Keeping up with the clinical advances: tardive dyskinesia.

Tardive dyskinesia (TD) was first described in 1964, but treatment for this sometimes poorly characterized condition lagged decades as it was labored by medico-legal implications. TD has often been lumped with other medication-induced disorders and incorrectly classified as extrapyramidal symptoms. TD is likely to be under-recognized for many of these reasons. Though diverse in its presentations, TD is distinct in terms of time course, pathophysiology, and phenomenology.

Improving tremor response to focused ultrasound thalamotomy.

MRI-guided high-intensity focused ultrasound thalamotomy is an incisionless therapy for essential tremor. To reduce adverse effects, the field has migrated to treating at 2 mm above the anterior commissure-posterior commissure plane. We perform MRI-guided high-intensity focused ultrasound with an advanced imaging targeting technique, four-tract tractography. Four-tract tractography uses diffusion tensor imaging to identify the critical white matter targets for tremor control, the decussating and non-decussating dentatorubrothalamic tracts, while the corticospinal tract and medial lemniscus are identified to be avoided. In some patients, four-tract tractography identified a risk of damaging the medial lemniscus or corticospinal tract if treated at 2 mm superior to the anterior commissure-posterior commissure plane. In these patients, we chose to target 1.2-1.5 mm superior to the anterior commissure-posterior commissure plane. In these patients, post-operative imaging revealed that the focused ultrasound lesion extended into the posterior subthalamic area. This study sought to determine if patients with focused ultrasound lesions that extend into the posterior subthalamic area have a differnce in tremor improvement than those without. Twenty essential tremor patients underwent MRI-guided high-intensity focused ultrasound and were retrospectively classified into two groups. Group 1 included patients with an extension of the thalamic-focused ultrasound lesion into the posterior subthalamic area. Group 2 included patients without extension of the thalamic-focused ultrasound lesion into the posterior subthalamic area. For each patient, the percent change in postural tremor, kinetic tremor and Archimedes spiral scores were calculated between baseline and a 3-month follow-up. Two-tailed Wilcoxon rank-sum tests were used to compare the improvement in tremor scores, the total number of sonications, thermal dose to achieve initial tremor response, and skull density ratio between groups. Group 1 had significantly greater postural, kinetic, and Archimedes spiral score percent improvement than Group 2 (P values: 5.41 × 10-5, 4.87 × 10-4, and 5.41 × 10-5, respectively). Group 1 also required significantly fewer total sonications to control the tremor and a significantly lower thermal dose to achieve tremor response (P values: 6.60 × 10-4 and 1.08 × 10-5, respectively). No significant group differences in skull density ratio were observed (P = 1.0). We do not advocate directly targeting the posterior subthalamic area with MRI-guided high-intensity focused ultrasound because the shape of the focused ultrasound lesion can result in a high risk of adverse effects. However, when focused ultrasound lesions naturally extend from the thalamus into the posterior subthalamic area, they provide greater tremor control than those that only involve the thalamus.

Through the Looking Glass: Remote Versus In-Person Videotaped Neurologic Assessment of Essential Tremor.

BACKGROUND: Remote assessment of essential tremor (ET) is unverified. OBJECTIVES: To compare assigned tremor scores from a remote videotaped research protocol with those from an in-person videotaped research protocol and assess the validity of remote and in-person videotape-based diagnoses when compared against the intake diagnosis (ET vs. control). METHODS: Participants with intake diagnoses of ET (11) or controls (15) completed a tremor examination that was filmed both remotely and in person. RESULTS: Agreement between the tremor ratings assigned during remote and in-person videos was substantial (composite κw, 0.67; mean Gwet's AC2 score, 0.92; mean percent agreement, 63.7%). In ET cases with less severe tremor, agreement was lower (p = 0.008). Diagnostic validity was high for both remote and in-person videos compared to the intake diagnosis. CONCLUSIONS: Remote video is a reasonable alternative to in-person video for the assessment of tremor severity and assignment of ET diagnoses. However, at low tremor amplitudes, agreement declines.

Focused ultrasound using a novel targeting method four-tract tractography for magnetic resonance-guided high-intensity focused ultrasound targeting.

Magnetic resonance-guided high-intensity focused ultrasound thalamotomy is a Food and Drug Administration-approved treatment for essential tremor. The target, the ventral intermediate nucleus of the thalamus, is not visualized on standard, anatomic MRI sequences. Several recent reports have used diffusion tensor imaging to target the dentato-rubro-thalamic-tract. There is considerable variability in fibre tracking algorithms and what fibres are tracked. Targeting discrete white matter tracts with magnetic resonance-guided high-intensity focused ultrasound is an emerging precision medicine technique that has the promise to improve patient outcomes and reduce treatment times. We provide a technical overview and clinical benefits of our novel, easily implemented advanced tractography method: four-tract tractography. Our method is novel because it targets both the decussating and non-decussating dentato-rubro-thalamic-tracts while avoiding the medial lemniscus and corticospinal tracts. Our method utilizes Food and Drug Administration-approved software and is easily implementable into existing workflows. Initial experience using this approach suggests that it improves patient outcomes by reducing the incidence of adverse effects.

The spiral axis: A comparison of unaffected first-degree relatives of essential tremor cases vs. controls.

We previously observed that during a spiral drawing task, in essential tremor (ET) cases, the tremor wave forms align along a single predominant axis. This interesting clinical feature can distinguish ET from dystonia cases. We now investigate whether the unaffected relatives of ET cases also express this trait, albeit perhaps in a milder form. To address our aim, we assessed the spiral axis in 237 unaffected first-degree relatives of ET cases (FD-ET), comparing them to 105 controls (Co). A movement disorder neurologist assessed four hand drawn spirals for the presence of a single identifiable tremor orientation axis. A spiral axis score (range = 0-4 [a single axis on 4 spirals]) was assigned to each enrollee. FD-ET had higher spiral axis scores than Co. In a contingency table, the distribution of spiral axis scores differed in the two groups: FD-ET (highest) and Co (lowest) (ordinal chi-square test p = 0.014). Furthermore, when spiral axis scores were examined as a continuous measure, the groups differed (Mann-Whitney test p = 0.03) - with the means being 0.51 (FD-ET) and 0.26 (Co). These data have scientific implications. They (1) show that such axes are more common in relatives of ET cases than controls, and (2) raise the possibility that the spiral axis may be an early subclinical feature of ET.

Lateralization of Motor Signs Affects Symptom Progression in Parkinson Disease.

Background: Asymmetry of motor signs is a cardinal feature of Parkinson disease which may impact phenotypic expression. Objective: To investigate the relationship between lateralization of motor signs and symptom progression and severity during longitudinal observation for up to 4 years in a naturalistic study. Methods: We analyzed data prospectively collected during the NINDS Parkinson Disease Biomarker Project (PDBP). We defined the Movement Disorder Society Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) part II as the primary measure of symptom progression. Left side predominant subjects were those whose lateralized motor scores on the MDS-UPDRS part III were ≥2 points higher on the left side than on the right side of the body. Multiple regression models (controlled for age, gender, education years, ethnicity, levodopa equivalent daily dose (LEDD) at baseline, and years with PD) were used to estimate the rate of symptom progression comparing left predominant (LPD) with non-left predominant (NLPD) subjects. A sensitivity analysis was performed using the same multiple regression models in the subgroups of low (0-26) or high (>27) MDS-UPDRS II score at baseline to determine if PD severity influenced the results. Results: We included 390 participants, 177 LPD and 213 NLPD. We found that MDS-UPDRS part II progression from baseline to 48 months was faster in LPD compared to NLPD (0.6 points per year faster in LPD, p = 0.05). Additionally, the LPD group was statistically significantly worse at baseline and at 48 months in several subparts of the MDS-UPDRS and the Parkinson's Disease Questionnaire-39 (PDQ-39) mobility score. Significantly slower progression (difference of -0.8, p = 0.01) and lower score at 48 months (difference of -3.8, p = 0.003) was seen for NLPD vs. LPD in the group with lower baseline MDS-UPDRS part II score. Conclusion: Left side lateralization was associated with faster symptom progression and worse outcomes in multiple clinical domains in our cohort. Clinicians should consider using motor predominance in their counseling regarding prognosis.

The role of extended-release amantadine for the treatment of dyskinesia in Parkinson's disease patients.

Levodopa is the most efficacious treatment for Parkinson's disease (PD). Long-term treatment with levodopa is limited due to dyskinesia. Dyskinesia in PD can be socially and functionally disabling. Extended-release amantadine (amantadine ER) is the first approved medication for the treatment of dyskinesia. When it is given at bedtime, it reaches plasma concentration approximately twice the level achieved by amantadine immediate release. Amantadine ER reduces the severity and duration of dyskinesia during the day, reduces OFF time and increases ON time without troublesome dyskinesia. The most common side effects are hallucination, dizziness, orthostatic hypotension and pedal edema. This review discusses the safety and efficacy of amantadine ER in dyskinesia in PD patients.