it as a combination of tremor, rigidity, postural abnormalities, and bradykinesia.

Definition

Parkinson’s disease is a progressive neurological disorder characterized by the preferential loss of dopaminergic neurons in the substantia nigra, which project to the striatum.

Parkinson’s disease (PD) is a neurodegenerative disease involving the basal ganglia, resulting in motor and extra-motor deficits. These extra-motor deficits may be reflective of a self-regulatory deficit impacting patients’ ability to regulate cognitive processes, thoughts, behaviors, and emotions.

With advances in knowledge disease, boundaries may change. Occasionally, these changes are of such a magnitude that they require redefinition of the disease. In recognition of the profound changes in our understanding of Parkinson’s disease (PD), the International Parkinson and Movement Disorders Society (MDS) commissioned a task force to consider a redefinition of PD.

Several critical issues were identified that challenge current PD definitions. First, new findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. Second, the increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. Third, there is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. Fourth, the recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early-stage and prodromal PD should be created; here, essential features of these criteria are proposed. Finally, there is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration 1).

see Parkinson’s Disease Dementia

Classification

Idiopathic Parkinson’s disease

Current subtype classifications may not be sufficiently robust to warrant formal delineation.

see also Tremor predominant Parkinson’s disease.

Sporadic Parkinson’s disease and some genetic forms such as GBA1-associated parkinsonism, LRRK2-associated Parkinson’s disease

Natural History

The natural history of PD may follow a more benign motor-predominant course in some patients, while in others the disabling non-motor features predominate. The underlying basis of the clinical heterogeneity is poorly understood, but it is becoming clear that this is, at least in part, due to genetic factors 2) 3) 4). One of these genetic risk factors is mutation in the GBA1 gene, which has emerged numerically as the most important genetic abnormality associated with PD 5) 6), being found in about 5% of patients with the so-called sporadic PD

Scales

UPDRS

Epidemiology

Parkinson’s Disease Epidemiology.

Etiology

see Parkinson’s disease etiology.

Pathogenesis

Parkinson’s disease Pathogenesis.

Pathophysiology

see Parkinson’s disease pathophysiology.

Pathology

The main neuropathological finding is Alpha-synuclein-containing Lewy bodies and loss of dopaminergic neurons in the substantia nigra, manifesting as reduced facilitation of voluntary movements. With progression of PD, Lewy body pathology spreads to neocortical and cortical regions. Several environmental factors are associated with increased risk of PD. Autopsy studies show that the clinical diagnosis of PD is not confirmed at autopsy in a significant proportion of patients. Revised diagnostic criteria are expected to improve the clinician´s accuracy in diagnosing PD. Increasing knowledge on genetic and environmental risk factors of PD will probably elucidate the cause of this disease within the near future 7)

Clinical Features

see Parkinson’s disease clinical features.

Diagnosis

Parkinson’s disease diagnosis.

Treatment

see Parkinson’s disease treatment.

Outcome

Parkinson’s disease outcome

Parkinson’s disease complications.

Research

Open science and collaboration are necessary to facilitate the advancement of Parkinson’s disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities, thus we coordinated a virtual 3-day hackathon event, during which 49 early-career scientists from 12 countries built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. Each team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. Hackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early-career researchers. The resources generated can be used to accelerate research on the genetics of PD 8).

Meta-analysis

A meta-analysis investigated the effectiveness of short pulse width DBS (spDBS) versus conventional DBS (cDBS) in patients with Parkinson’s disease.

Four databases (PubMed, Cochrane, Web of Science, and Embase) were independently searched until October 2021 by two reviewers. They utilized the following scales and items: therapeutic windows (TW), efficacy threshold, side effect threshold, Movement Disorder Society-Sponsored Revision Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III off-medication score, Speech Intelligence Test (SIT), and Freezing of Gait Questionnaire (FOG-Q).

The analysis included seven studies with a total of 87 patients. The results indicated that spDBS significantly widened the therapeutic windows (0.99, 95% CI = 0.61 to 1.38) while increasing the threshold amplitudes of side effects (2.25, 95% CI = 1.69 to 2.81) and threshold amplitudes of effects (1.60, 95% CI = 0.84 to 2.36). There was no statistically significant difference in UPDRS part III, SIT, and FOG-Q scores between spDBS and cDBS groups, suggesting that treatment with both cDBS and spDBS may result in similar effects of improved dysarthria and gait disorders.

Compared with cDBS, spDBS is effective in expanding therapeutic windows (TW). Both types of deep brain stimulation resulted in improved gait disorders and speech intelligibility 9)

Case series

see Parkinson’s disease case series.

Case reports

Parkinson´s disease case reports.

1)

Berg D, Postuma RB, Bloem B, Chan P, Dubois B, Gasser T, Goetz CG, Halliday GM, Hardy J, Lang AE, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov Disord. 2014 Apr;29(4):454-62. doi: 10.1002/mds.25844. Epub 2014 Mar 11. PubMed PMID: 24619848.
2)

Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386(9996):896–912.
3)

Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet. 2014;46(9):989–93.
4)

Williams-Gray CH, Goris A, Saiki M, Foltynie T, Compston DA, Sawcer SJ, et al. Apolipoprotein E genotype as a risk factor for susceptibility to and dementia in Parkinson’s disease. J Neurol. 2009;256(3):493–8.
5)

Gan-Or Z, Giladi N, Rozovski U, Shifrin C, Rosner S, Gurevich T, et al. Genotype-phenotype correlations between GBA mutations and Parkinson’s disease risk and onset. Neurology. 2008;70(24):2277–83.
6)

Migdalska-Richards A, Schapira AH. The relationship between glucocerebrosidase mutations and Parkinson’s disease. J Neurochem. 2016 Oct;1(139 Suppl):77–90.
7)

Tysnes OB, Storstein A. Epidemiology of Parkinson’s disease. J Neural Transm (Vienna). 2017 Aug;124(8):901-905. doi: 10.1007/s00702-017-1686-y. Epub 2017 Feb 1. PMID: 28150045.
8)

Leonard HL, Murtadha R, Martinez-Carrasco A, Jama A, Müller-Nedebock AC, Gil-Martinez AL, Illarionova A, Moore A, Bustos BI, Jadhav B, Huxford B, Storm C, Towns C, Vitale D, Chetty D, Yu E, Grenn FP, Salazar G, Rateau G, Iwaki H, Elsayed I, Foote IF, Jansen van Rensburg Z, Kim JJ, Yuan J, Lake J, Brolin K, Senkevich K, Wu L, Tan MMX, Periñán MT, Makarious MB, Ta M, Pillay NS, Betancor OL, Reyes-Pérez PR, Alvarez Jerez P, Saini P, Al-Ouran R, Sivakumar R, Real R, Reynolds RH, Hu R, Abrahams S, Rao SC, Antar T, Leal TP, Iankova V, Scotton WJ, Song Y, Singleton A, Nalls MA, Dey S, Bandres-Ciga S, Blauwendraat C, Noyce AJ; International Parkinson Disease Genomics Consortium (IPDGC) and The Global Parkinson’s Genetics Program (GP2). The IPDGC/GP2 Hackathon – an open science event for training in data science, genomics, and collaboration using Parkinson’s disease data. NPJ Parkinsons Dis. 2023 Mar 4;9(1):33. doi: 10.1038/s41531-023-00472-6. PMID: 36871034.
9)

Zou X, Shi Y, Wu X, Ye Q, Lin F, Cai G. Efficacy of short pulse and conventional deep brain stimulation in Parkinson’s disease: a systematic review and meta-analysis. Neurol Sci. 2022 Nov 16. doi: 10.1007/s10072-022-06484-z. Epub ahead of print. PMID: 36383263.

Parkinson’s Disease Treatment Guidelines

Parkinson’s Disease Treatment Guidelines

An update of the Parkinson’s Disease treatment Guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist should know the therapies and their place in the treatment pathway.

Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging-guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (Intrajejunal levodopa-carbidopa therapy) [LCIG]) was also included. Changes in motor features, health-related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high-class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, a clinical consensus of the guideline task force was gathered.

Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson’s disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as a change compared with current medical treatment. Subthalamic deep brain stimulation for Parkinson’s disease is the best-studied intervention for advanced disease with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi-DBS can also be offered. For early PD with early fluctuations, STN-DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. The clinical consensus was reached on the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment-resistant fluctuations, and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication-resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended.

Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis 1) 2).

European Academy of Neurology/Movement Disorder Society-European Section Guidelines on Pallidotomy for Parkinson’s Disease 3).

1)

Deuschl G, Antonini A, Costa J, Śmiłowska K, Berg D, Corvol JC, Fabbrini G, Ferreira J, Foltynie T, Mir P, Schrag A, Seppi K, Taba P, Ruzicka E, Selikhova M, Henschke N, Villanueva G, Moro E. European Academy of Neurology/Movement Disorder Society-European Section Guideline on the Treatment of Parkinson’s Disease: I. Invasive Therapies. Mov Disord. 2022 Jul;37(7):1360-1374. doi: 10.1002/mds.29066. Epub 2022 Jul 6. PMID: 35791767.
2)

Deuschl G, Antonini A, Costa J, Śmiłowska K, Berg D, Corvol JC, Fabbrini G, Ferreira J, Foltynie T, Mir P, Schrag A, Seppi K, Taba P, Ruzicka E, Selikhova M, Henschke N, Villanueva G, Moro E. European Academy of Neurology/Movement Disorder Society – European Section guideline on the treatment of Parkinson’s disease: I. Invasive therapies. Eur J Neurol. 2022 Sep;29(9):2580-2595. doi: 10.1111/ene.15386. Epub 2022 Jul 6. PMID: 35791766.
3)

Hariz M, Bronstein JM, Cosgrove GR, de Bie RMA, DeLong MR, Gross RE, Krack P, Krauss JK, Lang AE, Lees AJ, Lozano AM, Obeso JA, Schuurman PR, Vitek JL. European Academy of Neurology/Movement Disorder Society-European Section Guidelines on Pallidotomy for Parkinson’s Disease: Let’s Be Accurate. Mov Disord. 2022 Sep 1. doi: 10.1002/mds.29210. Epub ahead of print. PMID: 36047463.

Deep brain stimulation for Parkinson’s disease

Deep brain stimulation for Parkinson’s disease

Subthalamic deep brain stimulation for Parkinson’s disease.

Cramer et al. from the University of Minnesota, sought to determine whether racial and socioeconomic disparity in the utilization of deep brain stimulation (DBS) for Parkinson’s disease (PD) have improved over time. They examined DBS utilization and analyzed factors associated with placement of DBS. The odds of DBS placement increased across the study period while White PD patients were 5 times more likely than Black patients to undergo DBS. Individuals, regardless of racial background, with two or more comorbidities were 14 times less likely to undergo DBS. Privately insured patients were 1.6 times more likely to undergo DBS. Despite increasing DBS utilization, significant disparities persist in access to DBS 1).

Methods

Modified power-on programming method.

Traditional power-on programming method.

Indications

Deep brain stimulation for Parkinson’s disease Indications.

Outcome

Deep brain stimulation for Parkinson’s disease outcome.

Case series

Deep brain stimulation for Parkinson’s disease case series.

1)

Cramer SW, Do TH, Palzer EF, Naik A, Rice AL, Novy SG, Hanson JT, Piazza AN, Howard MA, Huling JD, Chen CC, McGovern RA. Persistent racial disparities in deep brain stimulation for Parkinson’s disease. Ann Neurol. 2022 Apr 19. doi: 10.1002/ana.26378. Epub ahead of print. PMID: 35439848.

Parkinson’s disease treatment

Parkinson’s disease treatment

The mainstay of Parkinson’s disease treatment is medical.

Antiparkinson drug

see Antiparkinson drugs.

Bladder dysfunction in Parkinson’s disease treatment

Bladder dysfunction in Parkinson’s disease treatment

Repetitive transcranial magnetic stimulation for Parkinson’s disease

see Repetitive transcranial magnetic stimulation for Parkinson’s disease.

Parkinson’s disease surgery

see Parkinson’s disease surgery.

Repetitive transcranial magnetic stimulation for Parkinson’s disease

Repetitive transcranial magnetic stimulation for Parkinson’s disease

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has been closely examined as possible Parkinson’s disease treatment.

Data were acquired during resting state on 34 Parkinson’s disease patients and 25 controls. The ratio of standard uptake value for PET images and the subthalamic nucleus (STN) Dynamic functional connectivity (FC) maps for fMRI data were generated. The metabolic connectivity mapping (MCM) approach that combines PET and fMRI data was used to evaluate the direction of the connectivity. Results showed that PD patients exhibited both increased FDG uptake and STN-FC in the sensorimotor area (PFDR < 0.05). MCM analysis showed higher cortical-STN MCM value in the PD group (F = 6.63, P = 0.013) in the left precentral gyrus. There was a high spatial overlap between the increased glucose metabolism and increased STN-FC in the sensorimotor area in PD. The MCM approach further revealed an exaggerated cortical input to the STN in PD, supporting the precentral gyrus as a target for treatment such as the repetitive transcranial magnetic stimulation 1).

40 Parkinson’s disease patients with freezing of gait, 31 without freezing of gait, and 30 normal controls. A subset of 30 patients with freezing of gait (verum group: N = 20; sham group: N = 10) who participated the aforementioned rTMS study underwent another scan after the treatments. Using the baseline scans, the imaging biomarkers for freezing of gait and Parkinson’s disease were developed by contrasting the connectivity profiles of patients with freezing of gait to those without freezing of gait and normal controls, respectively. These two biomarkers were then interrogated to assess the rTMS effects on connectivity patterns. Results showed that the freezing of gait biomarker was negatively correlated with Freezing of Gait Questionnaire score (r = -0.6723, p < 0.0001); while the Parkinson’s disease biomarker was negatively correlated with MDS-UPDRS motor score (r = -0.7281, p < 0.0001). After the rTMS treatment, both the freezing of gait biomarker (0.326 ± 0.125 vs. 0.486 ± 0.193, p = 0.0071) and Parkinson’s disease biomarker (0.313 ± 0.126 vs. 0.379 ± 0.155, p = 0.0378) were significantly improved in the verum group; whereas no significant biomarker changes were found in the sham group. The findings indicate that high-frequency rTMS over the supplementary motor area confers the beneficial effect jointly through normalizing abnormal brain functional connectivity patterns specifically associated with freezing of gait, in addition to normalizing overall disrupted connectivity patterns seen in Parkinson’s disease 2).

In 2017 a study aimed to review the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for Parkinson’s disease (PD). Randomized, double-blind, sham-controlled, multicenter studies on rTMS for PD have been conducted three times in Japan (in 2003, 2008, and 2013). These studies revealed that 5-Hz rTMS over the supplementary motor area (SMA) is the most effective modality for improving motor symptoms. Several functional imaging studies showed reduced SMA excitability in patients with PD, probably secondary to basal ganglia dysfunction. Therefore, 5-Hz rTMS is assumed to normalize SMA excitability and amend basal ganglia function secondarily. Currently, a phase III trial is being conducted in Japan. Therefore, in the near future, 5-Hz rTMS can be used as a therapeutic modality for PD treatment. In addition, several powerful rTMS have been developed recently, including quadripulse stimulation (QPS), which most potently induces neural plasticity. QPS is also expected to be a potential therapeutic tool to treat patients with PD 3).

In 2015 Twenty studies with a total of 470 patients were included. Random-effects analysis revealed a pooled SMD of 0.46 (95% CI, 0.29-0.64), indicating an overall medium effect size favoring active rTMS over sham rTMS in the reduction of motor symptoms (P<.001). Subgroup analysis showed that the effect sizes estimated from high-frequency rTMS targeting the primary motor cortex (SMD, 0.77; 95% CI, 0.46-1.08; P<.001) and low-frequency rTMS applied over other frontal regions (SMD, 0.50; 95% CI, 0.13-0.87; P=.008) were significant. The effect sizes obtained from the other 2 combinations of rTMS frequency and rTMS site (ie, high-frequency rTMS at other frontal regions: SMD, 0.23; 95% CI, -0.02 to 0.48, and low primary motor cortex: SMD, 0.28; 95% CI, -0.23 to 0.78) were not significant. Meta-regression revealed that a greater number of pulses per session or across sessions is associated with larger rTMS effects. Using the Grading of Recommendations, Assessment, Development, and Evaluation criteria, we characterized the quality of evidence presented in this meta-analysis as moderate quality.

The pooled evidence suggests that rTMS improves motor symptoms for patients with PD. Combinations of rTMS site and frequency as well as the number of rTMS pulses are key modulators of rTMS effects. The findings of our meta-analysis may guide treatment decisions and inform future research 4).

Randomized, double-blind, sham-controlled, multicenter studies on rTMS for PD have been conducted three times in Japan (in 2003, 2008, and 2013). These studies revealed that 5-Hz rTMS over the supplementary motor area (SMA) is the most effective modality for improving motor symptoms. Several functional imaging studies showed reduced SMA excitability in patients with PD, probably secondary to basal ganglia dysfunction. Therefore, 5-Hz rTMS is assumed to normalize SMA excitability and amend basal ganglia function secondarily. Currently, a phase III trial is being conducted in Japan. Therefore, in the near future, 5-Hz rTMS can be used as a therapeutic modality for PD treatment. In addition, several powerful rTMS have been developed recently, including quadripulse stimulation (QPS), which most potently induces Neuroplasticity. QPS is also expected to be a potential therapeutic tool to treat patients with PD 5).

52 Parkinson’s disease (PD) patients were randomly classified into two groups. The first group received 20 Hz and the 2nd group received 1 Hz Repetitive Transcranial Magnetic Stimulation (rTMS) with a total of 2000 pulses over M1of each hemisphere for ten days. Effects were assessed with the Unified Parkinson’s Disease Rating Scale part III (UPDRS), Instrumental Activity of Daily Living (IADL), and a self-assessment score (SA) before, after the last session, and one month later. Cortical excitability was measured before and after the end of sessions.

There was a significant improvement on all rating scales after either 1 Hz or 20 Hz rTMS, but the effect persisted for longer after 20 Hz (treatment X time interaction for UPDRS and IADL (P = 0.075 and 0.04, respectively). Neither treatment affected motor thresholds, but 20 Hz rTMS increased MEP amplitude and the duration of transcallosal inhibition. In an exploratory analysis, each group was subdivided into akinetic-rigid and tremor dominant subgroups and the effects of 1 Hz and 20 Hz treatment recalculated. There was weak evidence that patients with an akinetic-rigid presentation may respond better than those with predominant tremor.

Both 20 Hz and 1 Hz rTMS improve motor function in PD, but 20 Hz rTMS is more effective 6).

1)

Zang Z, Song T, Li J, Nie B, Mei S, Zhang C, Wu T, Zhang Y, Lu J. Simultaneous PET/fMRI revealed increased motor area input to subthalamic nucleus in Parkinson’s disease. Cereb Cortex. 2022 Feb 23:bhac059. doi: 10.1093/cercor/bhac059. Epub ahead of print. PMID: 35196709.
2)

Mi TM, Garg S, Ba F, Liu AP, Liang PP, Gao LL, Jia Q, Xu EH, Li KC, Chan P, McKeown MJ. Repetitive transcranial magnetic stimulation improves Parkinson’s freezing of gait via normalizing brain connectivity. NPJ Parkinsons Dis. 2020 Jul 17;6:16. doi: 10.1038/s41531-020-0118-0. PMID: 32699818; PMCID: PMC7368045.
3)

Matsumoto H, Ugawa Y. [Repetitive Transcranial Magnetic Stimulation for Parkinson’s Disease: A Review]. Brain Nerve. 2017 Mar;69(3):219-225. Japanese. doi: 10.11477/mf.1416200730. PMID: 28270631.
4)

Chou YH, Hickey PT, Sundman M, Song AW, Chen NK. Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease: a systematic review and meta-analysis. JAMA Neurol. 2015 Apr;72(4):432-40. doi: 10.1001/jamaneurol.2014.4380. Review. PubMed PMID: 25686212; PubMed Central PMCID: PMC4425190.
5)

Matsumoto H, Ugawa Y. [Repetitive Transcranial Magnetic Stimulation for Parkinson’s Disease: A Review]. Brain Nerve. 2017 Mar;69(3):219-225. doi: 10.11477/mf.1416200730. Review. Japanese. PubMed PMID: 28270631.
6)

Khedr EM, Al-Fawal B, Wraith AA, Saber M, Hasan AM, Bassiony A, Eldein AN, Rothwell JC. The Effect of 20 Hz versus 1 Hz Repetitive Transcranial Magnetic Stimulation on Motor Dysfunction in Parkinson’s Disease: Which Is More Beneficial? J Parkinsons Dis. 2019 Mar 21. doi: 10.3233/JPD-181540. [Epub ahead of print] PubMed PMID: 30909248.

Subthalamic deep brain stimulation for Parkinson’s disease outcome

The bilateral effects of deep brain stimulation (DBS) on motor and non-motor symptoms of Parkinson’s disease (PD) have been extensively studied and reviewed. However, the unilateral effects-in particular, the potential lateralized effects of left- versus right-sided DBS-have not been adequately recognized or studied.

Lin et al. summarized the current evidence and controversies in the literature regarding the lateralized effects of DBS on motor and non-motor outcomes in PD patients. Publications in the English language before February 2021 were obtained from the PubMed database and included if they directly compared the effects of unilateral versus contralateral side DBS on the motor or non-motor outcomes in PD. The current literature is overall of low-quality and is biased by various confounders. Researchers have investigated mainly PD patients receiving subthalamic nucleus (STN) DBS while the potential lateralized effects of globus pallidus internus (GPi) DBS have not been adequately studied. Evidence suggests potential lateralized effects of STN DBS on axial motor symptoms and deleterious effects of left-sided DBS on language-related functions, in particular, the verbal fluency, in PD. The lateralized DBS effects on appendicular motor symptoms as well as other neurocognitive and neuropsychiatric domains remain inconclusive. Future studies should control for varying methodological approaches as well as clinical and DBS management heterogeneities, including symptom laterality, stimulation parameters, location of active contacts, and lead trajectories. This would contribute to improved treatment strategies such as personalized target selection, surgical planning, and postoperative management that ultimately benefit patients 1).

The surgical and clinical outcomes of asleep DBS for Parkinson’s disease are comparable to those of awake DBS 2).

Suboptimal targeting within the STN can give rise to intolerable sensorimotor side effects, such as dysarthria, contractions and paresthesias 3) 4) 5). eye movement perturbations, and psychiatric symptoms 6) 7) 8), limiting the management of motor symptoms. The small size of the STN motor territory and the consequences of spreading current to immediately adjacent structures obligate precise targeting. Neurosurgeons therefore rely on a combination of imaging, electrophysiology, kinesthetic responses, and stimulation testing to accurately place the DBS lead into the sensorimotor domain of STN 9) 10) 11).

Deep Brain Stimulation has been associated with post-operative neuropsychology changes, especially in verbal memory.

Deep brain stimulation (DBS) of subthalamic nucleus (STN) is widely accepted to treat advanced Parkinson disease (PD). However, published studies were mainly conducted in Western centers 12).

High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) improves the cardinal motor signs of Parkinson’s disease (PD) and attenuates STN alpha/beta band neural synchrony in a voltage-dependent manner. While there is a growing interest in the behavioral effects of lower frequency (60 Hz) DBS, little is known about its effect on STN neural synchrony.

Low-frequency stimulation of the subthalamic nucleus via the optimal contacts is effective in improving overall motor function of patients with Parkinson Disease 13). In Parkinson’s disease significantly improved important aspects of QoL as measured by PDQ-39. The improvements were maintained at 2 years follow-up except for social support and communication. Sobstyl et al., demonstrated a positive correlation between changes in the off condition of motor UPDRS scores and Unified Dyskinesia Rating Scale in several PDQ-39 dimensions, whereas fluctuation UPDRS scores were negatively correlated with PDQ-39 mobility scores 14).

The degree of clinical improvement achieved by deep brain stimulation (DBS) is largely dependent on the accuracy of lead placement.

A study reports on the evaluation of intraoperative MRI (iMRI) for adjusting deviated electrodes to the accurate anatomical position during DBS surgery and acute intracranial changes 15).

Although dementia is a contraindication in deep brain stimulation for Parkinson’s disease, the concept is supported by little scientific evidence. Moreover, it is unclear whether PD with mild cognitive impairment (PD-MCI) or domain-specific cognitive impairments affect the outcome of DBS in non-demented PD patients.

Baseline cognitive levels of patients with PD who underwent DBS were classified into PD with dementia (PDD) (n = 15), PD-MCI (n = 210), and normal cognition (PD-NC) (n = 79). The impact of the cognitive level on key DBS outcome measures [mortality, nursing home admission, progression to Hoehn&Yahr (HY) stage 5 and progression to PDD] were analyzed using Cox regression models. Park et al. also investigated whether impairment of a specific cognitive domain could predict these outcomes in non-demented patients.

Results: Patients with PDD showed a substantially higher risk of nursing home admission and progression to HY stage 5 compared with patients with PD-MCI [hazard ratio (HR) 4.20, P = .002; HR = 5.29, P < .001] and PD-NC (HR 7.50, P < .001; HR = 7.93, P < .001). MCI did not alter the prognosis in patients without dementia, but those with visuospatial impairment showed poorer outcomes for nursing home admission (P = .015), progression to HY stage 5 (P = .027) and PDD (P = .006).

Conclusions: Cognitive profiles may stratify the pre-operative risk and predict long-term outcomes of DBS in PD 16).

References

1)

Lin Z, Zhang C, Li D, Sun B. Lateralized effects of deep brain stimulation in Parkinson’s disease: evidence and controversies. NPJ Parkinsons Dis. 2021 Jul 22;7(1):64. doi: 10.1038/s41531-021-00209-3. PMID: 34294724.
2)

Wang J, Ponce FA, Tao J, Yu HM, Liu JY, Wang YJ, Luan GM, Ou SW. Comparison of Awake and Asleep Deep Brain Stimulation for Parkinson’s Disease: A Detailed Analysis Through Literature Review. Neuromodulation. 2019 Dec 12. doi: 10.1111/ner.13061. [Epub ahead of print] Review. PubMed PMID: 31830772.
3) , 10)

Benabid AL, Chabardes S, Mitrofanis J, Pollak P: Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol 8:67–81, 2009
4) , 11)

Groiss SJ, Wojtecki L, Südmeyer M, Schnitzler A: Deep brain stimulation in Parkinson’s disease. Ther Adv Neurol Disorder 2:20–28, 2009
5)

Zhang S, Zhou P, Jiang S, Wang W, Li P: Interleaving subthalamic nucleus deep brain stimulation to avoid side effects while achieving satisfactory motor benefits in Parkinson disease: a report of 12 cases. Medicine (Baltimore) 95:e5575, 2016
6)

Kulisevsky J, Berthier ML, Gironell A, Pascual-Sedano B, Molet J, Parés P: Mania following deep brain stimulation for Parkinson’s disease. Neurology 59:1421–1424, 2002
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Mallet L, Schüpbach M, N’Diaye K, Remy P, Bardinet E, Czernecki V, et al: Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior. Proc Natl Acad Sci U S A 104:10661–10666, 2007
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Raucher-Chéné D, Charrel CL, de Maindreville AD, Limosin F: Manic episode with psychotic symptoms in a patient with Parkinson’s disease treated by subthalamic nucleus stimulation: improvement on switching the target. J Neurol Sci 273:116–117, 2008
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Abosch A, Timmermann L, Bartley S, Rietkerk HG, Whiting D, Connolly PJ, et al: An international survey of deep brain stimulation procedural steps. Stereotact Funct Neurosurg 91:1–11, 2013
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Chiou SM, Lin YC, Huang HM. One-year Outcome of Bilateral Subthalamic Stimulation in Parkinson Disease: An Eastern Experience. World Neurosurg. 2015 Jun 10. pii: S1878-8750(15)00709-3. doi: 0.1016/j.wneu.2015.06.002. [Epub ahead of print] PubMed PMID: 26072454.
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Khoo HM, Kishima H, Hosomi K, Maruo T, Tani N, Oshino S, Shimokawa T, Yokoe M, Mochizuki H, Saitoh Y, Yoshimine T. Low-frequency subthalamic nucleus stimulation in Parkinson’s disease: A randomized clinical trial. Mov Disord. 2014 Jan 21. doi: 10.1002/mds.25810. [Epub ahead of print] PubMed PMID: 24449169.
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Sobstyl M, Ząbek M, Górecki W, Mossakowski Z. Quality of life in advanced Parkinson’s disease after bilateral subthalamic stimulation: 2 years follow-up study. Clin Neurol Neurosurg. 2014 Sep;124:161-5. doi: 10.1016/j.clineuro.2014.06.019. Epub 2014 Jun 23. PubMed PMID: 25051167.
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Cui Z, Pan L, Song H, Xu X, Xu B, Yu X, Ling Z. Intraoperative MRI for optimizing electrode placement for deep brain stimulation of the subthalamic nucleus in Parkinson disease. J Neurosurg. 2016 Jan;124(1):62-9. doi: 10.3171/2015.1.JNS141534. Epub 2015 Aug 14. PubMed PMID: 26274983.
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Park KW, Jo S, Kim MS, et al. Cognitive profile as a predictor of the long-term outcome after deep brain stimulation in Parkinson’s disease [published online ahead of print, 2020 Jul 28]. J Neurol Sci. 2020;417:117063. doi:10.1016/j.jns.2020.117063

Asleep subthalamic deep brain stimulation for Parkinson’s disease

Asleep subthalamic deep brain stimulation for Parkinson’s disease

Recent advances in methods used for deep brain stimulation (DBS) include subthalamic nucleus electrode implantation in the “asleep” patient without the traditional use of microelectrode recordings or intraoperative test stimulation.

Meta-Analysis

2019

Liu et al. systematically reviewed the literature to compare the efficacy and safety of awake and asleep deep brain stimulation surgery. They identified cohort studies from the Cochrane library, MEDLINE, and EMBASE (January 1970 to August 2019) by using Review Manager 5.3 software to conduct a meta-analysis following the PRISMA guidelines. Fourteen cohort studies involving 1,523 patients were included. The meta-analysis results showed that there were no significant differences between the GA and LA groups in UPDRSIII score improvement (standard mean difference [SMD] 0.06; 95% CI -0.16 to 0.28; p = 0.60), postoperative LEDD requirement (SMD -0.17; 95% CI -0.44 to 0.12; p = 0.23), or operation time (SMD 0.18; 95% CI -0.31 to 0.67; p = 0.47). Additionally, there was no significant difference in the incidence of adverse events (OR 0.98; 95% CI 0.53-1.80; p = 0.94), including postoperative speech disturbance and intracranial hemorrhage. However, the volume of intracranial air was significantly lower in the GA group than that in the LA group. In a subgroup analysis, there was no significant difference in clinical efficacy between the microelectrode recording (MER) and non-MER groups. We demonstrated equivalent clinical outcomes of DBS surgery between GA and LA in terms of improvement of symptoms and the incidence of adverse events. Key Messages: MER might not be necessary for DBS implantation. For patients who cannot tolerate DBS surgery while being awake, GA should be an appropriate alternative 1).

Case series

A retrospective review of clinical outcomes of 152 consecutive patients. Their outcomes at 1 yr postimplantation are reported; these include Unified Parkinson’s Disease Rating Scale (UPDRS) assessment, Mobility Tinetti Test, PDQ-39 quality of life assessment, Mattis Dementia Rating Scale, Beck Depression Inventory, and Beck Anxiety Inventory. They also report on a new parietal trajectory for electrode implantation.

UPDRS III improved from 39 to 20.5 (47%, P < .001). The total UPDRS score improved from 67.6 to 36.4 (46%, P < .001). UPDRS II scores improved from 18.9 to 10.5 (44%, P < .001) and UPDRS IV scores improved from 7.1 to 3.6 (49%, P < .001). There was a significant reduction in levodopa equivalent daily dose after surgery (mean: 35%, P < .001). PDQ-39 summary index improved by a mean of 7.1 points. There was no significant difference found in clinical outcomes between the frontal and parietal approaches.

“Asleep” robot-assisted DBS of the subthalamic nucleus demonstrates comparable outcomes with traditional techniques in the treatment of Parkinson’s disease. 2).

The objective of a study of Senemmar et al. was to investigate whether asleep deep brain stimulation surgery of the subthalamic nucleus (STN) improves therapeutic window (TW) for both directional (dDBS) and omnidirectional (oDBS) stimulation in a large single-center population.

A total of 104 consecutive patients with Parkinson’s disease (PD) undergoing STN-DBS surgery (80 asleep and 24 awake) were compared regarding TW, therapeutic threshold, side effect threshold, improvement of Unified PD Rating Scale motor score (UPDRS-III) and degree of levodopa equivalent daily dose (LEDD) reduction.

Asleep DBS surgery led to significantly wider TW compared to awake surgery for both dDBS and oDBS. However, dDBS further increased TW compared to oDBS in the asleep group only and not in the awake group. Clinical efficacy in terms of UPDRS-III improvement and LEDD reduction did not differ between groups.

The study provides first evidence for improvement of therapeutic window by asleep surgery compared to awake surgery, which can be strengthened further by dDBS. These results support the notion of preferring asleep over awake surgery but needs to be confirmed by prospective trials 3).

Clinical outcome studies have shown that “asleep” DBS lead placement, performed using intraoperative imaging with stereotactic accuracy as the surgical endpoint, has motor outcomes comparable to traditional “awake” DBS using microelectrode recording (MER), but with shorter case times and improved speech fluency 4).

Ninety-six patients were retrospectively matched pairwise (48 asleep and 48 awake) and compared regarding improvement of Unified PD Rating Scale Motor Score (UPDRS-III), cognitive function, Levodopa-equivalent-daily-dose (LEDD), stimulation amplitudes, side effects, surgery duration, and complication rates. Routine testing took place at three months and one year postoperatively.

Results: Chronic DBS effects (UPDRS-III without medication and with stimulation on [OFF/ON]) significantly improved UPDRS-III only after awake surgery at three months and in both groups one year postoperatively. Acute effects (percentage UPDRS-III reduction after activation of stimulation) were also significantly better after awake surgery at three months but not at one year compared to asleep surgery. UPDRS-III subitems “freezing” and “speech” were significantly worse after asleep surgery at three months and one year, respectively. LEDD was significantly lower after awake surgery only one week postoperatively. The other measures did not differ between groups.

Overall motor function improved faster in the awake surgery group, but the difference ceased after one year. However, axial subitems were worse in the asleep surgery group suggesting that worsening of axial symptoms was risked improving overall motor function. Awake surgery still seems advantageous for STN-DBS in PD, although asleep surgery may be considered with lower threshold in patients not suitable for awake surgery 5).

References

1)

Liu Z, He S, Li L. General Anesthesia versus Local Anesthesia for Deep Brain Stimulation in Parkinson’s Disease: A Meta-Analysis. Stereotact Funct Neurosurg. 2019;97(5-6):381-390. doi:10.1159/000505079
2)

Moran CH, Pietrzyk M, Sarangmat N, Gerard CS, Barua N, Ashida R, Whone A, Szewczyk-Krolikowski K, Mooney L, Gill SS. Clinical Outcome of “Asleep” Deep Brain Stimulation for Parkinson Disease Using Robot-Assisted Delivery and Anatomic Targeting of the Subthalamic Nucleus: A Series of 152 Patients. Neurosurgery. 2020 Sep 28:nyaa367. doi: 10.1093/neuros/nyaa367. Epub ahead of print. PMID: 32985669.
3)

Senemmar F, Hartmann CJ, Slotty PJ, Vesper J, Schnitzler A, Groiss SJ. Asleep Surgery May Improve the Therapeutic Window for Deep Brain Stimulation of the Subthalamic Nucleus [published online ahead of print, 2020 Jul 13]. Neuromodulation. 2020;10.1111/ner.13237. doi:10.1111/ner.13237
4)

Mirzadeh Z, Chen T, Chapple KM, Lambert M, Karis JP, Dhall R, Ponce FA. Procedural Variables Influencing Stereotactic Accuracy and Efficiency in Deep Brain Stimulation Surgery. Oper Neurosurg (Hagerstown). 2018 Oct 18. doi: 10.1093/ons/opy291. [Epub ahead of print] PubMed PMID: 30339204.
5)

Blasberg F, Wojtecki L, Elben S, Slotty PJ, Vesper J, Schnitzler A, Groiss SJ. Comparison of Awake vs. Asleep Surgery for Subthalamic Deep Brain Stimulation in Parkinson’s Disease. Neuromodulation. 2018 Aug;21(6):541-547. doi: 10.1111/ner.12766. Epub 2018 Mar 13. PubMed PMID: 29532

Today:MiddleEast Camp for Parkinson’s, Movement Disorders and Neuromodulation. Indian Society of Paediatric Neurosurgery 26th Annual Conference. 28th Annual Conference of Pakistan Society of Neurosurgeons

2nd MiddleEast Camp for Parkinson’s, Movement Disorders and Neuromodulation

November 19 — November 21

Dubai, UAE
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Indian Society of Paediatric Neurosurgery 26th Annual Conference 2015

November 19 — November 22

Kochi, Kerala, India
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28th Annual Conference of Pakistan Society of Neurosurgeons

November 19 — November 22

Karachi, Pakistan
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Enfermedad de Parkinson y pesticidas

La enfermedad de Parkinson (EP) se caracteriza por la pérdida de neuronas de dopamina en la sustancia negra (SN). Aunque la etiología exacta es desconocida, la enfermedad de Parkinson esporádica puede ser resultado de la susceptibilidad genética y la interactuación con un factor ambiental. Los estudios epidemiológicos sugieren que la exposición a pesticidas está vinculada a un mayor riesgo de EP, pero no hay estudios que demuestren cambios en la SN con la exposición a pesticidas crónica en sujetos humanos.
En un estudio los cambios detectados por resonancia magnética pueden marcar “uno de los factores” que conduce a la EP, y ser la base del mayor riesgo de PD en los usuarios de plaguicidas que se encuentran en los estudios epidemiológicos. Otros estudios en humanos con la asistencia de estos marcadores de imagen pueden ser útiles en la comprensión de la etiología de la EP ((Du G, Lewis MM, Sterling NW, Kong L, Chen H, Mailman RB, Huang X.
Microstructural changes in the substantia nigra of asymptomatic agricultural
workers. Neurotoxicol Teratol. 2013 Dec 12;41C:60-64. doi:
10.1016/j.ntt.2013.12.001. [Epub ahead of print] PubMed PMID: 24334261.))

Las células madre contra el párkinson se probarán en pacientes en dos años

La gran promesa de la emergente medicina regenerativa es convertir las células madre derivadas de un paciente en tejidos que se le puedan trasplantar para tratar su enfermedad. La idea superó una prueba crucial con la demostración, por científicos japoneses, de que las neuronas dopaminérgicas –cuya destrucción causa el párkinson— derivadas de células madre pueden trasplantarse al cerebro de los primates sin apenas rechazo inmunológico. Esto despeja el camino hasta el punto de que los ensayos clínicos con pacientes humanos de párkinson empezarán en dos años, según el responsable de la investigación.
En ensayos previos la respuesta inmunitaria arruinaba el trabajo
Las células iPS (induced pluripotent stem cells, o células madre de pluripotencia inducida) son la gran promesa de la investigación biomédica. Son unas células madre tan versátiles como las embrionarias -capaces de convertirse en cualquier tejido y órgano del cuerpo-, pero que se obtienen reprogramando, o retrasando el reloj de simples células de la piel u otro tejido del paciente. No solo eluden el uso de embriones humanos, sino que además son genéticamente idénticas al paciente. Los trasplantes derivados de ellas no deberían, por tanto, generar rechazo inmunológico.
Pero las predicciones más razonables fallan a menudo en biología. En los últimos dos años, algunos experimentos con ratones habían arrojado un jarro de agua helada sobre esas expectativas. Varios tipos de trasplantes derivados de células madre iPS indujeron una fuerte respuesta inmunológica en el ratón receptor, pese a que el trasplante procedía de un ratón genéticamente idéntico a él. Por alguna razón que sigue sin estar del todo clara, las células iPS parecen generar rechazo en esos sufridos roedores de laboratorio.
Takahashi, Yamanaka y sus colegas muestran ahora que, pese a todas esas prevenciones, el proceso funciona en primates no humanos. Han utilizado ocho macacos (Macaca fascicularis) criados para este propósito, les han extraído unas pocas células de la piel o de la sangre y les han retrasado el reloj para convertirlas en células madre iPS. Esta es la receta por la que Yamanaka ganó el Nobel, basada en solo cuatro factores de transcripción, o genes que regulan a otros genes.
Después han usado un protocolo –a base de factores de diferenciación y otras moléculas con actividad biológica— que, paso a paso, va convirtiendo (o diferenciando, en la jerga) a las células madre iPS primero en precursores de las neuronas, luego en neuronas y por último en neuronas dopaminérgicas, esto es, productoras del neurotransmisor dopamina. La destrucción de este tipo de neuronas en una parte del cerebro (la sustancia negra), y el consiguiente déficit de dopamina en los circuitos cerebrales normalmente alimentados por ellas, es la causa directa del párkinson.
Los científicos japoneses han trasplantado esas neuronas a los mismos ocho macacos de los que habían partido, pero en dos tipos de condiciones: trasplantes autólogos (al mismo mono del que provenían las células iPS) o heterólogos (a otro mono distinto). El trabajo está diseñado cuidadosamente para examinar la cuestión crucial del rechazo. Y el resultado es un fuerte rechazo inmunológico en los trasplantes heterólogos; y uno muy débil en los trasplantes autólogos. Es la mejor noticia que podía esperar el sector –y el Nobel Yamanaka— tras el último año de depresión por los experimentos con ratones.
El experimento no aborda si las neuronas dopaminérgicas trasplantadas a los macacos pueden o no aliviar los síntomas del párkinson: los monos no tenían párkinson y no había por tanto nada que aliviar. Lo que sí es específico del párkinson es el tipo de neuronas producidas y el lugar del cerebro en el que deberían ser trasplantadas si los pacientes fueran humanos. Los autores han utilizado seis inyecciones en el cuerpo estriado izquierdo del cerebro, cada una con 800.000 neuronas.
Los animales del estudio estaban sanos, por lo que no hay evidencia médica
Takahashi considera que sus resultados ofrecen “una lógica para empezar a probar los trasplantes autólogos en situaciones clínicas, al menos con células neuronales”. También piensa que el trasplante de neuronas derivadas de células iPS al mismo paciente del que fueron obtenidas, o incluso a otro paciente que case con él inmunológicamente –como se hace ahora con los trasplantes de médula— puede ser posible sin necesidad de utilizar fármacos inmunosupresores. La respuesta inmunológica no es nula, pero sí lo bastante baja para que las células trasplantadas sobrevivan a largo plazo.