X-Linked Dystonia-Parkinsonism ("Lubag") May Present with Peripheral Synucleinopathy.

BACKGROUND: X-linked dystonia parkinsonism (XDP) or "Lubag" is a genetic dystonia syndrome observed among Filipinos that can present with levodopa-responsive parkinsonism and abnormal dopamine transporter (DAT) imaging. OBJECTIVE: The aim of this study is to describe the results of skin biopsies for phosphorylated α-synuclein (P-SYN) in XDP. METHOD: This study used the retrospective chart review. RESULTS: We report 6 patients who carried the XDP gene mutation with DAT imaging and skin biopsies to detect P-SYN. Five had segmental or multifocal dystonia and parkinsonism: 4 were levodopa-responsive and 1 non-levodopa-responsive. One patient was asymptomatic but had mild bradykinesia. Cutaneous P-SYN and abnormal DAT scans were noted in the 4 levodopa-responsive patients and 1 asymptomatic patient. CONCLUSION: We report for the first time the presence of cutaneous P-SYN in XDP. Our findings suggest that XDP may be a hitherto-undescribed synucleinopathy or that some XDP patients may have concurrent Parkinson's disease.

Thalamic Deep Brain Stimulation May Improve Restless Legs Syndrome in Patients With Essential Tremor.

OBJECTIVES: To determine change in restless legs syndrome (RLS) symptoms in essential tremor (ET) patients undergoing bilateral thalamic ventral intermedius (VIM) deep brain stimulation (DBS) surgery. MATERIALS AND METHODS: We retrospectively reviewed our database of ET patients with RLS who had undergone VIM DBS for tremor from 2012 to 2020. We reviewed the patients with available International Restless Leg Syndrome Study Group RLS scale scores before and after DBS. Percentage of responders, defined as proportion of patients experiencing three or more point improvement of RLS scores post-DBS, was calculated. We performed two-tailed t-test of pre-DBS and post-DBS RLS scores. RESULTS: We identified 13 patients with ET and RLS who had undergone bilateral VIM DBS, of whom nine (69%) were responders post-DBS. Five of 13 patients (38%) had complete resolution of RLS post-DBS. For all patients, mean pre-DBS RLS score was 15.8 ± 7.9 which improved by 46% post-DBS to a mean of 8.5 ± 8.8 (p = 0.007). Four patients rated their RLS scale one night with the stimulator OFF and another night with the stimulator ON. The mean RLS score with stimulator ON was 15.5 ± 7.6 which improved by 53% to a mean of 6.25 ± 7.8 (p = 0.008), with two having complete resolution of RLS with stimulator ON. Of the nine responders, six preferred to keep their stimulator ON at night due to relief of RLS and better subjective quality of sleep. CONCLUSIONS: We report for the first time improvement of RLS in patients with ET after bilateral thalamic DBS. Although many ET patients with nonrechargeable DBS systems switch off their stimulator at night to conserve battery life, those with RLS may potentially benefit from keeping their stimulator ON at night to relieve their RLS.

Short-Lasting Unilateral Neuralgiform Headache With Conjunctival Injection and Tearing (SUNCT) Improves With Bilateral Ventral Tegmental Area Deep Brain Stimulation.

BACKGROUND: Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a severe headache disorder characterized by clustered episodes of extreme pain. Refractory to most interventions, ipsilateral unilateral ventral tegmental area (VTA) deep brain stimulation (DBS) has been previously reported to be efficacious in 14 cases. METHODS AND RESULTS: Herein, we report the first case of an individual with medically refractory SUNCT who underwent bilateral VTA DBS. The patient experienced better improvement of his headaches with bilateral stimulation compared to unilateral stimulation. He also had a return of severe headaches within a few hours after his stimulator was switched off during sleep, with rebound worsening of his headaches over several days. The main side effects were double vision and difficulty focusing while reading, which were observed primarily with unipolar stimulation that required high voltages, high frequencies, and multiple negative contacts to control the headaches. The side effects were minimized with bipolar and interleaving stimulation with comparable control of his headaches. CONCLUSION: Bilateral VTA DBS may be effective in alleviating medical refractory SUNCT.

Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes.

Potassium channel mutations have been described in episodic neurological diseases. We report that K+ channel mutations cause disease phenotypes with neurodevelopmental and neurodegenerative features. In a Filipino adult-onset ataxia pedigree, the causative gene maps to 19q13, overlapping the SCA13 disease locus described in a French pedigree with childhood-onset ataxia and cognitive delay. This region contains KCNC3 (also known as Kv3.3), encoding a voltage-gated Shaw channel with enriched cerebellar expression. Sequencing revealed two missense mutations, both of which alter KCNC3 function in Xenopus laevis expression systems. KCNC3(R420H), located in the voltage-sensing domain, had no channel activity when expressed alone and had a dominant-negative effect when co-expressed with the wild-type channel. KCNC3(F448L) shifted the activation curve in the negative direction and slowed channel closing. Thus, KCNC3(R420H) and KCNC3(F448L) are expected to change the output characteristics of fast-spiking cerebellar neurons, in which KCNC channels confer capacity for high-frequency firing. Our results establish a role for KCNC3 in phenotypes ranging from developmental disorders to adult-onset neurodegeneration and suggest voltage-gated K+ channels as candidates for additional neurodegenerative diseases.

A randomized, double-blind study of repeated incobotulinumtoxinA (Xeomin(®)) in cervical dystonia.

IncobotulinumtoxinA (Xeomin(®), NT 201), a preparation without accessory (complexing) proteins, has shown comparable efficacy and safety to onabotulinumtoxinA in treating cervical dystonia (CD). This study evaluated the efficacy and safety of repeated incobotulinumtoxinA injections in subjects with CD. Following a ≤20-week placebo-controlled, randomized, double-blind, single-dose main period, subjects could enter a ≤68-week prospective, randomized, double-blind, repeated-dose, flexible-interval (minimum 6 weeks) extension period with 240 U or 120 U of incobotulinumtoxinA (≤5 injections). Outcome measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and adverse events (AEs). Of 219 subjects completing the main period, 214 were randomized in the extension period to receive incobotulinumtoxinA 240 U (n = 111) or 120 U (n = 103); 169 subjects completed the extension period, with 90 receiving five injection sessions. Both doses of incobotulinumtoxinA provided statistically significant and clinically relevant improvements in mean TWSTRS-Total, -Severity, -Disability, and -Pain scores, from each injection session to respective 4-week follow-up visits. The most frequently reported AE was dysphagia (240 U: 23.4 %; 120 U: 12.6 %), which did not result in any study withdrawals. There was no impact of injection interval on the incidence of AEs (post hoc analysis). A major limitation of this study was the fixed dose design requested by regulatory authorities, which does not reflect clinical practice. However, repeated incobotulinumtoxinA injections (240 or 120 U; flexible intervals) provided sustained efficacy and were well tolerated, with no unexpected safety risks following repeated injections. The incidence of AEs was similar in subjects requiring repeated injections at shorter intervals (≤12 weeks) compared with those treated using longer intervals (>12 weeks).

Direct targeting of the ventral intermediate nucleus of the thalamus in deep brain stimulation for essential tremor: a prospective study with comparison to a historical cohort.

OBJECTIVE: The ventral intermediate nucleus of the thalamus (VIM) is an effective target for deep brain stimulation (DBS) to control symptoms related to essential tremor. The VIM is typically targeted using indirect methods, although studies have reported visualization of the VIM on proton density-weighted MRI. This study compares the outcomes between patients who underwent VIM DBS with direct and indirect targeting. METHODS: Between August 2013 and December 2019, 230 patients underwent VIM DBS at the senior author's institution. Of these patients, 92 had direct targeting (direct visualization on proton density 3-T MRI). The remaining 138 patients had indirect targeting (relative to the third ventricle and anterior commissure-posterior commissure line). RESULTS: Coordinates of electrodes placed with direct targeting were significantly more lateral (p < 0.001) and anterior (p < 0.001) than those placed with indirect targeting. The optimal stimulation amplitude for devices measured in voltage was lower for those who underwent direct targeting than for those who underwent indirect targeting (p < 0.001). Patients undergoing direct targeting had a greater improvement only in their Quality of Life in Essential Tremor Questionnaire hobby score versus those undergoing indirect targeting (p = 0.04). The direct targeting group had substantially more symptomatic hemorrhages than the indirect targeting group (p = 0.04). All patients who experienced a postoperative hemorrhage after DBS recovered without intervention. CONCLUSIONS: Patients who underwent direct VIM targeting for DBS treatment of essential tremor had similar clinical outcomes to those who underwent indirect targeting. Direct VIM targeting is safe and effective.

Tardive Blepharospasm May Respond to Bilateral Pallidal Deep Brain Stimulation.

Background: To date, there have been no reports of tardive blepharospasm being treated with deep brain stimulation (DBS), though there have been two reports of focal blepharospasm responding favorably to bilateral pallidal DBS. Case: A 34 year old man with tardive blepharospasm that was refractory to oral medications as well as botulinum toxin types A and B underwent bilateral pallidal DBS under general anesthesia. He had significant improvement of his severe blepharospasm by one and half months post-DBS which was sustained at last follow-up 30 months post-DBS. The best programming parameters included pulse widths of 90-100 µsec, frequencies of 140-150 Hz, and stimulating the ventral contacts in each side. Conclusion: Our case represents the first report of medically refractory tardive blepharospasm responding favorably to bilateral pallidal DBS.

An update on the neurologic applications of botulinum toxins.

Initially used to treat strabismus in the 1970s, botulinum toxin now has more than a hundred possible medical applications. Its utility in neurologic conditions has largely involved treating movement disorders (particularly dystonia and conditions with muscle hyperactivity), although practically any hyperkinetic movement disorder may be relieved by botulinum toxin, including hemifacial spasm, tremor, tics, myoclonus, and spasticity. Although initially thought to inhibit acetylcholine release only at the neuromuscular junction, botulinum toxins are now recognized to inhibit acetylcholine release at autonomic cholinergic nerve terminals, as well as peripheral release of neurotransmitters involved in pain regulation. Thus, their use in neurology has been expanded to include headache and other pain syndromes, as well as hypersecretory disorders. This article highlights some of the common neurologic conditions currently improved by botulinum toxins and reviews the scientific evidence from research studies and clinical experience with these conditions.

Long-term follow-up of deep brain stimulation for Meige syndrome.

OBJECT: Meige syndrome is characterized by blepharospasm, cervical dystonia, and facial oromandibular dystonia. The medical treatment of this condition is largely unsuccessful over time and is a major source of decreased quality of life in those patients suffering from this disease. Recent advances in the application of deep brain stimulation (DBS) surgery techniques for many disorders have prompted several recent reports of DBS for medically refractory cases of Meige syndrome. While the etiology for this disorder is unknown, it is considered by many investigators to be a form of idiopathic torsion dystonia. Pallidal stimulation is widely considered to be effective for dystonia. METHODS: The authors report the long-term results of bilateral globus pallidus internus (GPi) or subthalamic nucleus (STN) stimulation in 3 patients with Meige syndrome and 1 patient with Parkinson disease and associated craniofacial dystonia treated at their center. RESULTS: Initial 12-month and long-term follow-up Burke-Fahn-Marsden scores were substantially improved in all 4 patients compared with preoperative scores. CONCLUSIONS: Bilateral GPi DBS may be an effective and safe treatment for medically refractory Meige syndrome. The results are comparable with those reported in the literature. Sustained and long-term improvement in symptoms does appear to be reproducible across reports. The authors' patient with Parkinson disease and associated craniofacial dystonia syndrome undergoing bilateral STN DBS noted immediate and sustained improvement in his symptoms. Further study is required, but these results, along with the other reports, suggest that bilateral GPi DBS is an effective treatment for medically refractory Meige syndrome.

Adductor Spasmodic Dysphonia Improves with Bilateral Thalamic Deep Brain Stimulation: Report of 3 Cases Done Asleep and Review of Literature.

Background: To date, there are only six published reports of adductor spasmodic dysphonia (SD) responding to awake thalamic deep brain stimulation (DBS). Methods: We retrospectively reviewed cases of Essential Tremor (ET) with SD that were seen in our center from 2012 to 2020. We further identified those that have undergone thalamic DBS, and had a blinded laryngologist rate first the audio voice recordings before and after DBS using the Unified Spasmodic Dysphonia Rating Scale (USDRS), and the video recordings last to rate the related movements and facial grimacing. Results: We identified three cases of adductor SD with ET that had undergone bilateral ventralis intermedius (VIM) DBS under general anesthesia. All patients noted improvement of their limb and voice tremor, as well as their SD post-DBS. Although improvement of tremor was observed even with initial programming in all three, improvement of SD was noted only upon reaching higher amplitudes or wider pulse widths. Blinded voice assessments showed improvement of USDRS scores post-DBS compared to pre-DBS, and with stimulator on compared to stimulator off. Discussion: We report the first three cases of SD responding favorably to bilateral VIM asleep DBS and summarize the nine cases so far of SD who have undergone thalamic DBS.

Responsiveness of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing to hypothalamic deep brain stimulation.

Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a severe primary headache disorder that is often refractory to medical therapy. Although the pathogenesis of this and other trigeminal autonomic cephalalgias is not completely understood, ipsilateral activation of the posterior and inferior hypothalamus has been identified on functional imaging studies during attacks. The authors report on a case of SUNCT syndrome successfully treated with hypothalamic deep brain stimulation and discuss the current literature.

Case series of painful legs and moving toes: clinical and electrophysiologic observations.

We present a retrospective review of cases of painful legs and moving toes (PLMT) syndrome. Out of 4,780 database patients with movement disorders diagnosed at Mayo Clinic Arizona from 1996 to 2006, we identified 14 cases of PLMT and its variants (6 men, 8 women). Ages ranged from 25 to 84 years (mean, 69 years). Movements were bilateral in 12 and unilateral in 2. Pain preceding the movements was most commonly burning; movements consisted of flexion/extension, abduction/adduction, fanning, or clawing of toes, fingers, and sometimes the foot or hand. The most common predisposing factors were neuropathy and radiculopathy. Surface electromyography showed movements suggestive of both chorea and dystonia. Movements were partially suppressible and were diminished but still apparent during light sleep. GABAergic agents were most effective in controlling the pain and the movements.

Orthostatic Tremor is Responsive to Bilateral Thalamic Deep Brain Stimulation: Report of Two Cases Performed Asleep.

Background: Orthostatic tremor (OT) is a hyperkinetic movement disorder characterized by rapid tremor in the lower extremities or trunk upon standing. Case Report: We report two patients presenting with OT, whose symptoms improved markedly following asleep bilateral thalamic deep brain stimulation (DBS) surgery. Discussion: Medically refractory OT can respond favorably to asleep bilateral DBS surgery similar to awake surgery, and may have the advantages of less psychological trauma to the patient, shorter procedure times, and less exposure to anesthesia.

Defining mild cognitive impairment in Parkinson's disease.

Our purpose was to characterize a state of mild cognitive impairment (MCI) in Parkinson's disease (PD) (PD-MCI) that would be analogous to the MCI that is posited as a precursor of Alzheimer's disease (AD). We categorized 86 PD subjects in a brain bank population as either cognitively normal (PD-CogNL), PD-MCI using criteria that included a 1.5 standard deviation or greater deficit upon neuropsychological testing consistently across at least one cognitive domain without dementia, and PD dementia (PD-D) using DSM-IV criteria. Twenty-one percent of our PD sample met criteria for PD-MCI, 62% were PD-CogNL, and 17% had PD-D. The mean duration of PD and MMSE scores of the PD-MCI group were intermediate and significantly different from both PD-CogNL and PD-D. The cognitive domain most frequently abnormal in PD-MCI was frontal/executive dysfunction followed by amnestic deficit. Single domain PD-MCI was more common than PD-MCI involving multiple domains. We conclude that a stage of clinical cognitive impairment in PD exists between PD-CogNL and PD-D, and it may be defined by applying criteria similar to the MCI that is posited as a precursor of AD. Defining PD-MCI offers an opportunity for further study of cognitive impairment in PD and targets for earlier therapeutic intervention.

Hemichorea-hemiballismus may respond to topiramate.

Topiramate is a broad-spectrum anticonvulsant that is now widely used for adult and pediatric epilepsy. In a singular case, topiramate was recently reported to benefit vascular hemichorea-hemiballismus. The authors describe three cases of hemichorea-hemiballismus, one of vascular etiology and two of metabolic etiology, effectively treated with topiramate.

Phenotypic and molecular analyses of X-linked dystonia-parkinsonism ("lubag") in women.

BACKGROUND: X-linked dystonia-parkinsonism (XDP) or "lubag" is an X-linked recessive disorder that afflicts Filipino men, and rarely, women. Genetic confirmation is performed through haplotyping or detection of disease-specific changes in the DYT3 gene. OBJECTIVE: To describe the phenotypes and molecular data of 8 symptomatic female patients with XDP from 5 kindreds. METHODS: Case series. RESULTS: The average age of onset of symptoms was 52 years (range, 26-75 years). Six of 8 patients had parkinsonism, whereas only 1 had dystonia. The initial symptom was focal tremor or parkinsonism in 4, chorea in 3, and focal dystonia (cervical) in 1. Seven of 8 patients had slow or no progression of their symptoms and required no treatment. The patient with disabling parkinsonism was responsive to carbidopa/levodopa. Seven were heterozygous for the XDP haplotype, whereas 1 was homozygous. CONCLUSIONS: The phenotypes of female patients with XDP may include parkinsonism, dystonia, myoclonus, tremor, and chorea. The dystonia, if present, is mild and usually nonprogressive. Similar to men with XDP, parkinsonism is a frequent symptom in women. In contrast to men, affected women have a more benign phenotype, older age of onset, and milder course. Extreme X-inactivation mosaic may be a cause of symptoms in women with XDP, but a homozygously affected woman has also been observed.

Piribedil as an adjunct to levodopa in advanced Parkinson's disease: the Asian experience.

Data on the efficacy and tolerability of piribedil in Asians are scarce. Forty-nine Filipino PD patients with motor fluctuations were enrolled in an 8-week trial of piribedil of up to 150 mg/day. Mean improvement was 48% for the motor UPDRS scores (tremor showed greatest change), and 43% for activities of daily living. Mean daily levodopa dose decreased by 17%, and mean duration of effect of levodopa increased by 1.3 h (45%). Most common side effects were hallucinations (20%), dyskinesias (20%), dizziness (8%), and sleepiness (6%). This trial shows that piribedil is effective and well-tolerated by Asian patients with advanced PD at least with short-term use.

Smell testing is abnormal in 'lubag' or X-linked dystonia-parkinsonism: a pilot study.

We administered a culturally corrected University of Pennsylvania Smell Identification Test (ccUPSIT) consisting of 25 odor items to 20 patients with 'Lubag' or X-linked dystonia-parkinsonism and 20 control subjects matched by sex, age, educational background, smoking history, and geographical origin. The mean ccUPSIT score of Lubag patients (18 +/- 3.19) was statistically lower (P = 0.003) than controls (20.5 +/- 3.02). The smell scores did not correlate with phenotype, severity of dystonia, or duration of disease. Nine of 20 Lubag patients (45%) had ccUPSIT scores below the mean, with the lowest score being 11. This pilot study suggests that olfactory dysfunction may occur in Lubag patients.