Publications by authors named "Alfonso Fasano"

341 Publications

Acute low frequency dorsal subthalamic nucleus stimulation improves verbal fluency in Parkinson's disease.

Brain Stimul 2021 Apr 30. Epub 2021 Apr 30.

Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, ON, M5T 2S8, Canada; Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada.

Background: Parkinson's disease (PD) is a common neurodegenerative disorder that results in movement-related dysfunction and has variable cognitive impairment. Deep brain stimulation (DBS) of the dorsal subthalamic nucleus (STN) has been shown to be effective in improving motor symptoms; however, cognitive impairment is often unchanged, and in some cases, worsened particularly on tasks of verbal fluency. Traditional DBS strategies use high frequency gamma stimulation for motor symptoms (∼130 Hz), but there is evidence that low frequency theta oscillations (5-12 Hz) are important in cognition.

Methods: We tested the effects of stimulation frequency and location on verbal fluency among patients who underwent STN DBS implantation with externalized leads. During baseline cognitive testing, STN field potentials were recorded and the individual patients' peak theta frequency power was identified during each cognitive task. Patients repeated cognitive testing at five different stimulation settings: no stimulation, dorsal contact gamma (130 Hz), ventral contact gamma, dorsal theta (peak baseline theta) and ventral theta (peak baseline theta) frequency stimulation.

Results: Acute left dorsal peak theta frequency STN stimulation improves overall verbal fluency compared to no stimulation and to either dorsal or ventral gamma stimulation. Stratifying by type of verbal fluency probes, verbal fluency in episodic categories was improved with dorsal theta stimulation compared to all other conditions, while there were no differences between stimulation conditions in non-episodic probe conditions.

Conclusion: Here, we provide evidence that dorsal STN theta stimulation may improve verbal fluency, suggesting a potential possibility of integrating theta stimulation into current DBS paradigms to improve cognitive outcomes.
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http://dx.doi.org/10.1016/j.brs.2021.04.016DOI Listing
April 2021

Concomitant Medication Usage with Levodopa-Carbidopa Intestinal Gel: Results from the COSMOS Study.

Mov Disord 2021 Apr 28. Epub 2021 Apr 28.

Department of Neurology, Hospital Universitario Fundación Alcorcón, Madrid, Spain.

Background: Levodopa-carbidopa intestinal gel (LCIG) is administered directly to the small intestine of patients with advanced Parkinson's disease (APD) to help maintain stable plasma levodopa levels.

Objective: The objective of this study was to investigate the effect of LCIG in reducing polypharmacy for the treatment of APD.

Methods: The COmedication Study assessing Mono- and cOmbination therapy with levodopa-carbidopa inteStinal gel (COSMOS) is a large, real-world, multinational observational study investigating comedication use with LCIG. All enrolled patients had used LCIG for ≥12 months and data were collected cross-sectionally (study visit) and retrospectively. The primary endpoint was the percentage of patients using LCIG as monotherapy (without add-on PD medications) at initiation and at 3, 6, 9, and 12 months thereafter.

Results: Overall, 409 patients were enrolled from 14 countries and were treated with LCIG for a mean of 35.8 ± 23.2 months. A total of 15.2% of patients initiated LCIG as monotherapy and 31.7% were receiving monotherapy at 12 months after initiation. The mean duration of LCIG monotherapy was 39.3 ± 25.6 months. Use of add-on medications decreased over time with all LCIG regimens. From LCIG initiation to the patient visit, mean off time decreased by 3.8, 4.6, and 3.9 hours/day for LCIG monotherapy, LCIG daytime monotherapy, and LCIG polytherapy groups, respectively, while duration of dyskinesia decreased by 1.7, 2.0, and 1.9 hours/day, respectively. Adverse events likely related to study treatment occurred in 112 patients (27.4%) during LCIG treatment.

Conclusions: LCIG is an effective long-term monotherapy option with a positive risk-benefit profile and contributes to reduced polypharmacy for patients with APD. © 2021 The AbbVie Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28596DOI Listing
April 2021

Corpus Callosum Hyperintensity in Normal Pressure Hydrocephalus After Ventriculoperitoneal Shunt.

Neurology 2021 Apr 23. Epub 2021 Apr 23.

Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada. Division of Neurology, University of Toronto, Toronto, Ontario, Canada

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http://dx.doi.org/10.1212/WNL.0000000000012041DOI Listing
April 2021

Clinical Outcome and Striatal Dopaminergic Function After Shunt Surgery in Patients With Idiopathic Normal Pressure Hydrocephalus.

Neurology 2021 Apr 23. Epub 2021 Apr 23.

Parkinson's Disease and Movement Disorders Unit, IRCCS Mondino Foundation, Pavia, Italy

Objective: To determine changes in clinical features and striatal dopamine reuptake transporter (DAT) density after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH).

Methods: Subjects with probable iNPH were assessed at baseline by means of clinical rating scales, brain MRI, and SPECT with [I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT). Levodopa responsiveness was also evaluated. Patients who did or did not undergo lumboperitoneal shunt were clinically followed up and repeated SPECT after 2 years.

Results: We enrolled 115 iNPH patients. Of 102 subjects without significant levodopa response and no signs of atypical parkinsonism, 92 performed FP-CIT SPECT (58 also at follow-up) and 59 underwent surgery. We identified a disequilibrium subtype (phenotype 1) and a locomotor subtype (phenotype 2) of higher-level gait disorder. Gait impairment correlated with caudate DAT density in both phenotypes, whereas parkinsonian signs correlated with putamen and caudate DAT binding in patients with phenotype 2, who showed more severe symptoms and lower striatal DAT density. Gait and caudate DAT binding improved in both phenotypes after surgery ( < 0.01). Parkinsonism and putamen DAT density improved in shunted patients with phenotype 2 ( < 0.001). Conversely, gait, parkinsonian signs, and striatal DAT binding worsened in subjects who declined surgery ( < 0.01).

Conclusions: This prospective interventional study highlights the pathophysiological relevance of striatal dopaminergic dysfunction in the motor phenotypic expression of iNPH. Absence of levodopa responsiveness, shunt-responsive parkinsonism, and post-surgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of iNPH patients.
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http://dx.doi.org/10.1212/WNL.0000000000012064DOI Listing
April 2021

Sign-specific stimulation 'hot' and 'cold' spots in Parkinson's disease validated with machine learning.

Brain Commun 2021 10;3(2):fcab027. Epub 2021 Mar 10.

University Health Network, Toronto, ON, Canada.

Deep brain stimulation of the subthalamic nucleus has become a standard therapy for Parkinson's disease. Despite extensive experience, however, the precise target of optimal stimulation and the relationship between site of stimulation and alleviation of individual signs remains unclear. We examined whether machine learning could predict the benefits in specific Parkinsonian signs when informed by precise locations of stimulation. We studied 275 Parkinson's disease patients who underwent subthalamic nucleus deep brain stimulation between 2003 and 2018. We selected pre-deep brain stimulation and best available post-deep brain stimulation scores from motor items of the Unified Parkinson's Disease Rating Scale (UPDRS-III) to discern sign-specific changes attributable to deep brain stimulation. Volumes of tissue activated were computed and weighted by (i) tremor, (ii) rigidity, (iii) bradykinesia and (iv) axial signs changes. Then, sign-specific sites of optimal ('hot spots') and suboptimal efficacy ('cold spots') were defined. These areas were subsequently validated using machine learning prediction of sign-specific outcomes with in-sample and out-of-sample data ( = 51 subthalamic nucleus deep brain stimulation patients from another institution). Tremor and rigidity hot spots were largely located outside and dorsolateral to the subthalamic nucleus whereas hot spots for bradykinesia and axial signs had larger overlap with the subthalamic nucleus. Using volume of tissue activated overlap with sign-specific hot and cold spots, support vector machine classified patients into quartiles of efficacy with ≥92% accuracy. The accuracy remained high (68-98%) when only considering volume of tissue activated overlap with hot spots but was markedly lower (41-72%) when only using cold spots. The model also performed poorly (44-48%) when using only stimulation voltage, irrespective of stimulation location. Out-of-sample validation accuracy was ≥96% when using volume of tissue activated overlap with the sign-specific hot and cold spots. In two independent datasets, distinct brain areas could predict sign-specific clinical changes in Parkinson's disease patients with subthalamic nucleus deep brain stimulation. With future prospective validation, these findings could individualize stimulation delivery to optimize quality of life improvement.
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http://dx.doi.org/10.1093/braincomms/fcab027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042250PMC
March 2021

Self-adjustment of deep brain stimulation delays optimization in Parkinson's disease.

Brain Stimul 2021 Apr 11;14(3):676-681. Epub 2021 Apr 11.

Edmond J. Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Division of Neurology, University of Toronto, Toronto, Ontario, Canada; Krembil Brain Institute, Toronto, Ontario, Canada; CenteR for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, ON, Canada. Electronic address:

Background: Parkinson's Disease patients undergo time-consuming programming to refine stimulation parameters after deep brain stimulation surgery.

Objective: To assess whether the use of the advanced functions of a patient's programmer would facilitate programming of deep brain stimulation.

Methods: Thirty patients were randomly allocated to the use of advanced versus simple mode of the patient programmer in this single-centre, prospective, randomized, controlled study. Primary outcome was the number of days required to optimize the stimulation settings.

Results: The number of days required to optimize stimulation was significantly lower in the simple mode (88.5 ± 33.1 vs. 142.1 ± 67.4, p = 0.01). In addition, the advanced mode group had a higher number of side effects (5.4 ± 3.1 vs. 2.6 ± 1.9, p = 0.0055).

Conclusions: The use of the advanced functions of patient programmer delays programming optimization and it is associated with a higher number of side effects. These findings highlight the need for other methods for faster and safer stimulation programming.
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http://dx.doi.org/10.1016/j.brs.2021.04.001DOI Listing
April 2021

Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation.

EMBO Mol Med 2021 Apr 14:e13258. Epub 2021 Apr 14.

Section Cell Biology, Center for Molecular Medicine, Institute of Biomembranes, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Vacuolar protein sorting 41 (VPS41) is as part of the Homotypic fusion and Protein Sorting (HOPS) complex required for lysosomal fusion events and, independent of HOPS, for regulated secretion. Here, we report three patients with compound heterozygous mutations in VPS41 (VPS41 and VPS41 ; VPS41 and VPS41 ) displaying neurodegeneration with ataxia and dystonia. Cellular consequences were investigated in patient fibroblasts and VPS41-depleted HeLa cells. All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo. By contrast, VPS41 enabled regulated secretion. Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation. Phosphorylation of mTORC1 substrates S6K1 and 4EBP1 was not affected. In a C. elegans model of Parkinson's disease, co-expression of VPS41 /VPS41 abolished the neuroprotective function of VPS41 against α-synuclein aggregates. We conclude that the VPS41 variants specifically abrogate HOPS function, which interferes with the TFEB/TFE3 axis of mTORC1 signaling, and cause a neurodegenerative disease.
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http://dx.doi.org/10.15252/emmm.202013258DOI Listing
April 2021

Reply to: "Gaps, Controversies, and Proposed Roadmap for Research in Normal Pressure Hydrocephalus".

Mov Disord 2021 Apr;36(4):1043-1044

Department of Neurosurgery, Medical School Hannover, Hannover, Germany.

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http://dx.doi.org/10.1002/mds.28573DOI Listing
April 2021

β-Blocker-Induced Tremor.

Mov Disord Clin Pract 2021 Apr 13;8(3):449-452. Epub 2021 Mar 13.

The Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Division of Neurology, Department of Medicine University of Toronto Toronto Ontario Canada.

Background: Although the β-blocker propranolol is considered one of the most effective tremor treatments and other β-blockers are often prescribed to patients with tremor, those with partial β-agonist activity on β-adrenoreceptors can theoretically induce or exacerbate tremor. Here we report 2 patients with tremor induced or worsened by such β-blockers.

Cases: Case 1 is a 38-year-old man with worsening of tremor in both upper extremities after the introduction of pindolol as an adjunct treatment for severe depression. The tremor improved 1 month after discontinuing this medication. Case 2 is a 77-year-old woman with new bilateral hand tremor after receiving labetalol for the management of hypertension during a hospital admission. Tremor markedly attenuated after eliminating labetalol.

Conclusion: β-Blockers with partial agonist activity can induce or exacerbate tremor.
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http://dx.doi.org/10.1002/mdc3.13176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015902PMC
April 2021

Advanced Therapies for the Management of Dopamine Dysregulation Syndrome in Parkinson's Disease.

Mov Disord Clin Pract 2021 Apr 11;8(3):400-405. Epub 2021 Mar 11.

Division of Neurology University of Toronto Toronto Ontario Canada.

Background: Dopamine Dysregulation Syndrome (DDS) is an adverse non-motor complication of dopamine replacement therapy in Parkinson's disease. The current literature on this syndrome is limited, and it remains underdiagnosed and challenging to manage.

Objective: To assess the role of advanced therapies in the management of DDS.

Methods: We performed a retrospective chart review and identified patients who fit the inclusion criteria for DDS. They were classified according to risk factors that have been identified in the literature, motor and complication scores, intervention (medical or surgical) and outcome. Multivariate analyses were performed to analyze these characteristics.

Results: Twenty-seven patients were identified (23 males, mean age of onset: 49 ± 8.8 years). Average levodopa equivalent daily dose was 1916.7 ± 804 mg and a history of impulse control disorders, psychiatric illness, and substance abuse was present in 89%, 70% and 3.7% of the patients, respectively. Overall 81.5% of patients had symptom resolution at follow up, on average 4.8 ± 3.5 years after management, with medication only (7/9), levodopa-carbidopa intestinal gel (1/3), deep brain stimulation of subthalamic nucleus (10/13), or globus pallidus pars interna (2/2). Reduction of medications occurred with deep brain stimulation of subthalamic nucleus ( = 0.01) but was associated with a relapse in two patients.

Conclusion: Although the small sample size of some subgroups limits our ability to draw meaningful conclusions, our results did not suggest superiority of a single treatment option. Advanced therapies including deep brain stimulation can be considered in patients with DDS refractory to conservative measures, but outcome is variable and relapse is possible.
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http://dx.doi.org/10.1002/mdc3.13154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015898PMC
April 2021

Extradural Motor Cortex Stimulation in Parkinson's Disease: Long-Term Clinical Outcome.

Brain Sci 2021 Mar 26;11(4). Epub 2021 Mar 26.

Neurosurgery Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.

Previous investigations have reported on the motor benefits and safety of chronic extradural motor cortex stimulation (EMCS) for patients with Parkinson's disease (PD), but studies addressing the long-term clinical outcome are still lacking. In this study, nine consecutive PD patients who underwent EMCS were prospectively recruited, with a mean follow-up time of 5.1 ± 2.5 years. As compared to the preoperatory baseline, the Unified Parkinson's Disease Rating Scale (UPDRS)-III in the off-medication condition significantly decreased by 13.8% at 12 months, 16.1% at 18 months, 18.4% at 24 months, 21% at 36 months, 15.6% at 60 months, and 8.6% at 72 months. The UPDRS-IV decreased by 30.8% at 12 months, 22.1% at 24 months, 25% at 60 months, and 36.5% at 72 months. Dopaminergic therapy showed a progressive reduction, significant at 60 months (11.8%). Quality of life improved by 18.0% at 12 months, and 22.4% at 60 months. No surgical complication, cognitive or behavioral change occurred. The only adverse event reported was an infection of the implantable pulse generator pocket. Even in the long-term follow-up, EMCS was shown to be a safe and effective treatment option in PD patients, resulting in improvements in motor symptoms and quality of life, and reductions in motor complications and dopaminergic therapy.
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http://dx.doi.org/10.3390/brainsci11040416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067040PMC
March 2021

Emerging concepts on bradykinesia in non-parkinsonian conditions.

Eur J Neurol 2021 Apr 1. Epub 2021 Apr 1.

IRCCS Neuromed, Pozzilli, IS, Italy.

Bradykinesia is one of the cardinal motor symptoms of Parkinson's disease. However, clinical and experimental studies indicate that bradykinesia may also be observed in various neurological diseases not primarily characterized by parkinsonism. These conditions include hyperkinetic movement disorders, such as dystonia, chorea, and essential tremor. Bradykinesia may also be observed in patients with neurological conditions that are not seen as "movement disorders", including those characterized by the involvement of the cerebellum and corticospinal system, dementia, multiple sclerosis, or psychiatric disorders. We provide an updated overview of bradykinesia in non-parkinsonian conditions and discuss the major findings of clinical reports and experimental studies. From a pathophysiological standpoint, bradykinesia in neurological conditions not primarily characterized by parkinsonism may be explained by brain network dysfunction. In addition to the pathophysiological implications, the present paper highlights important terminological issues and the need for a new, more accurate, and more widely-used definition of bradykinesia in the context of movement disorders and other neurological conditions.
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http://dx.doi.org/10.1111/ene.14851DOI Listing
April 2021

Mind over motor.

J Neurol Neurosurg Psychiatry 2021 Mar 30. Epub 2021 Mar 30.

Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada

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http://dx.doi.org/10.1136/jnnp-2020-326002DOI Listing
March 2021

A literature review of magnetic resonance imaging sequence advancements in visualizing functional neurosurgery targets.

J Neurosurg 2021 Mar 26:1-14. Epub 2021 Mar 26.

1University Health Network, Toronto.

Objective: Historically, preoperative planning for functional neurosurgery has depended on the indirect localization of target brain structures using visible anatomical landmarks. However, recent technological advances in neuroimaging have permitted marked improvements in MRI-based direct target visualization, allowing for refinement of "first-pass" targeting. The authors reviewed studies relating to direct MRI visualization of the most common functional neurosurgery targets (subthalamic nucleus, globus pallidus, and thalamus) and summarize sequence specifications for the various approaches described in this literature.

Methods: The peer-reviewed literature on MRI visualization of the subthalamic nucleus, globus pallidus, and thalamus was obtained by searching MEDLINE. Publications examining direct MRI visualization of these deep brain stimulation targets were included for review.

Results: A variety of specialized sequences and postprocessing methods for enhanced MRI visualization are in current use. These include susceptibility-based techniques such as quantitative susceptibility mapping, which exploit the amount of tissue iron in target structures, and white matter attenuated inversion recovery, which suppresses the signal from white matter to improve the distinction between gray matter nuclei. However, evidence confirming the superiority of these sequences over indirect targeting with respect to clinical outcome is sparse. Future targeting may utilize information about functional and structural networks, necessitating the use of resting-state functional MRI and diffusion-weighted imaging.

Conclusions: Specialized MRI sequences have enabled considerable improvement in the visualization of common deep brain stimulation targets. With further validation of their ability to improve clinical outcomes and advances in imaging techniques, direct visualization of targets may play an increasingly important role in preoperative planning.
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http://dx.doi.org/10.3171/2020.8.JNS201125DOI Listing
March 2021

Sleep disturbance in movement disorders: insights, treatments and challenges.

J Neurol Neurosurg Psychiatry 2021 Mar 19. Epub 2021 Mar 19.

Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK

Sleep and circadian rhythm disturbances are central features of many movement disorders, exacerbating motor and non-motor symptoms and impairing quality of life. Understanding these disturbances to sleep is clinically important and may further our understanding of the underlying movement disorder. This review evaluates the current anatomical and neurochemical understanding of normal sleep and the recognised primary sleep disorders. In addition, we undertook a systematic review of the evidence for disruption to sleep across multiple movement disorders. Rapid eye movement sleep behaviour disorder has emerged as the most reliable prodromal biomarker for the alpha synucleinopathies, including Parkinson's disease and multiple system atrophy, often preceding motor symptom onset by several years. Abnormal sleep has also been described for many other movement disorders, but further evidence is needed to determine whether this is a primary or secondary phenotypic component of the underlying condition. Medication used in the treatment of motor symptoms also affects sleep and can aggravate or cause certain sleep disorders. Within the context of movement disorders, there is also some suggestion of a shared underlying mechanism for motor and sleep pathophysiology, with evidence implicating thalamic and brainstem structures and monoaminergic neurotransmission. This review highlights the need for an understanding of normal and abnormal sleep within the movement disorder clinic, an ability to screen for specific causes of poor sleep and to treat sleep disturbance to improve quality of life. Key sleep disorders also act as important biomarkers and have implications in diagnosis, prognosis and the development of future therapies.
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http://dx.doi.org/10.1136/jnnp-2020-325546DOI Listing
March 2021

Theta Burst Deep Brain Stimulation in Movement Disorders.

Mov Disord Clin Pract 2021 Feb 11;8(2):282-285. Epub 2021 Jan 11.

Edmond J. Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital and Division of Neurology, UHN, Division of Neurology University of Toronto Toronto Ontario Canada.

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http://dx.doi.org/10.1002/mdc3.13130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906022PMC
February 2021

Functional Dyskinesias following Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A Report of Three Cases.

Mov Disord Clin Pract 2021 Jan 2;8(1):114-117. Epub 2020 Dec 2.

Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Centre Toronto Western Hospital, UHN Toronto Ontario Canada.

Background: Functional (psychogenic) dyskinesias in patients with Parkinson's disease (PD) are exceedingly rare.

Cases: Herein we report three patients with PD who presented with functional dyskinesias in the first 3 months after subthalamic nucleus deep brain stimulation (DBS). All patients presented with chorea mimicking levodopa or stimulation-induced dyskinesias in the first 24 hours following stimulation adjustment. Two patients had generalized chorea and one, hemichorea. In all patients the abnormal movements could be induced or resolved with placebo/nocebo changes to the stimulation parameters. Following the diagnosis of a functional movement disorder (FMD), all patients improved with appropriate management.

Conclusions: Functional chorea following DBS might mimic organic dyskinesias in PD but can be accurately diagnosed using suggestibility and placebo responses to sham stimulation adjustments. Recognizing the presence of FMD following DBS is important for proper management of these patients.
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http://dx.doi.org/10.1002/mdc3.13111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906021PMC
January 2021

Motor blocks during bilateral stepping in Parkinson's disease and effects of dopaminergic medication.

Parkinsonism Relat Disord 2021 Feb 18;85:1-4. Epub 2021 Feb 18.

Department of Medicine, University of Toronto and Division of Brain, Imaging & Behaviour, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada; Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. Electronic address:

Introduction: Freezing of gait (FOG) is a complex symptom in Parkinson's disease (PD) that manifests during walking as limited forward progression despite the intention to walk. It is unclear if lower limb motor blocks (LLMB) that occur independently from FOG are related to overground FOG and the effects of dopaminergic medications.

Methods: Nineteen patients with PD were tested on two separate days in the dopaminergic medication "on" and "off" states. The patients completed a series of freezing-provoking tasks while videotaped. Raters assessed videos for FOG presence using Movement Disorders Society Unified Parkinson's Disease Rating Scale item 3.11 score greater than or equal to 1 and FOG severity using the standardized FOG score. Whilst seated in a virtual environment, patients and 20 healthy controls stepped in right-left sequence on foot pedals. Frequency and percent time in LLMB were assessed for accurate classification of FOG presence and correlation to the FOG score.

Results: Frequency and percent time spent in LLMB predicted the presence of FOG in both medication states. Percent time spent in LLMB correlated with FOG severity in both medication states. LLMB frequency predicted FOG severity in the "off" state only.

Conclusions: LLMB during bilateral stepping in a virtual environment predicted the presence and severity of FOG in PD in both "on" and "off" medication states. These findings support the use of this non-walking paradigm to detect and assess FOG in PD patients unable or unsafe to walk.
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http://dx.doi.org/10.1016/j.parkreldis.2021.02.015DOI Listing
February 2021

Parkinson's Disease and COVID-19: Do We Need to Be More Patient?

Mov Disord 2021 02;36(2):277

Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada and Division of Neurology, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/mds.28469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014182PMC
February 2021

The 5 Pillars in Tourette Syndrome Deep Brain Stimulation Patient Selection: Present and Future.

Neurology 2021 04 16;96(14):664-676. Epub 2021 Feb 16.

From the Department of Clinical Neurosciences (D.M., T.M.P.), Cumming School of Medicine, University of Calgary, Calgary AB, Canada; Hotchkiss Brain Institute (D.M., T.M.P.), University of Calgary, Calgary AB, Canada; Alberta Children's Hospital Research Institute (D.M.), University of Calgary, Calgary AB, Canada; Mathison Centre for Mental Health Research and Education (D.M., T.M.P.), Calgary, AB, Canada; UMass Memorial Medical Center and UMass Medical School (W.D.), Worcester, MA, United States; Department of Neurology (J.J.-S.), Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Neurology (I.M., M.S.O.), Norman Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, United States; Department of Psychiatry (T.M.P.), Pediatrics and Community Health Sciences, University of Calgary, AB, Canada; Edmond J. Safra Program in Parkinson's Disease (A.F.), Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada; Division of Neurology, University of Toronto, Toronto, Ontario, Canada; Krembil Brain Institute (A.F.), Toronto, Ontario, Canada; CenteR for Advancing Neurotechnological Innovation to Application (CRANIA) (A.F.), Toronto, ON, Canada; Movement Disorders and Neuromodulation Unit (C.G.), Charité, University Medicine Berlin, Department of Neurology, Berlin, Germany; and Strategic Regulatory Partners (W.W.), LLC.

The selection of patients with Tourette syndrome (TS) for deep brain stimulation (DBS) surgery rests on 5 fundamental pillars. However, the operationalization of the multidisciplinary screening process to evaluate these pillars remains highly diverse, especially across sites. High tic severity and tic-related impact on quality of life (first 2 pillars) require confirmation from objective, validated measures, but malignant features of TS should per se suffice to fulfill this pillar. Failure of behavioral and pharmacologic therapies (third pillar) should be assessed taking into account refractoriness through objective and subjective measures supporting lack of efficacy of all interventions of proven efficacy, as well as true lack of tolerability, adherence, or access. Educational interventions and use of remote delivery formats (for behavioral therapies) play a role in preventing misjudgment of treatment failure. Stability of comorbid psychiatric disorders for 6 months (fourth pillar) is needed to confirm the predominant impact of tics on quality of life, to prevent pseudo-refractoriness, and to maximize the future DBS response. The 18-year age limit (fifth pillar) is currently under reappraisal, considering the potential impact of severe tics in adolescence and the predictive effect of tic severity in childhood on tic severity when transitioning into adulthood. Future advances should aim at a consensus-based definition of failure of specific, noninvasive treatment strategies for tics and of the minimum clinical observation period before considering DBS treatment, the stability of behavioral comorbidities, and the use of a prospective international registry data to identify predictors of positive response to DBS, especially in younger patients.
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http://dx.doi.org/10.1212/WNL.0000000000011704DOI Listing
April 2021

Non-Motor Fluctuations in Parkinson's Disease: Validation of the Non-Motor Fluctuation Assessment Questionnaire.

Mov Disord 2021 Feb 15. Epub 2021 Feb 15.

James J. and Joan A. Gardner Center for Parkinson's Disease and Movement Disorders Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA.

Background: In patients with Parkinson's disease (PD), sleep, mood, cognitive, autonomic, and other non-motor symptoms may fluctuate in a manner similar to motor symptoms.

Objectives: To validate a final version of a patient-rated questionnaire that captures the presence and severity of non-motor fluctuations in levodopa-treated PD patients (NoMoFA).

Methods: We recruited PD subjects from five movement disorders centers across the US and Canada. We assessed the internal consistency, floor and ceiling effects, test-retest reliability, and concurrent validity of NoMoFA. Classical test theory and item response theory methods informed item reduction and Delphi process yielded a final questionnaire.

Results: Two hundred subjects and their care-partners participated in the study (age: 66.4 ± 9.6 years; disease duration: 9 ± 5.5 years; median Hoehn and Yahr [H&Y] OFF: 3 [range 1-5]; mean Unified Parkinson's Disease Rating Scale (UPDRS) III ON score: 27.4 ± 14.9). Acceptability of the scale was adequate. There were floor effects in 8/28 items. Cronbach's alpha was 0.894. While eight items had "item-to-total" correlations below the cutoff of 0.4, removing these items did not improve Cronbach's alpha. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] 0.73; 95% confidence interval, 0.64-0.80). Concurrent validity was adequate with all Spearman's rho values comparing NoMoFA score to other measures of parkinsonian severity showing significance and in the expected direction. A final Delphi panel eliminated one item to avoid redundancy.

Conclusions: The final 27-item self-administered NoMoFA is a valid and reliable questionnaire, capturing both static and fluctuating non-motor symptoms in PD. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28507DOI Listing
February 2021

Characterizing Advanced Parkinson's Disease: Romanian Subanalysis from the OBSERVE-PD Study.

Parkinsons Dis 2021 25;2021:6635618. Epub 2021 Jan 25.

Department of Neurology, University Emergency Hospital, "Carol Davila" University of Medicine and Pharmacy, Bucharest 020021, Romania.

OBSERVE-PD was a cross-sectional, multicountry, observational study conducted in 128 Movement Disorders Centers (MDCs) in 18 countries. Overall, the study enrolled 2615 patients. The aim was to determine the proportion of patients with advanced Parkinson's disease (APD) versus non-APD from MDCs and to uncover the clinical burden of APD, as well as a correlation between overall assessment of APD and several indicators of APD. The advanced stage of the disease and severity were assessed by investigators using their clinical judgement. Data were collected during a single visit between February 2015 and January 2016. Agreement on physician judgement of APD diagnosis and fulfillment of at least one previously established APD indicator was calculated. Motor and nonmotor symptoms (NMSs), activities of daily living, treatment complications, quality of life (QoL), conventional treatments, and device-aided therapy (DAT) eligibility were assessed. Here, country-specific results of 161 Romanian patients with PD are presented. In total, 59.0% of patients were diagnosed with APD and 78.8% met at least one APD indicator. There was only moderate agreement between clinical judgement of APD and overall fulfillment of APD indicators. All scores related to motor symptoms, NMSs, and treatment complications, as well as to QoL, showed a higher disease burden for patients with APD versus non-APD. Physicians considered 73.7% of patients with APD eligible for DAT. The majority of patients eligible for DAT (54.3%) did not receive such treatment. Our results highlight the importance of earlier recognition of APD, by combining clinical judgement with more standardized clinical tools, such as generally recognized APD criteria. However, timely diagnosis of APD alone is not enough to improve patient outcomes. Other critical factors include patient acceptance and access to appropriate treatment.
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http://dx.doi.org/10.1155/2021/6635618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850828PMC
January 2021

VPS16 and VPS41: The List of Genes Causing Early-Onset Dystonia Keeps Expanding.

Mov Disord 2021 03 26;36(3):609. Epub 2021 Jan 26.

Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/mds.28511DOI Listing
March 2021

Parkinson's Disease and the COVID-19 Pandemic.

J Parkinsons Dis 2021 ;11(2):431-444

Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital - UHN, Division of Neurology, University of Toronto, Toronto, Ontario, Canada.

Studies focusing on the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19), and Parkinson's disease (PD) have provided conflicting results. We review the literature to investigate: 1) Are PD patients at higher risk for contracting COVID-19 and are there specific contributing factors to that risk? 2) How does COVID-19 affect PD symptoms? 3) How does COVID-19 present in PD patients? 4) What are the outcomes in PD patients who contract COVID-19? 5) What is the impact of COVID-19 on PD care? 6) Does COVID-19 increase the risk of developing PD? A literature search was performed from 1979 to 2020 using the terms: 'Parkinson's disease' and 'parkinsonism' combined with: 'COVID-19'; 'SARS-CoV-2' and 'coronavirus'. It does not appear that PD is a specific risk factor for COVID-19. There is evidence for direct/indirect effects of SARS-CoV-2 on motor/non-motor symptoms of PD. Although many PD patients present with typical COVID-19 symptoms, some present atypically with isolated worsening of parkinsonian symptoms, requiring increased anti-PD therapy and having worse outcomes. Mortality data on PD patients with COVID-19 is inconclusive (ranging from 5.2%to 100%). Patients with advanced PD appear to be particularly vulnerable. Single cases of acute hypokinetic-rigid syndrome have been described but no other convincing data has been reported. The rapidity with which COVID-19 has swept across the globe has favored the proliferation of studies which lack scientific rigor and the PD literature has not been immune. A coordinated effort is required to assimilate data and answer these questions in larger PD cohorts.
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http://dx.doi.org/10.3233/JPD-202320DOI Listing
May 2021

Reply to: Standardized 25-Hydroxyvitamin D Measurements in Parkinson's Disease Patients With COVID-19.

Mov Disord 2020 09;35(9):1498

Fondazione Grigioni per il Morbo di Parkinson, Milano, Italy.

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September 2020

Mapping efficacious deep brain stimulation for pediatric dystonia.

J Neurosurg Pediatr 2021 Jan 1:1-11. Epub 2021 Jan 1.

4Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Division of Neurology, University of Toronto.

Objective: The objective of this study was to report the authors' experience with deep brain stimulation (DBS) of the internal globus pallidus (GPi) as a treatment for pediatric dystonia, and to elucidate substrates underlying clinical outcome using state-of-the-art neuroimaging techniques.

Methods: A retrospective analysis was conducted in 11 pediatric patients (6 girls and 5 boys, mean age 12 ± 4 years) with medically refractory dystonia who underwent GPi-DBS implantation between June 2009 and September 2017. Using pre- and postoperative MRI, volumes of tissue activated were modeled and weighted by clinical outcome to identify brain regions associated with clinical outcome. Functional and structural networks associated with clinical benefits were also determined using large-scale normative data sets.

Results: A total of 21 implanted leads were analyzed in 11 patients. The average follow-up duration was 19 ± 20 months (median 5 months). Using a 7-point clinical rating scale, 10 patients showed response to treatment, as defined by scores < 3. The mean improvement in the Burke-Fahn-Marsden Dystonia Rating Scale motor score was 40% ± 23%. The probabilistic map of efficacy showed that the voxel cluster most associated with clinical improvement was located at the posterior aspect of the GPi, comparatively posterior and superior to the coordinates of the classic GPi target. Strong functional and structural connectivity was evident between the probabilistic map and areas such as the precentral and postcentral gyri, parietooccipital cortex, and brainstem.

Conclusions: This study reported on a series of pediatric patients with dystonia in whom GPi-DBS resulted in variable clinical benefit and described a clinically favorable stimulation site for this cohort, as well as its structural and functional connectivity. This information could be valuable for improving surgical planning, simplifying programming, and further informing disease pathophysiology.
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http://dx.doi.org/10.3171/2020.7.PEDS20322DOI Listing
January 2021