Deep Brain Stimulation and Dantrolene for Secondary Dystonia in X-Linked Adrenoleukodystrophy

Abstract

Deep brain stimulation (DBS) has been used to treat secondary dystonias caused by inborn errors of metabolism with varying degrees of effectiveness. Here we report for the first time the application of DBS as treatment for secondary dystonia in a 22-year-old male with X-linked adrenoleukodystrophy (X-ALD). The disease manifested at age 6 with ADHD, tics, and dystonic gait, and deteriorated to loss of ambulation by age 11, and speech difficulties, seizures, and characteristic adrenal insufficiency by age 16. DBS in the globus pallidus internus was commenced at age 18. However, after 25 months, no improvement in dystonia was observed (Burke-Fahn-Marsden (BFM) scores of 65.5 and 62 and disability scores of 28 and 26, pre-and post-DBS, respectively) and the DBS device was removed. Treatment with dantrolene reduced skeletal muscle tone and improved movement (Global Dystonia Rating Scores from 5 to 1 and BFM score 42). Therefore, we conclude that DBS was a safe but ineffective intervention in our case with longstanding dystonia, whereas treatment of spasticity with dantrolene did improve the movement disorder in this young man with X-ALD. ReportDeep brain stimulation (DBS) has demonstrated variable effectiveness in secondary dystonias caused by inborn errors of metabolism (e.g., homocystinuria, PKAN, GM1-gangliosidosis) (Andrews et al. 2010;Aydin et al. 2011). The present report of DBS in a now 22-year-old man with a diagnosis of X-linked adrenoleukodystrophy (X-ALD, OMIM# 300100) (Vidailhet et al. 2005) is its first reported application in X-ALD.The patient presented at age 6 with ADHD, tics, and a dystonic gait. Neuroimaging revealed symmetrical occipito-parietal demyelination and abnormal signal intensities in the basal ganglia and thalamus (Fig. 1). Diagnosis was confirmed by elevated very long chain fatty acids in plasma. He lost the ability to ambulate within 5 years, and was wheelchair-bound by age 11. His speech deteriorated and was barely intelligible by age 16. Seizure disorder and adrenal insufficiency were effectively controlled with carbamazepine and clobazam, and hydrocortisone, respectively. Initially the dystonia affected only the lower extremities, but quickly generalized. At age 11 years, mild athetoid movements of the head, neck, and extremities were observed. He held the neck in a flexed position, but was able to extend it on request. He had a tendency to elevate the right upper extremity, with his right wrist in a flexed position and fingers extended. There was mild intermittent flexion of the wrist. Knees were held in an extended position, with ankles plantar flexed and feet inverted (left greater than right). Tone was difficult to assess due to the dystonia. Deep tendon reflexes were brisk, especially at the knees; plantar responses were difficult to assess due to dystonia. Hoffman's sign was absent.For dystonia, botox, levodopa/carbidopamine, trihexyphenidyl, pergolide, and pramipexole were ineffective. Intrathecal baclofen to reduce muscle tone was refused by the patient.Repeat gadoli...

Dantrolene, A Treatment for Alzheimer Disease?

“…94-99 The most common side effects of dantrolene are dizziness, drowsiness, light headedness, headaches, anorexia, diarrhea, nausea, and vomiting. Chronic oral use can be associated with liver dysfunction.…”

Deep brain stimulation for movement disorders

“…Less is known about the impact of DBS on rarer inherited causes of dystonia, in particular heredodegenerative diseases with a phenotype characterized by a progressive generalized dystonia, parkinsonism and other neurological signs (Table 3) [60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78].…”

“…Very recently, a doubleblind, randomized crossover trial on GPi DBS has reported a significant improvement in tic severity, with an overall acceptable safety profile [99 && ]. Wilson's disease [62] Neuro-acantocytosis [63] Senataxin mutation-related dystonia [64] Paroxysmal nonkinesigenic dyskinesia [65] Stereotypies in autism spectrum disorders à [66] Variable/negative results DRD (tyrosine hydroxylase with status dystonicus) [67] Lesch-Nyhan [68] Cockayne syndrome [69] Dystonia-deafness [70] Rapid-onset dystonia-parkinsonism [71] GM1 gangliosidosis [72] X-linked adrenoleukodystrophy [73] Homocystinuria [74] SCA 1 [75] SCA 17 [64] Ataxia-telangiectasia Ãà Klinefelter syndrome [76] Tremor associated with demyelinating neuropathy ÃÃà [77] Orthostatic tremor [78] Methylmalonic …”