Purpose of review
Deep brain stimulation (DBS) is currently the most effective treatment for medically refractory dystonia with globus pallidus internus (GPi) usually the preferred target. Despite ...the overall success of DBS in dystonia, there remains variability in treatment outcome in both short and long-term follow-up, due to various factors. Factors contributing to variability in outcome comprise ’Dystonia Related’ including dystonia classification, semiology, duration, body distribution, orthopaedic deformity, aetiology and genetic cause. The majority of these factors are identifiable from clinical assessment, brain MRI and genetic testing, and therefore merit careful preoperative consideration. ’DBS related’ factors include brain target, accuracy of lead placement, stimulation parameters, time allowed for response, neurostimulation technology employed and DBS induced side-effects. In this review, factors contributing to variability in short and long-term dystonia DBS outcome are reviewed and discussed.
Recent findings
The recognition of differential DBS benefit in monogenic dystonia, increasing experience with subthalamic nucleus (STN) DBS and in DBS for Meige syndrome, elucidation of DBS side effects and novel neurophysiological and imaging techniques to assist in predicting clinical outcome.
Summary
Improved understanding of factors contributing to variability of DBS outcome in dystonia may assist in patient selection and predicting surgical outcomes.
Globus pallidus internus deep brain stimulation (GPi DBS) is the most effective intervention for medically refractory segmental and generalized dystonia in both children and adults. Predictive ...factors for the degree of improvement after GPi DBS include shorter disease duration and dystonia subtype with idiopathic isolated dystonia usually responding better than acquired combined dystonias. Other factors contributing to variability in outcome may include body distribution, pattern of dystonia and DBS related factors such as lead placement and stimulation parameters. The responsiveness to DBS appears to vary between different monogenic forms of dystonia, with some improving more than others. The first observation in this regard was reports of superior DBS outcomes in DYT-TOR1A (DYT1) dystonia, although other studies have found no difference. Recently a subgroup with young onset DYT-TOR1A, more rapid progression and secondary worsening after effective GPi DBS, has been described. Myoclonus dystonia due to DYT-SCGE (DYT11) usually responds well to GPi DBS. Good outcomes following GPi DBS have also been documented in X-linked dystonia Parkinsonism (DYT3). In contrast, poorer, more variable DBS outcomes have been reported in DYT-THAP1 (DYT6) including a recent larger series. The outcome of GPi DBS in other monogenic isolated and combined dystonias including DYT-GNAL (DYT25), DYT-KMT2B (DYT28), DYT-ATP1A3 (DYT12), and DYT-ANO3 (DYT24) have been reported with varying results in smaller numbers of patients. In this article the available evidence for long term GPi DBS outcome between different genetic dystonias is reviewed to reappraise popular perceptions of expected outcomes and revisit whether genetic diagnosis may assist in predicting DBS outcome.
Within the field of movement disorders, the conceptual understanding of dystonia has continued to evolve. Clinical advances have included improvements in recognition of certain features of dystonia, ...such as tremor, and understanding of phenotypic spectrums in the genetic dystonias and dystonia terminology and classification. Progress has also been made in the understanding of underlying biological processes which characterize dystonia from discoveries using approaches such as neurophysiology, functional imaging, genetics, and animal models. Important advances include the role of the cerebellum in dystonia, the concept of dystonia as an aberrant brain network disorder, additional evidence supporting the concept of dystonia endophenotypes, and new insights into psychogenic dystonia. These discoveries have begun to shape treatment approaches as, in parallel, important new treatment modalities, including magnetic resonance imaging-guided focused ultrasound, have emerged and existing interventions such as deep brain stimulation have been further refined. In this review, these topics are explored and discussed.
Deep brain stimulation (DBS) of the thalamus is an effective treatment for medically refractory essential, dystonic and Parkinson's tremor. It may also provide benefit in less common tremor syndromes ...including, post-traumatic, cerebellar, Holmes, neuropathic and orthostatic tremor. The long-term benefit of DBS in essential and dystonic tremor (ET/DT) often wanes over time, a phenomena referred to as stimulation “tolerance” or “habituation”. While habituation is generally accepted to exist, it remains controversial. Attempts to quantify habituation have revealed conflicting reports. Placebo effects, loss of micro-lesional effect, disease related progression, suboptimal stimulation and stimulation related side-effects may all contribute to the loss of sustained long-term therapeutic effect. Habituation often presents as substantial loss of initial DBS benefit occurring as early as a few months after initial stimulation; a complex and feared issue when faced in the setting of optimal electrode placement. Simply increasing stimulation current tends only to propagate tremor severity and induce stimulation related side effects. The report by Paschen and colleagues of worsening tremor scores in the “On” vs. “Off” stimulation state over time, even after accounting for “rebound” tremor, supports the concept of habituation. However, these findings have not been consistent across all studies. Chronic high intensity stimulation has been hypothesized to induce detrimental plastic effects on tremor networks, with some lines of evidence that DT and ET may be more susceptible than Parkinson's tremor to habituation. However, Tsuboi and colleague's recent longitudinal follow-up in dystonic and “pure” essential tremor suggests otherwise. Alternatively, post-mortem findings support a biological adaption to stimulation. The prevalence and etiology of habituation is still not fully understood and management remains difficult. A recent study reported that alternating thalamic stimulation parameters at weekly intervals provided improved stability of tremor control consistent with reduced habituation. In this article the available evidence for habituation after DBS for tremor syndromes is reviewed; including its prevalence, time-course, possible mechanisms; along with expected long-term outcomes for tremor and factors that may assist in predicting, preventing and managing habituation.
To describe novel neurological manifestations associated with glutamic acid decarboxylase (GAD65) autoimmunity.
This retrospective study (1987-2003) describes 62 patients incidentally found to have a ...serum autoantibody that bound selectively to synapse-rich central nervous system tissues. The immunostaining pattern was determined to be GAD65-specific by radioimmunoprecipitation assay. These cases were identified among samples submitted for paraneoplastic autoantibody evaluation using indirect immunofluorescence. In no case had GAD65 or any other islet cell antibody testing been requested.
In most cases, the patients' presentations were initially considered neurodegenerative or inflammatory (multiple sclerosis or paraneoplastic). Median age at onset was 50 years, and 77% were women. Of the 44 patients seen at the Mayo Clinic, 23% were African American; in contrast, less than 10% of Mayo Clinic's neurology patients are African American. Median follow-up was 24 months. The radioimmunoprecipitation assay values for GAD65 antibody were extremely high (median, 1429 nmol/L; interquartile range, 643-3078 nmol/L) and correlated significantly with immunofluorescence titers (median, 3840; interquartile range, 1920-15,360;
r=0.81;
P<.001). Neurological manifestations were multifocal in 41 patients and included cerebellar ataxia (63%), brainstem involvement (29%), seizures (27%), stiff-man phenomena (26%), extrapyramidal signs (16%), and myelopathy (8%). One third of the patients had type 1 diabetes mellitus, 53% had thyroid autoantibodies, and 16% had vitiligo. Eleven of 20 patients identified as African American had brainstem involvement. Some patients appeared to benefit from short-term immunosuppression (none received long-term therapy).
The neurological spectrum of GAD65 autoimmunity includes brainstem, extrapyramidal, and spinal cord syndromes. In our experience, African American patients were disproportionately affected. A patient with a presumed neurodegenerative disorder of new onset, with high levels of GAD65 antibody (>20 nmol/L), merits consideration of immunotherapy.
•GLP-1 receptor agonists are neuroprotective and disease-modifying in PD animal models.•This is true for both histological measures and motor outcomes.•There is sufficient evidence for the creation ...of more human clinical trials.
Parkinson’s Disease (PD) is a progressive neurodegenerative condition associated with significant morbidity. Currently, there are limited pharmacological options and none of the therapies available are disease-modifying. This systematic review and meta-analysis considers a novel drug class through the research question – in pre-clinical rodent models of PD, is GLP-1 receptor agonist therapy neuroprotective when compared to vehicle controls?
A literature search was conducted to locate relevant pre-clinical studies. Two separate outcomes were considered. The primary outcome was indicators of dopaminergic neurotransmission. The secondary outcome was indicators of motor symptoms. Untreated PD models were compared to PD-models treated with GLP-1 receptor agonists. The final meta-analysis was conducted using the Cochrane RevMan software and represented continuous data using the inverse variance statistical method and random effects analysis model. The final study statistic was represented as an SMD value with a p-value < 0.05 considered statistically significant. Study heterogeneity and publication bias was assessed using I2 values and funnel plots respectively.
Eleven studies fit the inclusion criteria and were included in the final analysis. For the primary outcome (n = 128), there was a statistically significant relative improvement of dopaminergic neurotransmission (SMD 1.71, 95% CI = 0.74–2.68, p = 0.0005, I2 = 76%). For the secondary outcome (n = 280), there was a statistically significant improvement in motor outcomes (SMD 2.11, 95% CI = 1.14–3.09, p < 0.0001, I2 = 89%).
GLP-1 receptor agonist therapy is neuroprotective in pre-clinical models of PD. This study provides the clinical foundation and research support for the design of rigorous clinical trials to further investigate these results in human PD populations.
The role of changes in inter-regional cortical synchronization in the pathophysiology of Parkinson's disease and the mechanism of action of dopaminergic therapy and high frequency subthalamic nucleus ...(STN) stimulation is unclear. We hypothesized that synchronization between distributed cortical areas would correlate with parkinsonism and that changes in synchronization with treatment would correlate with improvements in parkinsonism. To this end, we recorded scalp EEG in parkinsonian patients off treatment (16 patients, 31 sides) and then separately during high frequency stimulation (HFS) of the STN (16 patients, 31 sides) and following drug treatment (12 patients, 24 sides). All recordings were made at rest to avoid the confounding effects of differences in task performance. The motor Unified Parkinson's Disease Rating Scale (UPDRS) score was determined in each state. We found that EEG–EEG coherence over ∼10–35 Hz correlated with the severity of parkinsonism, and reductions in cortical coupling over this frequency range with both l-dopa and STN stimulation correlated with clinical improvement. These results suggest that both dopaminergic therapy and STN stimulation may support the restoration of normal cortico-cortical interactions in the frequency domain. This mechanistic similarity may underscore the strong clinical correlation between the therapeutic effects of these treatment modalities.
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