Long-term outcomes of pallidal deep brain stimulation in X-linked dystonia parkinsonism (XDP): Up to 84 months follow-up and review of literature.

INTRODUCTION: X-linked dystonia-parkinsonism (XDP/DYT3/Lubag) patients had improved dystonia and parkinsonism with bilateral pallidal deep brain stimulation (DBS) in the literature. METHOD: We reviewed eleven XDP patients who underwent bilateral pallidal DBS from October 2009 to September 2018. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Unified Parkinson's Disease Rating Scale (UPDRS)-III scores were reviewed from baseline up to the longest follow-up together with the demographic and clinical data. The published case reports on DBS in XDP were also reviewed. RESULTS: The mean age was 39 ±â€¯9.2 years with a mean disease duration of 3 years (range 1-9 years). An immediate response for dystonia post-DBS (1 month) was seen in all cases, with a mean BFMDRS score of 23.3 ±â€¯12.12 [from a mean baseline of 36.3 ±â€¯12.1] and a small change in the mean UPDRS-III score of 20 ±â€¯10.39 [from a mean baseline of 24.04 ±â€¯8.74]. At 12 months (n = 10), the mean BFMDRS score was 13.7 ±â€¯10.63 and the mean UPDRS-III score was 19 ±â€¯13.19. There was improvement in the clinical and functional stage of the patients, with majority in Stage 1 (n = 3) and Stage 2 (n = 5) at their last follow-up. CONCLUSION: Bilateral pallidal DBS should be considered as a treatment option for XDP. It is effective in the first 12 months in controlling dystonia with variable response in controlling parkinsonism. It may be effective in up to 72-84 months, as seen in three patients.

Deep Brain Stimulation for Parkinson Disease in the Philippines: Outcomes of the Philippine Movement Disorder Surgery Center.

OBJECTIVE: Deep brain stimulation (DBS) is an established treatment modality for Parkinson disease (PD). The first DBS for PD in the Philippines was performed at the Philippine Movement Disorder Surgery Center in 2006. There are no Philippine data on DBS for PD. We aim to determine the motor improvement and reduction in medication dosage of all patients with PD who underwent DBS at the Philippine Movement Disorder Surgery Center. METHODS: This is a retrospective study of all patients with PD (n = 17) who underwent DBS from 2006 to 2016. The change in the Unified Parkinson's Disease Rating Scale (UPDRS) motor and levodopa equivalent dose were determined. RESULTS: There was a statistically significant reduction in the UPDRS motor in all patients off medication at 3 months (48.2%; P = 0.004), 1 year (47.3%; P = 0.026), 2 years (48.4%; P = 0.021), and 3 years (66.0%; P = 0.032) after DBS and on medication at 3 months (43.3%; P = 0.023), 6 months (24.7%; P = 0.053), and 1 year (38.1%; P = 0.033). A significant reduction in the dosage of PD medications was also seen until the second year of follow-up (52.3%; P < 0.001). Adverse events included an attempted suicide and a device-related infection. CONCLUSIONS: DBS for PD improves the UPDRS motor score in the off-medication and on-medication state, with the maximal benefit seen at 3 years after surgery and reduces PD medication dosage by half. Although the benefit from DBS is undeniable, the high cost of the procedure precludes more patients from benefitting from it. There is a need for government support to expand access to DBS.

Validation of the XDP-MDSP rating scale for the evaluation of patients with X-linked dystonia-parkinsonism.

X-linked dystonia-parkinsonism(XDP) is a neurodegenerative disorder endemic to the Philippines. A rating scale was developed by the authors under the guidance of the Movement Disorder Society of the Philippines (MDSP) to assess XDP severity and progression, functional impact, and response to treatment in future clinical trials. Our main objective was to validate our new scale, the XDP-MDSP scale. The initial validation process included pragmatic testing to XDP patients followed by a modified Delphi procedure with an international advisory panel of dystonia, parkinsonism and scale development experts. Pearson correlation was used to assess construct validity of our new scale versus the assess construct validity of our new scale versus standard dystonia, parkinsonism, non-motor and functional scales; and also to assess divergent validity against behavioral and cognitive scales. The 37-item XDP-MDSP scale has five parts: I-dystonia, II-parkinsonism, III-non-motor features, IV-ADL, and V-global impression. After initial validation, the scale was administered to 204 XDP patients. Inter-domain correlation for the first four parts was acceptable. The correlation between these domains and the global rating was slightly lower. Correlations between Parts I, II, III, and IV versus standard dystonia, parkinsonism, non-motor and functional scales were acceptable with values ranging from 0.323 to 0.428. For divergent validity, a significant correlation was seen with behavioral scales. No significant correlation was noted with the cognitive scale. The proposed XDP-MDSP scale is internally valid but the global rating subscale may need to be modified or eliminated. While there is convergent validity, divergent validation was successful only on cognitive and not behavioral scales. The frequent co-occurrence of anxiety and depression, and its effect on the motor and functional state, may explain this finding.

The promise of deep brain stimulation in X-linked dystonia parkinsonism.

X-Linked dystonia parkinsonism (XDP) is a rapidly progressive and disabling neurodegenerative disease affecting mainly male Filipinos with origins from Panay Island. We reviewed all the past neurosurgical ablative procedures done for XDP patients listed in the Philippine XDP registry. From 1960 to 1982, six patients had undergone bilateral chemopallidotomies or bilateral thalomotomies staged over time. Half of these patients had significant improvement in their symptoms but five of the six patients (83%) developed postoperative morbidities, mainly speech impairment or hemiparesis. All the five reported GPi deep brain stimulation (DBS) cases for XDP were also reviewed, showing consistently immediate improvement of symptoms (61.5%-88.3% decrease in the Burke-Marsden-Fahn Dystonia Rating Scale) lasting up to a year with no adverse effects noted. We also present the first Philippine case of GPi DBS done in the youngest XDP patient to date. This present case showed dramatic improvement (88.3% decrease of the Burke-Marsden-Fahn Dystonia Rating Scale) of his dystonic symptoms, without incurring any persistent adverse effects. The results of these early cases of pallidal DBS for XDP show that DBS is generally a safe and effective procedure for alleviating the disabling symptoms of XDP in contrast to previous ablative surgeries performed on these patients.

The broadening application of chemodenervation in X-linked dystonia-parkinsonism (Part I): muscle afferent block versus botulinum toxin-A in cervical and limb dystonias.

Botulinum toxin (BoNT) is an established mainstay treatment for dystonia. However, its use, especially in developing countries, is significantly limited by its cost. Chemodenervation with muscle afferent block (MAB) using lidocaine-ethanol may provide a more cost-effective alternative to traditional BoNT injections. A study comparing MAB with BoNT type-A in cases of X-linked dystonia-Parkinsonism (XDP) having cervical dystonia indicated a modest and short-lived efficacy with MAB, while a more robust efficacy in dystonia and pain parameters, lasting up to 11 weeks, was observed in the two BoNT type-A preparations (Dysport® and Botox®). In another study comparing BoNT type-A formulations for limb dystonia of XDP, a prior MAB was used to select target muscles for toxin injection. During toxin injections in the limb muscles, Dysport® and Botox® did not show significant differences with regard to global severity and disability scales, duration of effect, and adverse event (AE) profile. Dysphagia was the most common AE following BoNT type-A injections in cervical dystonia, while weakness was the most frequent AE noted with injections for limb dystonia. MAB injections carried a high incidence of dizziness and pain during injections. However, because MAB is a more cost-effective alternative that can be given repeatedly, it has been used in the XDP population while awaiting funds for BoNT type-A and/or for selecting muscles for injection as a test drug.

Understanding XDP through imaging, pathology, and genetics.

The X-linked dystonia-parkinsonism (XDP) is a severe, progressive, adult-onset, X-linked endemic disorder in Filipinos, which is characterized by dystonic movements that start in the third or fourth decade, and replaced by parkinsonism beyond the 10th year of illness. Understanding the pathophysiology of XDP and development of rational therapies will depend on observations from imaging, pathological, and genetic studies. In this paper we summarize the results of these studies on patients with XDP. The cranial magnetic resonance imaging shows hyperintense putaminal rim in both dystonic and parkinsonian stages, and atrophy of the caudate head or putamen in the parkinsonian stage. Neuropathological findings show atrophy of the caudate nucleus and putamen, with mild to severe neuronal loss and gliosis. In the neostriatum, the dystonic phase of XDP shows the involvement of striosomes and matrix sparing, while the later, i.e., parkinsonian phase, shows matrix involvement as well. In the dystonic phase, the loss of striosomal inhibitory projections lead to disinhibition of nigral dopaminergic neurons, perhaps resulting in a hyperkinetic state; while in the parkinsonian phase, severe and critical reduction of matrix-based projection may result in extranigral parkinsonism. Genetic sequencing of the XDP critical region in Xq13.1 has revealed an SVA retrotransposon insertion in an intron of TAF1. This may reduce neuron-specific expression of the TAF1 isoform in the caudate nucleus, and subsequently interfere with the transcription of many neuronal genes, including DRD2. Findings from imaging, pathology, and genetics studies are gradually shedding light on the pathophysiology of XDP, which hopefully will lead to more rational and directed therapies.

The unique phenomenology of sex-linked dystonia parkinsonism (XDP, DYT3, "Lubag").

Sex-linked dystonia parkinsonism (XDP, DYT3, "Lubag") is an adult-onset, progressive, debilitating movement disorder first described in Filipino males from Panay Islands in 1975. XDP manifests predominantly as torsion dystonia, later combined with or sometimes replaced with parkinsonism. Within the Island of Panay, the prevalence rate is highest in the province of Capiz, where 1:4000 men suffer from the disorder. There is a high degree of penetrance and generalization. While women often serve as carriers, XDP is not limited to men. An updated XDP Philippine registry (as of January 2010) has identified 505 cases, with 500 males and 5 females. While some report that females may carry a milder form of the disorder, in our experience, both sexes generally follow a similar progressive clinical course.

Effect of increasing doses of aspirin on platelet aggregation among stroke patients.

BACKGROUND AND PURPOSE: Aspirin has been shown to reduce the risk of myocardial infarction and stroke. Some investigators believe that low-dose aspirin inhibits platelet aggregation to the same degree as high-dose aspirin. Our study aimed to assess the effect of increasing doses of aspirin on the degree of platelet aggregation induced by collagen and adenosine diphosphate (ADP) among stroke patients. METHODS: Sixteen poststroke patients were prescribed aspirin at daily doses of 40, 80, 160, 325, 650, and 1,300 mg, each dose to be taken for 14 days (total duration 12 weeks). Platelet aggregation studies using 2 microgram/ml collagen and 2 microM ADP were performed on platelet-rich plasma at baseline and on the 14th day of each dose. RESULTS: Platelet aggregation studies using 2 microgram/ml collagen at the start of treatment and at the 14th day of each dose revealed dose-dependent inhibition by aspirin starting at 40 mg/day, but was optimal at 80- 160 mg/day. ADP-induced platelet aggregation inhibition appears to be dose dependent up to 1,300 mg/day. CONCLUSION: Inhibition of collagen-induced platelet aggregation by aspirin appears to be optimal at 80-160 mg/day, while ADP-induced platelet aggregation inhibition by aspirin appears to be dose dependent up to 1,300 mg/day in our poststroke patients, albeit to a less remarkable degree at higher doses.