For medical and health professionals
Management
In general, XDP response to oral medical therapy has not been consistent (Jamora et al., 2011). Best results are found in patients who have undergone deep brain stimulation (DBS) surgery (Oyama et al. 2010; Wadia et al. 2010; Rosales et al. 2011; Whitmer et al. 2013; Patel et al. 2014). Remaining symptoms are addressed with zolpidem and botulinum toxin injections.
Medical Management
Medications attempted in treatment of XDP include benzodiazepines (e.g., clonazepam, diazepam), anticholinergic agents (e.g., biperiden, trihexyphenidyl), antipsychotic agents (e.g., haloperidol) and antihistamines (e.g., diphenhydramine), including anti-parkinsonian medications (e.g., levodopa/carbidopa). Most have failed to show convincing efficacy in XDP (Rosales, 2010).
Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1 (ω1), was found to improve clinical symptoms of dystonia in a limited number of case reports (Miyazaki et al., 2012). To date, it is the most effective drug for XDP. In the predominantly phasic type of generalized dystonic movements, zolpidem may effect nearly 100% improvement of dystonia, lasting a variable amount of time, typically for a few hours. The clinical effect of zolpidem may last six to eight hours per 10 mg dose in the first few weeks. Over time, whether from declining efficacy or progression of the disease, the effect becomes progressively shorter, decreasing to two to three hours (Evidente, 2002; Rosales et al., 2011).
The parkinsonian symptoms of XDP directly suggest levodopa-carbidopa as a natural candidate for pharmaceutical treatment. In practice, while levodopa-carbidopa was found to be safe and well-tolerated, it did not have any significant effect in alleviating neither the symptoms of dystonia nor of parkinsonism in XDP (R. D. Jamora et al., 2018).
Chemodenervation
Botulinum toxin (BT) injection is an established treatment for muscle hyperactivity in dystonia (Dressler et al., 2021). When injected into dystonic muscles, it produces a peripheral paresis which is localised, well controllable and follows a distinct and predictable time course of around 3 months. Adverse effects are always transient and usually mild, long-term application is safe.
Botulinum toxin injection is efficacious in XDP and has been used in focal and regional dystonias for temporary relief (Doquenia et al., 2024; Rosales, 2018; Rosales et al., 2011). Aside from botulinum toxin resistance, it appears to be still efficacious over years.
Surgical Management
Pallidal deep brain stimulation was first performed on a patient with XDP in 2007 (Evidente et al., 2007), and the first local Philippine implantation in 2011 (Aguilar et al., 2011). Deep brain stimulation is effective for XDP, with an average 50-60% reduction in BFMDRS and 20-30% reduction in UPDRS (Abejero et al., 2019; Brüggemann et al., 2019). Peripheral dystonia responds best, and axial symptoms to a lesser extent. The least responsive are jaw opening, dysphagia, and some blepharospasm. Dystonic pains respond very well to deep brain stimulation. The level of response appears similar between males and females. Parkinsonian motor symptoms respond little if at all to pallidal stimulation. The benefits of deep brain stimulation appeards to be sustained over time.
Most patients start improving with a programming setting of a single contact (typically the second lowest contact) at about 3 to 5 mA. More rapid improvement occurs with double or triple monopolar contacts. As the disease progresses, there is a need to go progressively higher in amperage and to add stimulation contacts.
Anecdotally, there are patients who have received DBS but subsequently did not proceed with IPG battery replacement. These patients still do well if they have entered the parkinsonian phase of XDP where the dystonia has largely self-ameliorated.
Unilateral posteroventral pallidotomy has been performed on two genetically confirmed XDP patients (Cataniag et al., 2024). In the first case, compared to the BFMDRS score from pre-op baseline, there was 38.46% decrease in at 2 weeks post-op, sustained to 41.66% decrease at 4 years post-surgery. In the second case, there was a 33.73% decrease at 2 months post-op, and a decrease of 86.74% in BFMDRS score at 3 years post-surgery. Both patients had slight ipsilateral improvement of their dystonic symptoms in addition to the major improvement contralaterally. There was little to no further improvement in dystonia after 1 year post-op, and both entered into the parkinsonian phase of the disease.
Unilateral pallidothalamic tractotomy using MRI-guided frequency ultrasound has been used on three genetically confirmed XDP patients (R. D. G. Jamora et al., 2021). There was a 36.2% reduction of BFMDRS from baseline at 6 months and 30.1% reduction at 1 year. Further studies on more patients are needed.
Cost of treatment in the Philippines
The estimated costs in the management of XDP was shown to be 30 times the average annual health expenditure of an average Filipino (De Roxas & Jamora, 2019). The mean total annual cost per patient was USD 4,861.23 ± 13,070.89 (1 USD = 50 PHP, as of January 2018) and the median cost was USD 1,969.02. The biggest expenditure of an XDP patient was the DBS (one time cost), followed by tube gastrostomy (one time cost), and BoNT-A injections (recurring cost).
Abejero, J. E. E., Jamora, R. D. G., Vesagas, T. S., Teleg, R. A., Rosales, R. L., Anlacan, J. P., Velasquez, M. S., & Aguilar, J. A. (2019). Long-term outcomes of pallidal deep brain stimulation in X-linked dystonia parkinsonism (XDP): Up to 84 months follow-up and review of literature. Parkinsonism and Related Disorders. https://doi.org/10.1016/j.parkreldis.2018.09.022
Aguilar, J. A., Vesagas, T. S., Jamora, R. D., Teleg, R. A., Ledesma, L., Rosales, R. L., Fernandez, H. H., & Lee, L. V. (2011). The promise of deep brain stimulation in X-linked dystonia parkinsonism. International Journal of Neuroscience, 121(SUPPL. 1), 57–63. https://doi.org/10.3109/00207454.2010.541573
Brüggemann, N., Domingo, A., Rasche, D., Moll, C. K. E., Rosales, R. L., Jamora, R. D. G., Hanssen, H., Münchau, A., Graf, J., Weissbach, A., Tadic, V., Diesta, C. C., Volkmann, J., Kühn, A., Münte, T. F., Tronnier, V., & Klein, C. (2019). Association of Pallidal Neurostimulation and Outcome Predictors with X-linked Dystonia Parkinsonism. JAMA Neurology, 76(2), 211–216. https://doi.org/10.1001/jamaneurol.2018.3777
Cataniag, P., Diesta, C., Villanueva, J., & Oropilla, J. (2024). Sustained Effect of Posteroventral Pallidotomy for X-Linked Dystonia Parkinsonism. MDS 2024 International Congress. https://doi.org/10.11648/j.ijn.20250901.13
De Roxas, R., & Jamora, R. D. G. (2019). Cost-Analysis of the Different Treatment Modalities in X-Linked Dystonia-Parkinsonism. Frontiers in Neurology, 10, 500. https://doi.org/10.3389/fneur.2019.00500
Doquenia, M. L., Tanglao, M., & Rosales, R. (2024). Botulinum Neurotoxin A Injection for X-Linked Dystonia Parkinsonism: A 3-Year Retrospective Single Center Study Conducted During the COVID-19 Pandemic. Toxicon, 237. https://doi.org/10.1016/j.toxicon.2024.107389
Dressler, D., Adib Saberi, F., & Rosales, R. L. (2021). Botulinum toxin therapy of dystonia. In Journal of neural transmission (Vienna, Austria : 1996) (Vol. 128, Issue 4). https://doi.org/10.1007/s00702-020-02266-z
Evidente, V. G. H. (2002). Zolpidem improves dystonia in “Lubag” or X-linked Dystonia-Parkinsonism syndrome. Neurology, 58(4). https://doi.org/10.1212/WNL.58.4.662
Evidente, V. G. H., Lyons, M. K., Wheeler, M., Hillman, R., Helepolelei, L., Beynen, F., Nolte, D., Müller, U., Starr, P. A., Muller, U., & Starr, P. A. (2007). First case of X-linked dystonia-parkinsonism (“Lubag”) to demonstrate a response to bilateral pallidal stimulation. Mov Disord, 22(0885-3185 (Print)), 1790–1793. https://doi.org/10.1002/mds.21420
Jamora, R. D., Diesta, C. C., Pasco, P. M., & Lee, L. V. (2011). Oral pharmacological treatment of X-linked dystonia parkinsonism: successes and failures. Int.J.Neurosci., 121 Suppl(1563-5279 (Electronic)), 18–21. https://pubmed.ncbi.nlm.nih.gov/21244304/
Jamora, R. D. G., Chang, W. C., & Taira, T. (2021). Transcranial magnetic resonance-guided focused ultrasound in x-linked dystonia-parkinsonism. Life, 11(5). https://doi.org/10.3390/life11050392
Jamora, R. D., Teleg, R. A., Cordero, C. P., Villareal-Jordan, R. F., Lee, L. V., & Pasco, P. M. (2018). Levodopa+carbidopa in X-linked dystonia parkinsonism (XDP/DYT3/Lubag): a randomized, double-blind, placebo-controlled trial. Acta Med Philipp, 52, 510–514. https://actamedicaphilippina.upm.edu.ph/index.php/acta/article/view/256
Miyazaki, Y., Sako, W., Asanuma, K., Izumi, Y., Miki, T., & Kaji, R. (2012). Efficacy of zolpidem for dystonia: A study among different subtypes. Frontiers in Neurology, APR. https://doi.org/10.3389/fneur.2012.00058
Rosales, R. L. (2010). X-Linked Dystonia Parkinsonism: Clinical Phenotype, Genetics and Therapeutics. Journal of Movement Disorders. https://doi.org/10.14802/jmd.10009
Rosales, R. L. (2018). Botulinum neurotoxin for lip and tongue dystonia: “Drooling along the way.” Toxicon, 156. https://doi.org/10.1016/j.toxicon.2018.11.238
Rosales, R. L., Santos, M. M. D. D., Ng, A. R., Teleg, R., Dantes, M., Lee, L. V., & Fernandez, H. H. (2011). The broadening application of chemodenervation in X-linked dystonia-parkinsonism (part I): Muscle afferent block versus botulinum toxin-A in cervical and limb dystonias. International Journal of Neuroscience, 121(SUPPL. 1). https://doi.org/10.3109/00207454.2010.544435