Electroencephalography in Orthostatic Tremor: A Prospective Study of 30 Patients.

Background: Orthostatic tremor (OT) is characterized by a sensation of instability while standing, associated with high frequency (1318 Hz) tremor in the legs. Small retrospective series have reported electroencephalography (EEG) findings in OT with discordant results. Methods: We prospectively enrolled 30 OT subjects. Mean age = 68.3 (range 5487) with mean disease duration 16.3 years (range 444). A modified 1020 system EEG recording with additional midline electrodes was obtained. EMG electrodes were placed on quadricep muscles. EEG recording was performed at rest, during sleep and while standing unassisted. Results: In all subjects, EEG showed normal background, normal drowsiness and/or stage 2 sleep, and normal responses to hyperventilation and photic stimulation. These normal results persisted during stance. EEG abnormalities were found in 3 subjects (anterior-mid temporal slow activity), but were not position-dependent and were judged unlikely to be related to OT. Tremor artifact while standing was noted in all subjects, however it was measurable in 26 with frequency in the OT range in 25. When compared with EMG, the average difference in frequency was small at 1.2 Hz (range 0.52.5, p 0.46). Visual EEG analysis in OT patients did not reveal electrographic abnormalities even upon standing unassisted. Discussion: EEG was normal on this prospective, relatively large OT series. Clinicians interpreting video-EEGs should be aware of the OT artifact that can be seen in EEG and EKG leads mostly while standing.

Ataxia Prevalence in Primary Orthostatic Tremor.

Background: The exact pathophysiology of primary Orthostatic Tremor (OT) is unknown. A central oscillator is assumed, and previous imaging studies show involvement of cerebellar pathways. However, the presence of ataxia on clinical exam is disputed. We set out to study ataxia in OT prospectively. Methods: EMG-confirmed primary OT subjects and spousal controls received a neurological exam with additional semiquantitative evaluations of ataxia as part of a multinational, prospective study. These included detailed limb coordination (DLC), detailed stance and gait evaluation (DS), and the Brief Ataxia Rating Scale (BARS). Intra- and inter-rater reliability were assessed and satisfactory. Results: 34 OT subjects (mean age = 67 years, 88% female) and 21 controls (mean age = 66 years, 65% male) were enrolled. Average disease duration was 18 years (range 4-44). BARS items were abnormal in 88% of OT patients. The OT subjects were more likely to have appendicular and truncal ataxia with significant differences in DLC, DS and BARS. Ocular ataxia and dysarthria were not statistically different between the groups. Discussion: Mild-to-moderate ataxia could be more common in OT than previously thought. This is supportive of cerebellar involvement in the pathophysiology of OT. We discuss possible implications for clinical care and future research. Highlights: Previous studies of Primary Orthostatic Tremor (OT) have proposed pathophysiologic involvement of the cerebellar pathways.However, presence of ataxia has not been systematically studied in OT.This is a prospective comprehensive ataxia assessment in OT compared to controls. Mild-to-moderate appendiculo-truncal ataxia was found to be common in OT.

Fractal auditory stimulation has greater benefit for people with Parkinson's disease showing more random gait pattern.

BACKGROUND: Healthy gait dynamics are characterized by the presence of fractal, persistent stride-to-stride variations, which become more random with Parkinson's disease (PD). Rhythmic auditory stimulation with fractal beat-to-beat variations can change gait dynamics in people with PD toward more persistence. RESEARCH QUESTION: How does gait in people with PD change when synchronizing steps with fractal melodic metronomes with different step-to-beat ratios, and which stimulus do they prefer? METHODS: In this cross-sectional study, 15 people with PD and 15 healthy older adults walked over-ground in three conditions: self-paced, paced by a fractal auditory stimulus with a 1:1 step-to-beat ratio ('metronome'), and fractal auditory stimulus with a 1:2 step-to-beat ratio ('music'). Gait dynamics were recorded with instrumented insoles, and detrended fluctuation analysis (DFA) was applied to the series of stride time intervals. Stimuli preference was assessed using Likert-like scales and open-ended questions. ANOVAs were used to compare mean, coefficient of variation, α-DFA, and the responses from the continuous Likert scales. Pearson correlations were used to assess the relationship between 'music' and 'metronome' enjoyment or difficulty with gait outcomes, and to determine the association between baseline α-DFA and changes due to the stimuli. RESULTS: Our major findings are that (i) stride-to-stride variations were more persistent with the 'metronome' compared to baseline for both groups, (ii) the effect was greater for people with lower α-DFA at baseline (i.e., more random stride-to-stride variations), and (iii) both groups found the 'metronome' less difficult to synchronize with. SIGNIFICANCE: This study showed that people with PD and healthy older adults walk with higher statistical persistence in their stride-to-stride variations when instructed to synchronize their steps with a fractal stimulus. Participants with lower persistence at baseline benefited the most from the fractal 'metronome', highlighting the importance to develop patient-centered tests and interventions.

Attending to Total Pain in Juvenile Huntington Disease: A Case Report Informed by Narrative Review of the Literature.

OBJECTIVES: To consider the impact of juvenile Huntington disease (JHD) from a biomedical, symptom burden, and total pain palliative care perspective. METHODS: This case report was informed by a narrative review of the literature with inclusion of expert opinion from pediatric palliative care, an adult and pediatric neurologist, and a child psychiatrist. Audio-recorded qualitative interview and coauthorship with the pediatric patient's primary caregiver (his mother). RESULTS: The JHD impacts all domains of child and family function. SIGNIFICANCE OF RESULTS: Application of the concept of total pain to JHD informs and guides care for this complex, challenging condition.

Gait Dynamics in Parkinson's Disease: Short Gait Trials "Stitched" Together Provide Different Fractal Fluctuations Compared to Longer Trials.

The fractal analysis of stride-to-stride fluctuations in walking has become an integral part of human gait research. Fractal analysis of stride time intervals can provide insights into locomotor function and dysfunction, but its application requires a large number of strides, which can be difficult to collect from people with movement disorders such as Parkinson's disease. It has recently been suggested that "stitching" together short gait trials to create a longer time series could be a solution. The objective of this study was to determine if scaling exponents from "stitched" stride time series were similar to those from continuous, longer stride time series. Fifteen young adults, fourteen older adults, and thirteen people with Parkinson's disease walked around an indoor track in three blocks: one time 15 min, five times 3 min, and thirty times 30 s. Stride time intervals were determined from gait events recorded with instrumented insoles, and the detrended fluctuation analysis was applied to each stride time series of 512 strides. There was no statistically significant difference between scaling exponents in the three blocks, but intra-class correlation revealed very low between-blocks reliability of scaling exponents. This result challenges the premise that the stitching procedure could provide reliable information about gait dynamics, as it suggests that fractal analysis of stitched time series does not capture the same dynamics as gait recorded continuously. The stitching procedure cannot be considered as a valid alternative to the collection of continuous, long trials. Further studies are recommended to determine if the application of fractal analysis is limited by its own methodological considerations (i.e., long time series), or if other solutions exists to obtain reliable scaling exponents in populations with movement disorders.

Comprehensive, blinded assessment of balance in orthostatic tremor.

INTRODUCTION: Orthostatic Tremor (OT) is a movement disorder characterized by a sensation of unsteadiness and tremors in the 13-18 Hz range present upon standing. The pathophysiology of OT is not well understood but there is a relationship between the sensation of instability and leg tremors. Despite the sensation of unsteadiness, OT patients do not fall often and balance in OT has not been formally assessed. We present a prospective blinded study comparing balance assessment in patients with OT versus healthy controls. METHODS: We prospectively enrolled 34 surface Electromyography (EMG)-confirmed primary OT subjects and 21 healthy controls. Participants underwent evaluations of balance by blinded physical therapists (PT) with standardized, validated, commonly used balance scales and tasks. RESULTS: OT subjects were mostly female (30/34, 88%) and controls were majority males (13/20, 65%). The average age of OT subjects was 68.5 years (range 54-87) and for controls was 69.4 (range 32-86). The average duration of OT symptoms was 18 years. OT subjects did significantly worse on all the balance scales and on most balance tasks including Berg Balance Scale, Functional Gait Assessment, Dynamic Gait Index, Unipedal Stance Test, Functional Reach Test and pull test. Gait speed and five times sit to stand were normal in OT. CONCLUSIONS: Common validated balance scales are significantly abnormal in primary OT. Despite the objective finding of impaired balance, OT patients do not commonly have falls. The reported sensation of unsteadiness in this patient population seems to be out of proportion to the number of actual falls. Further studies are needed to determine which components of commonly used balance scales are affected by a sensation of unsteadiness and fear of falling.

Smartphone Apps Provide a Simple, Accurate Bedside Screening Tool for Orthostatic Tremor.

BACKGROUND: Orthostatic Tremor (OT) is characterized by the presence of a sensation of instability while standing, associated with high frequency (13-18 Hz) lower extremity tremor. Diagnosis is confirmed with surface electromyography (EMG). An accurate screening tool that could be used in the routine clinical setting, without any specialized equipment, would be useful in earlier detection of OT and judicial use of additional testing. OBJECTIVE: The objective of this study was to evaluate OT diagnostic test characteristics at bedside using iPhone's built-in accelerometer and available applications for tremor recordings. METHODS: We obtained recordings using iPhones (Model 5, 5s, and 6) and free Applications ("LiftPulse" by LiftLabs [App1] and "iSeismometer" by ObjectGraph LLC [App2]) at default settings. RESULTS: 24 EMG-confirmed OT subjects (mostly females, 22/24) and 15 age-matched controls (mostly males, 11/15) were evaluated. App1 detected OT range tremor in 22/24 patients and none of the controls. (Sensitivity = 92%, Specificity = 100%, NPV = 88%). App2 detected OT range tremor in 21/24 patients and in 1/13 controls (Sensitivity = 88%, Specificity = 92%, NPV = 80%). When combined, 24/24 patients and 1/13 controls had OT range tremor (Sensitivity = 100%, Specificity = 92%, NPV = 100%). CONCLUSIONS: Smartphone apps that use the built-in accelerometer provide a simple, accurate and inexpensive bedside screening diagnostic tool for patients with OT.

Continuous non-invasive monitoring to detect covert autonomic dysfunction in Parkinson's disease.

BACKGROUND: Lightheadedness on standing is a disabling symptom in Parkinson's disease associated with orthostatic hypotension and is thought to represent cardiovascular autonomic dysfunction. Traditional orthostatic blood pressures are normal in some patients with lightheadedness and other measures of cardiovascular dysautonomia can be insensitive. In this study, we used continuous non-invasive arterial pressure monitoring to measure beat-to-beat changes in blood pressure and heart rate on standing and during Valsalva as a potential marker of autonomic dysfunction. METHODS: Subjects had a diagnosis of Parkinson's disease with or without documented orthostatic hypotension. Each participant underwent traditional measurement of orthostatic blood pressure and heart rate as well as measurement of beat-to-beat blood pressure and heart rate using continuous non-invasive arterial pressure monitoring during Valsalva maneuver and in response to standing. Orthostatic change in blood pressure and heart rate, and frequencies of normal and abnormal blood pressure responses to Valsalva maneuver were analyzed. RESULTS: In subjects without documented orthostatic hypotension, there was a higher proportion of abnormal blood pressure responses to Valsalva in subjects with symptoms of lightheadedness or dizziness upon standing compared to those without symptoms (p = 0.03). Additionally, the proportion of abnormal blood pressure responses during Valsalva observed in symptomatic subjects without orthostatic hypotension was indistinguishable from those with documented orthostatic hypotension (p = 0.7). CONCLUSIONS: Our findings suggest that continuous non-invasive arterial pressure monitoring may be more sensitive than traditional measurement of orthostatic blood pressure to detect subtle cardiac dysautonomia in Parkinson's disease and helpful in the diagnosis of unexplained lightheadedness.

Botulinum toxin in the management of blepharospasm: current evidence and recent developments.

Blepharospasm is a focal (although usually bilateral) dystonia of the orbicularis oculi muscles, producing excessive eye closure. This produces significant disability through functional blindness. Botulinum neurotoxins (BoNT) have become the treatment of choice for blepharospasm; the impressive response rate and the tolerable safety profile have been proven through multiple clinical studies. There are currently four BoNT approved in the United States for different indications - we review the data on blepharospasm for each of these drugs. Currently, incobotulinumtoxinA and onabotulinumtoxinA have the most evidence of benefit for patients with blepharospasm. Current evidence, recent development and future directions are discussed.

Hydrodynamic determinants of cell necrosis and molecular delivery produced by pulsed laser microbeam irradiation of adherent cells.

Time-resolved imaging, fluorescence microscopy, and hydrodynamic modeling were used to examine cell lysis and molecular delivery produced by picosecond and nanosecond pulsed laser microbeam irradiation in adherent cell cultures. Pulsed laser microbeam radiation at λ = 532 nm was delivered to confluent monolayers of PtK2 cells via a 40×, 0.8 NA microscope objective. Using laser microbeam pulse durations of 180-1100 ps and pulse energies of 0.5-10.5 µJ, we examined the resulting plasma formation and cavitation bubble dynamics that lead to laser-induced cell lysis, necrosis, and molecular delivery. The cavitation bubble dynamics are imaged at times of 0.5 ns to 50 µs after the pulsed laser microbeam irradiation, and fluorescence assays assess the resulting cell viability and molecular delivery of 3 kDa dextran molecules. Reductions in both the threshold laser microbeam pulse energy for plasma formation and the cavitation bubble energy are observed with decreasing pulse duration. These energy reductions provide for increased precision of laser-based cellular manipulation including cell lysis, cell necrosis, and molecular delivery. Hydrodynamic analysis reveals critical values for the shear-stress impulse generated by the cavitation bubble dynamics governs the location and spatial extent of cell necrosis and molecular delivery independent of pulse duration and pulse energy. Specifically, cellular exposure to a shear-stress impulse J≳0.1 Pa s ensures cell lysis or necrosis, whereas exposures in the range of 0.035≲J≲0.1 Pa s preserve cell viability while also enabling molecular delivery of 3 kDa dextran. Exposure to shear-stress impulses of J≲0.035 Pa s leaves the cells unaffected. Hydrodynamic analysis of these data, combined with data from studies of 6 ns microbeam irradiation, demonstrates the primacy of shear-stress impulse in determining cellular outcome resulting from pulsed laser microbeam irradiation spanning a nearly two-orders-of-magnitude range of pulse energy and pulse duration. These results provide a mechanistic foundation and design strategy applicable to a broad range of laser-based cellular manipulation procedures.

Examination of axonal injury and regeneration in micropatterned neuronal culture using pulsed laser microbeam dissection.

We describe the integrated use of pulsed laser microbeam irradiation and microfluidic cell culture methods to examine the dynamics of axonal injury and regeneration in vitro. Microfabrication methods are used to place high purity dissociated central nervous system neurons in specific regions that allow the axons to interact with permissive and inhibitory substrates. Acute injury to neuron bundles is produced via the delivery of single 180 ps duration, lambda = 532 nm laser pulses. Laser pulse energies of 400 nJ and 800 nJ produce partial and complete transection of the axons, respectively, resulting in elliptical lesions 25 mum and 50 mum in size. The dynamics of the resulting degeneration and regrowth of proximal and distal axonal segments are examined for up to 8 h using time-lapse microscopy. We find the proximal and distal dieback distances from the site of laser microbeam irradiation to be roughly equal for both partial and complete transection of the axons. In addition, distinct growth cones emerge from the proximal neurite segments within 1-2 h post-injury, followed by a uniform front of regenerating axons that originate from the proximal segment and traverse the injury site within 8 h. We also examine the use of EGTA to chelate the extracellular calcium and potentially reduce the severity of the axonal degeneration following injury. While we find the addition of EGTA to reduce the severity of the initial dieback, it also hampers neurite repair and interferes with the formation of neuronal growth cones to traverse the injury site. This integrated use of laser microbeam dissection within a micropatterned cell culture system to produce precise zones of neuronal injury shows potential for high-throughput screening of agents to promote neuronal regeneration.

Biophysical response to pulsed laser microbeam-induced cell lysis and molecular delivery.

Cell lysis and molecular delivery in confluent monolayers of PtK(2) cells are achieved by the delivery of 6 ns, lambda = 532 nm laser pulses via a 40x, 0.8 NA microscope objective. With increasing distance from the point of laser focus we find regions of (a) immediate cell lysis; (b) necrotic cells that detach during the fluorescence assays; (c) permeabilized cells sufficient to facilitate the uptake of small (3 kDa) FITC-conjugated Dextran molecules in viable cells; and (d) unaffected, viable cells. The spatial extent of cell lysis, cell detachment, and molecular delivery increased with laser pulse energy. Hydrodynamic analysis from time-resolved imaging studies reveal that the maximum wall shear stress associated with the pulsed laser microbeam-induced cavitation bubble expansion governs the location and spatial extent of each of these regions independent of laser pulse energy. Specifically, cells exposed to maximum wall shear stresses tau(w, max) > 190 +/- 20 kPa are immediately lysed while cells exposed to tau(w, max) > 18 +/- 2 kPa are necrotic and subsequently detach. Cells exposed to tau(w, max) in the range 8-18 kPa are viable and successfully optoporated with 3 kDa Dextran molecules. Cells exposed to tau(w, max) < 8 +/- 1 kPa remain viable without molecular delivery. These findings provide the first direct correlation between pulsed laser microbeam-induced shear stresses and subsequent cellular outcome.

Laser-induced mixing in microfluidic channels.

We demonstrate a novel strategy for mixing solutions and initiating chemical reactions in microfluidic systems. This method utilizes highly focused nanosecond laser pulses from a Q-switched Nd:YAG laser at lambda = 532 nm to generate cavitation bubbles within 100- and 200-microm-wide microfluidic channels containing the parallel laminar flow of two fluids. The bubble expansion and subsequent collapse within the channel disrupts the laminar flow of the parallel fluid streams and produces a localized region of mixed fluid. We use time-resolved imaging and fluorescence detection methods to visualize the mixing process and to estimate both the volume of mixed fluid and the time scale for the re-establishment of laminar flow. The results show that mixing is initiated by liquid jets that form upon cavitation bubble collapse and occurs approximately 20 micros following the delivery of the laser pulse. The images also reveal that mixing occurs on the millisecond time scale and that laminar flow is re-established on a 50-ms time scale. This process results in a locally mixed fluid volume in the range of 0.5-1.5 nL that is convected downstream with the main flow in the microchannel. We demonstrate the use of this mixing technique by initiating the horseradish peroxidase-catalyzed reaction between hydrogen peroxide and nonfluorescent N-acetyl-3,7-dihydroxyphenoxazine (Amplex Red) to yield fluorescent resorufin. This approach to generate the mixing of adjacent fluids may prove advantageous in many microfluidic applications as it requires neither tailored channel geometries nor the fabrication of specialized on-chip instrumentation.

Pulsed laser microbeam-induced cell lysis: time-resolved imaging and analysis of hydrodynamic effects.

Time-resolved imaging was used to examine the use of pulsed laser microbeam irradiation to produce cell lysis. Lysis was accomplished through the delivery of 6 ns, lambda=532 nm laser pulses via a 40x, 0.8 NA objective to a location 10 microm above confluent monolayers of PtK2 cells. The process dynamics were examined at cell surface densities of 600 and 1000 cells/mm2 and pulse energies corresponding to 0.7x, 1x, 2x, and 3x the threshold for plasma formation. The cell lysis process was imaged at times of 0.5 ns to 50 micros after laser pulse delivery and revealed the processes of plasma formation, pressure wave propagation, and cavitation bubble dynamics. Cavitation bubble expansion was the primary agent of cell lysis with the zone of lysed cells fully established within 600 ns of laser pulse delivery. The spatial extent of cell lysis increased with pulse energy but decreased with cell surface density. Hydrodynamic analysis indicated that cells subject to transient shear stresses in excess of a critical value were lysed while cells exposed to lower shear stresses remained adherent and viable. This critical shear stress is independent of laser pulse energy and varied from approximately 60-85 kPa for cell monolayers cultured at a density of 600 cells/mm2 to approximately 180-220 kPa for a surface density of 1000 cells/mm2. The implications for single cell lysis and microsurgery are discussed.