Alpha-Synuclein RT-QuIC in Idiopathic Normal Pressure Hydrocephalus.

This study quantified the occurrence of an underlying synucleinopathy in 50 patients with idiopathic normal pressure hydrocephalus by means of real-time quaking-induced conversion, a highly sensitive and specific technique capable of detecting and amplifying misfolded aggregated forms of α-synuclein in the cerebrospinal fluid. Seven patients were positive and they did not differ from negative cases, except for a more frequent L-dopa responsiveness and gait characterized by a wider base. The two groups did not differ in terms of response rate to tap test or shunt surgery, although step length and gait velocity improved by a lesser extent in positive cases. ANN NEUROL 2022;92:985-991.

Probabilistic Mapping of Deep Brain Stimulation: Insights from 15 Years of Therapy.

Deep brain stimulation (DBS) depends on precise delivery of electrical current to target tissues. However, the specific brain structures responsible for best outcome are still debated. We applied probabilistic stimulation mapping to a retrospective, multidisorder DBS dataset assembled over 15 years at our institution (ntotal = 482 patients; nParkinson disease = 303; ndystonia = 64; ntremor = 39; ntreatment-resistant depression/anorexia nervosa = 76) to identify the neuroanatomical substrates of optimal clinical response. Using high-resolution structural magnetic resonance imaging and activation volume modeling, probabilistic stimulation maps (PSMs) that delineated areas of above-mean and below-mean response for each patient cohort were generated and defined in terms of their relationships with surrounding anatomical structures. Our results show that overlap between PSMs and individual patients' activation volumes can serve as a guide to predict clinical outcomes, but that this is not the sole determinant of response. In the future, individualized models that incorporate advancements in mapping techniques with patient-specific clinical variables will likely contribute to the optimization of DBS target selection and improved outcomes for patients. ANN NEUROL 2021;89:426-443.

Ipsilateral and axial tremor response to focused ultrasound thalamotomy for essential tremor: clinical outcomes and probabilistic mapping.

BACKGROUND: MR-guided focused ultrasound (MRgFUS) thalamotomy has been shown to be a safe and effective treatment for essential tremor (ET). OBJECTIVE: To investigate the effects of MRgFUS in patients with ET with an emphasis on ipsilateral-hand and axial tremor subscores. METHODS: Tremor scores and adverse effects of 100 patients treated between 2012 and 2018 were assessed at 1 week, 3, 12, and 24 months. A subgroup analysis of ipsilateral-hand tremor responders (defined as patients with ≥30% improvement at any time point) and non-responders was performed. Correlations and predictive factors for improvement were analysed. Weighted probabilistic maps of improvement were generated. RESULTS: Significant improvement in axial, contralateral-hand and total tremor scores was observed at all study visits from baseline (p<0.0001). There was no significant improvement in ipsilateral subscores. A subset of patients (n=20) exhibited group-level ipsilateral-hand improvement that remained significant through all follow-ups (p<0.001). Multivariate regression analysis revealed that higher baseline scores predict better improvement in ipsilateral-hand and axial tremor. Probabilistic maps demonstrated that the lesion hotspot for axial improvement was situated more medially than that for contralateral improvement. CONCLUSION: MRgFUS significantly improved axial, contralateral-hand and total tremor scores. In a subset of patients, a consistent group-level treatment effect was observed for ipsilateral-hand tremor. While ipsilateral improvement seemed to be less directly related to lesion location, a spatial relationship between lesion location and axial and contralateral improvement was observed that proved consistent with the somatotopic organisation of the ventral intermediate nucleus. TRIAL REGISTRATION NUMBERS: NCT01932463, NCT01827904, and NCT02252380.

A Distinct EEG Marker of Celiac Disease-Related Cortical Myoclonus.

BACKGROUND: Celiac disease is associated with motor cortex hyperexcitability and neurological manifestations including cortical myoclonus. Electroencephalography abnormalities have been described, but no distinct pattern has been reported. METHODS: We describe the neurophysiological characteristics of 3 patients with celiac-associated cortical myoclonus using electroencephalography, magnetoencephalography, and transcranial magnetic stimulation. RESULTS: Electroencephalography in all cases demonstrated lateralized low-amplitude, electropositive beta-frequency polyspike activity over the central head region, corresponding to motor cortex contralateral to the myoclonic limb. Jerk-locked back-averaging demonstrated a preceding cortical potential; magnetoencephalography source localization revealed a cortical generator in the posterior wall of the precentral gyrus for the back-averaged potential and oscillatory abnormality. In 1 patient, cerebellar inhibition of the motor cortex was physiologically normal. CONCLUSIONS: Central head oscillatory, low-amplitude, electropositive electroencephalography polyspike activity may be a distinct marker of celiac-related cortical myoclonus and is consistent with celiac-related motor cortex hyperexcitability, which may not necessarily result from cerebellar disinhibition. © 2020 International Parkinson and Movement Disorder Society.

Modulation of inhibitory plasticity in basal ganglia output nuclei of patients with Parkinson's disease.

Deep brain stimulation of certain target structures within the basal ganglia is an effective therapy for the management of the motor symptoms of Parkinson's disease. However, its mechanisms, as well as the pathophysiology of Parkinson's disease, are varied and complex. The classical model of Parkinson's disease states that symptoms may arise as a result of increased neuronal activity in the basal ganglia output nuclei due to downregulated GABAergic striato-nigral/-pallidal projections. We sought to investigate the stimulation and levodopa induced effects on inhibitory synaptic plasticity in these basal ganglia output nuclei, and to determine the clinical relevance of altered plasticity with respect to patients' symptoms. Two closely spaced microelectrodes were advanced into the substantia nigra pars reticulata (potential novel therapeutic target for axial motor symptoms) or globus pallidus internus (conventional therapeutic target) in each of 28 Parkinson's disease patients undergoing subthalamic or pallidal deep brain stimulation surgery. Sets of 1 Hz test-pulses were delivered at different cathodal pulse widths (25, 50, 100, 150, 250 µs) in randomized order, before and after a train of continuous high frequency stimulation at 100 Hz. Increasing the pulse width led to progressive increases in both the amplitudes of extracellular focally evoked inhibitory field potentials and durations of neuronal silent periods. Both of these effects were augmented after a train of continuous high frequency stimulation. Additionally, reductions in the baseline neuronal firing rate persisted beyond 1 min after high frequency stimulation. We found greater enhancements of plasticity in the globus pallidus internus compared to the substantia nigra pars reticulata, and that intraoperative levodopa administration had a potent effect on the enhancement of nigral plasticity. We also found that lower levels of nigral plasticity were associated with higher severity motor symptoms. The findings of this study demonstrate that the efficacy of inhibitory synaptic transmission may be involved in the pathophysiology of Parkinson's disease, and furthermore may have implications for the development of novel stimulation protocols, and advancement of DBS technologies.

Are smartphones and machine learning enough to diagnose tremor?

BACKGROUND: Patients with essential tremor (ET), Parkinson's disease (PD) and dystonic tremor (DT) can be difficult to classify and often share similar characteristics. OBJECTIVES: To use ubiquitous smartphone accelerometers with and without clinical features to automate tremor classification using supervised machine learning, and to use unsupervised learning to evaluate if natural clusterings of patients correspond to assigned clinical diagnoses. METHODS: A supervised machine learning classifier was trained to classify 78 tremor patients using leave-one-out cross-validation to estimate performance on unseen accelerometer data. An independent cohort of 27 patients were also studied. Next, we focused on a subset of 48 patients with both smartphone-based tremor measurements and detailed clinical assessment metrics and compared two separate machine learning classifiers trained on these data. RESULTS: The classifier yielded a total accuracy of 74.4% and F1-score of 0.74 for a trinary classification with an area under the curve of 0.904, average F1-score of 0.94, specificity of 97% and sensitivity of 84% in classifying PD from ET or DT. The algorithm classified ET from non-ET with 88% accuracy, but only classified DT from non-DT with 29% accuracy. A poorer performance was found in the independent cohort. Classifiers trained on accelerometer and clinical data respectively obtained similar results. CONCLUSIONS: Machine learning classifiers achieved a high accuracy of PD, however moderate accuracy of ET, and poor accuracy of DT classification. This underscores the difficulty of using AI to classify some tremors due to lack of specificity in clinical and neuropathological features, reinforcing that they may represent overlapping syndromes.

Mapping efficacious deep brain stimulation for pediatric dystonia.

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.

Flexible vs. standard subthalamic stimulation in Parkinson disease: A double-blind proof-of-concept cross-over trial.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamus (STN) is effective for the treatment of cardinal motor signs of Parkinson disease (PD). Structures around the STN can suppress dyskinesia and tremor (zona incerta) and improve gait and balance (substantia nigra pars reticulata). OBJECTIVE: Is the newer 8-contact linear lead connected to a 'flexible' DBS system superior to standard 4-contact stimulation in PD patients receiving STN DBS? METHODS: After 3 months of open label programming, 10 patients were randomized to standard or flexible stimulation before crossing over to the other arm (3 months each period). Patients and assessors were blinded. RESULTS: A trend to improvement in Patient Global Impression of Change scores was seen with standard to flexible stimulation and worsening from flexible to standard stimulation (mean ± SD: 0.7 ± 1.2 and -0.4 ± 1.5 respectively, p = 0.152). There was a significant reduction in the number of troublesome symptoms reported prior to DBS (2.6 ± 3.3 per patient), more so with flexible stimulation (0.4 ± 0.6 vs. 1.5 ± 1.6 with standard stimulation, p = 0.001 and p = 0.034). There was no significant difference between the flexible and standard stimulation groups. CONCLUSION: Further studies confirming that flexible stimulation is superior to standard DBS are warranted.

Association Between Cerebrospinal Fluid Biomarkers and Age-related Brain Changes in Patients with Normal Pressure Hydrocephalus.

Our study aimed to: 1)investigate the diagnostic utility of CSF Aß42, t-tau, and p-tau to differentiate normal-pressure-hydrocephalus(NPH) from Alzheimer's-disease(AD) and normal-controls; and 2)investigate if age and ventricular size affect the levels of CSF biomarkers in NPH patients. We recruited 131 participants: (a)Suspected-NPH: 72 with ventriculomegaly and clinical symptoms of NPH. These participants were then divided into two groups of 1)Probable-NPH (N = 38) and 2)Unlikely-NPH (N = 34) based on whether participants experienced gait improvement after removal of a large amount of CSF; (b)AD group: 30 participants with CSF biomarkers and cognitive symptoms consistent with AD; (c)Control-group: 29 participants who were cognitively and functionally normal. Lower levels of CSF Aß42 and p-tau were observed in the probable-NPH compared to the normal controls(444.22 ± 163.3 vs. 1213.75 ± 556.5; and 26.05 ± 9.2 vs. 46.16 ± 13.3 pg/mL; respectively). Lower levels of CSF p-tau and t-tau were found in the probable-NPH compared to the AD(26.05 ± 9.2 vs. 114.95 ± 28.2; and 193.29 ± 92.3 vs. 822.65 ± 311.5 pg/mL; respectively) but the CSF-Aß42 was low in both the probable-NPH and AD. CSF-Aß42 correlated with age and Evans-index only in the probable-NPH(r = 0.460, p = 0.004; and r = -0.530, p = 0.001; respectively). Our study supports the hypothesis that age-related atrophy results in better Aß42 clearance in the CSF because of the increase in the interstitial space.

Unusual gait disorders: a phenomenological approach and classification.

INTRODUCTION: Gait impairment is a very common problem in clinical practice. Multiple classifications of gait disorders are available based on anatomy, etiology, pathology and phenomenology. These classifications provide a diagnostic guide but do not clearly explain the pathophysiology of some gait disorders, which can sometimes hinder the diagnostic process. In this context, unusual gait disorders become an even more difficult clinical challenge. Areas covered: The scientific and non-scientific literature contains illustrative descriptions of unusual gait disorders based on their predominant signs and/or comparisons with normal and abnormal zoological and folkloric patterns. Unusual gait disorder phenomenology can be carefully deconstructed in order to achieve an integral approach. We present a pragmatic, phenomenological approach to various unusual gait disorders and highlight key features underlying their phenotypes. We also propose unifying terminology to facilitate diagnosis and academic communication. Expert commentary: Advanced gait analysis, neurophysiological and neuroimaging techniques have allowed for us to recognize that locomotion is a complex motor behavior that requires simultaneous integration of multiple neurological and non-neurological systems. A phenomenological approach such as the one proposed in this review could be useful while those objective techniques become more widely available in clinical practice.

Dystonia as complication of thalamic neurosurgery.

BACKGROUND: Thalamotomy and deep brain stimulation of the ventralis intermedius nucleus are effective symptomatic treatments for tremor, irrespective of the underlying diagnosis. METHODS AND RESULTS: Herein we describe six tremor patients (2 Parkinson's disease, 1 dystonic tremor, 2 Essential tremor plus dystonia, 1 Essential tremor plus ataxia) who underwent thalamic neurosurgery and acutely or sub-acutely developed dystonia that was permanent in three cases and could not be managed with any adjustments in the stimulation settings. Tremor response was excellent. We argue that thalamic procedures disrupted either or both the cerebello-thalamic and the cortico-striato-pallido-thalamo-cortical loop resulting in an increase of the thalamo-cortical outflow and subsequent change in the clinical picture from tremor to dystonia. CONCLUSION: Thalamic neurosurgery might be rarely complicated by dystonia. Why some patients are more prone to develop this adverse event is still unknown and possibly related to intrinsic factors, which certainly need further studies.

Beyond dystonia and ataxia: Expanding the phenotype of SQSTM1 mutations.

BACKGROUND: Homozygous sequestomosome-1 gene mutations have been recently linked to neurodegeneration with dystonia, ataxia and gaze palsy. Seven affected families were identified thus far. OBJECTIVE: To describe four new cases with additional phenotypical features. RESULTS: Four affected patients from two unrelated families were identified. Two compound heterozygous variants of the gene (c.257_259delins35 and c.301+1G > T) were found in one family (cases 1 and 2), and homozygous c.823_824delAG variant was identified in cases 3 and 4. In addition to the previously described syndrome characterized by cerebellar ataxia, dystonia, choreoathetosis, cognitive impairment and gaze palsy, two subjects presented with iridoplegia. Furthermore, we report dysautonomic features such as orthostatic hypotension and sudomotor dysfunction, along with other non-motor symptoms. CONCLUSIONS: We expand the phenotype of dystonia caused by Sequestomosome-1 gene by identifying dysautonomic features along with other non-motor symptoms.

The overlap between Essential tremor and Parkinson disease.

INTRODUCTION: Essential tremor (ET) and Parkinson's disease (PD) are common disorders especially in the aging population and can have overlapping features that can make it difficult to differentiate between the two. In addition, a possible overlap from a pathophysiological standpoint has been often advocated in the past. METHODS: In this review article, we gather the recent evidence in favor or against a possible relationship between ET and PD. This exercise follows the new advances in the field of tremor from both a pathophysiological and nosological perspective. RESULTS: Dividing ET patients into early onset and late onset disease subtypes can prove useful in ascertaining the phenotypic, epidemiological and genetic characteristics defining its relationships to PD. The only way to ascertain whether ET increases the risk of future PD would be to conduct a longitudinal cohort study on early-onset ET patients. On the other hand, ET-plus patients or late-onset cases with ET of short-duration might represent a group of PD patients in their pre-diagnostic phase after the pre-motor stage. CONCLUSION: In spite of the growing body of literature in recent years of an overlap between ET and PD, we are far from elucidating the relationship (if any) between these two common disorders.

Optic nerve sheath meningocele.

Optic nerve sheath meningocele, also called dural ectasia of the optic nerve, is a benign dilation of the optic nerve sheath. We report two interesting cases of primary optic nerve sheath meningocele. Etiology, clinical features, and management options are discussed.

The role of biomarkers and imaging in Parkinson's disease.

The diagnosis of Parkinson's disease (PD) currently relies on the appearance of certain clinical features. However, these features appear only years after the loss of nigral dopaminergic neurons. The progression of PD may be measured using clinical rating scales that are subjective and that have a variable inter-rater consistency. There is a growing need for a biomarker that will allow for early detection of the disease as well as provide a measure of disease progression. In this article, we review different biomarkers, with a focus on functional imaging techniques, which while imperfect, currently provide the best approach to this problem. We also discuss the use of structural imaging and emerging progress in other biochemical and molecular markers. While there is no single biomarker that will satisfy all requirements, a combination is likely to be of great use in identifying those subjects most likely to benefit from neuroprotective therapies, as well as in monitoring the effects of any interventions.