Levodopa‐induced dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa‐to‐dopamine conversion in ...serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine‐releasing axons. Delay in initiating levodopa is no longer recommended, as dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in‐development treatments for peak‐dose dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. Ann Neurol 2018;84:797–811
Idiopathic normal pressure hydrocephalus (NPH) remains both oversuspected on clinical grounds and underconfirmed when based on immediate and sustained response to cerebrospinal fluid diversion. Poor ...long‐term postshunt benefits and findings of neurodegenerative pathology in most patients with adequate follow‐up suggest that hydrocephalic disorders appearing in late adulthood may often result from initially unapparent parenchymal abnormalities. We critically review the NPH literature, highlighting the near universal lack of blinding and controls, absence of specific clinical, imaging, or pathological features, and ongoing dependence for diagnostic confirmation on variable cutoffs of gait response to bedside fluid‐drainage testing. We also summarize our long‐term institutional experience, in which postshunt benefits in patients with initial diagnosis of idiopathic NPH persist in only 32% of patients at 36 months, with known revised diagnosis in over 25% (Alzheimer's disease, dementia with Lewy bodies, and progressive supranuclear palsy). We postulate that previously reported NPH cases with “dual” pathology (ie, developing a “second” disorder) more likely represent ventriculomegalic presentations of selected neurodegenerative disorders in which benefits from shunting may be short‐lived, with a consequently unfavorable risk‐benefit ratio. Ann Neurol 2017;82:503–513
Gene therapy is a rapidly evolving technology that has predominantly utilized viral vectors to effectively deliver genetic material inside neurons to modulate the expression of one or more particular ...genes. Several gene therapy clinical trials have been conducted in Parkinson's disease (PD) by exploring strategies to either restore dopamine synthesis, enhance the production of trophic factors, enhance lysosomal function, or modify the interaction between different functional nodes of the basal ganglia.
In this review, the authors sought to discuss contemporary practice, emerging concepts, and unmet needs for the future of gene therapy in PD.
While safety has been demonstrated, clinical trials on gene therapy for PD highlight the need for higher than anticipated volumes of infusion in order to optimize dose and vector coverage. Neurosurgical delivery techniques for gene therapy have rapidly evolved from the use of multiple trans-frontal trajectories to a single parietooccipital shape-conforming infusion. The employment of convection-enhanced delivery with reflux-resistant cannulas has further improved the vector diffusion into the target structures. Future technological developments will reduce the invasiveness and duration of surgery, improve specificity and transduction capacity with novel capsid designs, and implement strategies to control transgene expression.
Essential pitfalls in “essential” tremor Espay, Alberto J.; Lang, Anthony E.; Erro, Roberto ...
Movement disorders,
March 2017, Letnik:
32, Številka:
3
Journal Article
Background
Postural instability is a disease milestone signaling advanced disease.
Objectives
To estimate the onset of postural instability in monogenic parkinsonisms.
Methods
We systematically ...reviewed studies (PubMed 1996–2017) in
SNCA
,
PRKN
,
PINK1
,
DJ-1
,
LRRK2
,
ATP13A2
,
FBXO7
,
VPS35
,
DNAJC6
, or
SYNJ1
-related monogenic parkinsonisms, with documented postural instability. Genes with ≥ 15 patients were included in an individual-patient meta-analysis and compared with a retrospectively collected sporadic Parkinson’s disease cohort from our center. The primary outcome measure was the progression-free survival from postural instability using Kaplan–Meier survival curves. Cox proportional hazards analyses were summarized using hazards ratio (HR).
Results
Of 2085 eligible studies, 124 met full criteria (636 patients) for the systematic review, whereas a total of 871 subjects (270 from sporadic cohort, 601 monogenic parkinsonisms) were included in the individual-patient meta-analysis. Postural instability was reported in 80% of
DJ-1
, 40% of
PRKN
, 39% of
PINK1
, 34% of
ATP13A2
, 31% of
LRRK2
, and 29% of
SNCA
patients. Progression-free survival from postural instability at 10 years after disease onset was longest in
ATP13A2
(97%) and shortest in
SNCA
(50%). Halfway between these two extremes were
PRKN
(88%),
PINK1
(87%), and
LRRK2
(81%), similar to sporadic Parkinson’s disease (72%). Higher risk of postural instability was observed in
SNCA
(HR = 3.2,
p
= 0.007) and
DJ-1
(HR = 3.96,
p
= 0.001) compared to sporadic Parkinson’s disease. Young age at onset in
PINK1
and female sex in
LRRK2
were associated with a decreased risk of postural instability.
Conclusions
Monogenic parkinsonisms exhibit differential timelines to postural instability, informing prognostic counseling and interpretation of future genotype-specific treatment trials.
Introduction
While subthalamic nucleus deep brain stimulation (STN-DBS) and levodopa improve motor symptoms in Parkinson disease (PD) to a similar magnitude, their combined effect remains unclear. We ...sought to evaluate whether STN-DBS and levodopa yield differential effects on motor outcomes, dyskinesia, and activities of daily living (ADL) when combined compared to when administered alone.
Methods
We conducted a meta-analysis of all studies reporting motor, dyskinesia, and ADL outcomes after bilateral STN-DBS in PD with presurgical Unified Parkinson’s Disease Rating Scale (UPDRS-III) in Medication-OFF and Medication-ON states and postsurgical assessments in four conditions: Stimulation-ON/Medication-ON, Stimulation-ON/Medication-OFF, Stimulation-OFF/Medication-ON, and Stimulation-OFF/Medication-OFF. Dyskinesia duration (UPDRS item 32) and ADL (UPDRS-II) were compared between high and low postsurgical levodopa equivalent daily dose (LEDD) reduction. Random-effects meta-analyses using generic-inverse variance were conducted. Confidence in outcomes effect sizes was assessed.
Results
Twelve studies were included (
n
= 401 patients). Stimulation-ON/Medication-ON was associated with an UPDRS-III improvement of − 35.7 points 95% confidence interval, − 40.4, − 31.0 compared with Stimulation-OFF/Medication-OFF, − 11.2 points − 14.0, − 8.4 compared with Stimulation-OFF/Medication-ON, and − 9.5 points − 11.0, − 8.0 compared to Stimulation-ON/Medication-OFF within 5 years. The difference was maintained beyond 5 years by − 28.6 − 32.8, − 24.4, − 8.1 − 10.2, − 5.9, and − 8.0 − 10.3, − 5.6, respectively. No difference was observed between Stimulation-ON/Medication-OFF and Stimulation-OFF/Medication-ON within and beyond 5 years. Dyskinesia duration and ADL outcomes were similar in high vs. low postsurgical LEDD reduction.
Conclusion
Subthalamic nucleus deep brain stimulation and levodopa independently lessened motor severity in PD to a similar magnitude, but their combined effect was greater than either treatment alone, suggesting therapeutic synergism.
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