doi:10.1093/brain/awq022 Brain 2010: 133; 701–712 | 701 BRAIN A JOURNAL OF NEUROLOGY Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation Downloaded from https://academic.oup.com/brain/article/133/3/701/277266 by guest on 28 September 2021 L. Timmermann,1,Ã K. A. M. Pauls,1,Ã K. Wieland,1 R. Jech,2 G. Kurlemann,3 N. Sharma,4 S. S. Gill,5 C. A. Haenggeli,6 S. J. Hayflick,7 P. Hogarth,7 K. L. Leenders,8 P. Limousin,9 C. J. Malanga,10 E. Moro,11 J. L. Ostrem,12 F. J. Revilla,13 P. Santens,14 A. Schnitzler,15 S. Tisch,9 F. Valldeoriola,16 J. Vesper,17 J. Volkmann,18 D. Woitalla19 and S. Peker20 1 Department of Neurology, Uniklinik Ko¨ ln, University of Cologne, Cologne, Germany 2 Department of Neurology, Charles University in Prague, First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic 3 Department of Paediatric Neurology, University Children’s Hospital, Muenster, Germany 4 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 5 Institute of Neurosciences, Frenchay Hospital, Bristol, UK 6Hoˆ pital des Enfants, Geneve, Switzerland 7 Oregon Health and Science University, Portland, OR, USA 8 Department of Neurology, University Medical Centre Groningen, Groningen, Netherlands 9 Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK 10 Department of Neurology, Division of Child Neurology, University of North Carolina at Chapel Hill, NC, USA 11 Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, Canada 12 Department of Neurology, University of California San Francisco, San Francisco, CA, USA 13 Department of Neurology, Movement Disorders Centre, University of Cincinnati, Cincinnati, OH, USA 14 Department of Neurology, Ghent University Hospital, Ghent, Belgium 15 Institute of Clinical Neuroscience and Medical Psychology, Department of Neurology, Heinrich Heine University, Du¨ sseldorf, Germany 16 Hospital Clinic, Institut de Neurociencies Universitat de Barcelona, Barcelona, Spain 17 Functional Neurosurgery, Department of Neurosurgery, Heinrich Heine University, Du¨ sseldorf, Germany 18 Department of Neurology, Christian-Albrechts-University, Kiel, Germany 19 Department of Neurology, St. Josef Hospital, Ruhr University, Bochum, Germany 20 Department of Neurosurgery, Hospital for Neurological Sciences, Acibadem University School of Medicine, Istanbul, Turkey ÃThese authors contributed equally to this work. Correspondence to: Prof. Dr Lars Timmermann, Klinik und Poliklinik fu¨ r Neurologie, Uniklinik Ko¨ ln, Kerpener Str. 62, 50924 Ko¨ ln, Germany E-mail: [email protected] Correspondence may also be addressed to: Dr Amande Pauls. E-mail: [email protected] Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia Received October 14, 2009. Revised December 18, 2009. Accepted January 18, 2010 ß The Author(s) 2010. Published by Oxford University Press on behalf of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 702 | Brain 2010: 133; 701–712 L. Timmermann et al. caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accu- mulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, mag- netic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale—Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale— Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2–6 and 9–15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2–6 months and 25.7% at 9–15 months. At 9–15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of Downloaded from https://academic.oup.com/brain/article/133/3/701/277266 by guest on 28 September 2021 dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9–15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2–6 months; this failed to reach significance at 9–15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improve- ment is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes. Keywords: Neurodegeneration with brain iron accumulation; dystonia; deep brain stimulation; globus pallidus Abbreviations: BFMDRS = Burke Fahn Marsden Dystonia Rating Scale; GPi-DBS = bilateral pallidal deep brain stimulation; NBIA = neurodegeneration with brain iron accumulation Introduction and swallowing, pain, respiratory distress and, in some cases, death due to dystonic storm, respiratory failure or infection. Due Neurodegeneration with brain iron accumulation (NBIA) encom- to small patient numbers, pharmacotherapy of dystonia in NBIA is passes a heterogeneous group of rare progressive disorders which not evidence-based, and thus guided by therapeutic experiences in are characterized by iron accumulation in the brain (Hayflick et al., other forms of dystonia. Patients are often treated with anticholi- 2003). Diagnosis is usually made according to the following crite- nergics, such as trihexiphenidyl or gamma-aminobutyric acid ago- ria: (i) progressive disorder; with (ii) at least one of the following nists such as benzodiazepines or baclofen, orally or intrathecally symptoms: dystonia, rigidity, tremor, bradykinesia or choreoathe- (Albright et al., 1996). There are some reports of botulinum toxin tosis; and (iii) an abnormal MRI with hypointensity of the pallidum being effective (Dressler et al., 2001) for particularly bothersome on the T2-weighted images (Swaiman, 2001). focal symptoms, and many patients receive regular botulinum Several genetic subtypes of NBIA are currently emerging. The toxin injections. Levodopa has been reported to have a positive most common subtype, pantothenate kinase-associated neurode- effect on some of the disabling movements seen in NBIA patients generation, is caused by mutations in the PANK2 gene (Zhou without PANK2 mutations (Gregory and Hayflick 2005; Clement et al., 2001) and accounts for 50% of cases of NBIA (Hayflick et al., 2007). However, in most cases with severe dystonia, phar- et al., 2003). Further genetic defects associated with NBIA are macological therapy, including botulinum toxin injections, is unsa- mutations in the PLA2G6 gene (Morgan et al., 2006), and disor- tisfactory. The limited benefits of medical treatments have ders of iron metabolism, such as aceruloplasminaemia (Harris, prompted early attempts with neurosurgical therapy. 1995) and neuroferritinopathy (Curtis et al., 2001). Patients exhi- Several cases have been published in which there has been biting symptoms typical of NBIA without any of these known improvement in dystonia associated with NBIA after bilateral tha- mutations are classified as ‘idiopathic NBIA’ and their disease is lamotomy (Tsukamoto et al., 1992) as well as unilateral (Justesen probably caused by, as yet unknown, other genes (Gregory et al., et al., 1999) or bilateral pallidotomy (Kyriagis et al., 2004; Balas 2009). et al., 2006). However, since stereotactic lesioning is an irrevers- The clinical presentation, the age of onset and the progression ible procedure, its use in children and adolescents raises several rate of NBIA are highly variable, even amongst siblings with iden- concerns (especially for bilateral procedures, which have higher tical underlying mutations, and there is a considerable degree of risk of severe side effects). With the advent of deep brain stimu- phenotypic