Deep brain stimulation improves quality of life in pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is an uncommon extrapyramidal movement disorder characterized by the progressive incapacitating dystonia. Medical management is often incapable of reversing the dystonic symptoms. In recent years, stereotactic procedure like deep brain stimulation has been found effective in resolving the disabling dystonia and improving the quality of life. There are few cases in the world literature highlighting the usefulness of this technique. We report a case of 10-year-old girl who underwent bilateral Globus pallidus internus stimulation for PKAN.

Introduction

Neurodegeneration with the brain iron accumulation (NBIA) encompasses a genetically heterogeneous group of disorders characterized by the progressive iron accumulation in the basal ganglia.[1]

Among different subtypes of NBIA, the term “pantothenate kinase-associated neurodegeneration (PKAN)” has been coined to describe the subgroup of patients harboring mutations in the PANK2 gene whose function is presumed to be related with the regulation of iron metabolism.[23] In addition, the “eye-of-the-tiger sign” is recognized as a characteristic brain magnetic resonance imaging (MRI) finding among patients with the PKAN, (hypo intensity with the central hyper intensity in the globus pallidus on T2 images), and predicts a PANK2 mutation in at least one allele.[2] Dystonia is the chief presentation and is least amenable to medical treatment. Deep brain stimulation (DBS) of the Globus pallidus internus (GPi), has been tried for these patients.[4-8] thereby modulating the abnormal tone in PKAN and has been found effective in such cases.[12] A young girl suffering from disabling dystonia secondary to PKAN is reported. After failed medical management, DBS was therapeutically tried. There was a significant improvement in the dystonia and quality of life.

Case Report

A 10-year-old girl born of non-consanguineous marriage was apparently well up to 2.5 years of age with the normal development. Thereafter, she developed frequent falls while walking without any visual disturbances and had mild slurring of speech. At this time, she had normal hearing and cognition. Physical examination revealed unsteady gait with mild dystonia in all extremities along with mild dysarthria with normal sensory and cranial nerve examination. Metabolic work-up was normal. Brain MRI revealed classical “eye of tiger” appearance (fluid attenuated inversion recovery sequence {FLAIR}) hyperintensities in bilateral globus pallidi with surrounding hypointensity). Diagnosis of Halloverdan Spatz disease (PKAN) was confirmed as PANK2 gene deletion testing was positive. Medical management comprising of trihexiphenidyl, baclofen, clonazepam, L-dopa, and botulinum toxin was tried with little therapeutic success in arresting the symptom progression. Over the ensuing years, there was gradual worsening in her mobility and ability to do activities of daily living. She developed severe generalized dystonia affecting her limbs, trunk, face, and tongue causing difficulty in walking, dressing, use of hands, difficulty in opening eyes due to severe blepharospasm and problems with chewing, deglutition, vocalization, and maintaining hygiene. She required gastrostomy tube feeding to maintain nutrition. She was totally wheel chair bound for mobility by 7 years of age. At the age of 9 years, she had severe dystonic spasms and marked discomfort from dystonia. She was offered DBS surgery at this stage. Pre-DBS assessment denoted “Burke-Fahn-Marsden (BFM) Dystonia Rating Scale Motor Score” 120/120 and “BFM Dystonia Rating Scale Disability Score” 28/29 implying severe generalized dystonia and severe difficulty in activities of daily living respectively. There was a definite improvement in the dystonia post-operatively, which was sustained even at 15 months post-DBS. The BFM Dystonia Rating Scale Motor Score improved to 42.5/120 while BFM dystonia Rating Scale Disability Score improved to 25/29. This was reflected in her ability to sit in a chair, stand and walk few steps with support, opening eyes and ease in chewing and swallowing food. However, there was no improvement in the speech yet.

Discussion

PKAN is a rare iron accumulating neurodegenerative movement disorder characterized by typical appearance of the globus pallidi on MRI and genetic studies positive for the PANK2 gene deletion in a subset of these children.[910] ′C.215_216insA′ is the most common PANK2 gene mutation observed in Indian population mostly belonging to the Agarwal community as also seen in our patient. Dystonia is the most distressing symptom and the least amenable to medical treatment. In the past, ablative procedure targeting the globus pallidi were performed to ameliorate the disabling dystonia.[9] However, it has fallen into disrepute on account of the irreversible nature and procedure related adverse effects including cognitive affection.[11] Recently, a new concept of electrically stimulating the specific part of the globus pallidus by surgically inserted electrodes, has gathered much interest in managing dystonia resistant to the pharmacological therapy.[12-14] While the beneficial effects and efficacy of this therapy, which was first introduced in 1977, have been established in primary dystonias, it still requires validation in the secondary dystonias where the effect is variable.[1415] Stimulation of postero-ventrolateral part of GPi reversibly inhibits the pathologically activated neuronal activity in this area and facilitates gamma-aminobutyric acid (GABA) activity thereby normalizing the increased motor tone. Precise target localization is essential for ensuring optimal benefits of the surgery and protecting adjacent vital areas. It can be achieved using a combination of MRI, ventriculography and perioperative microelectrode recording data. Following the target localization, the therapeutic setting involves establishing optimal frequency, amplitude and pulse width, which is titrated to the desired outcome thereby balancing the benefits and untoward effects of the procedure.[1617] The extent of disability preoperatively is compared with post-operative assessment using BFM dystonia rating Motor and Disability scores.[11] The beneficial effect is protracted over months but is sustained for up to 8 years post-operatively. Although speech and swallowing improve marginally, axial dystonia significantly improves with reduced pain and improved quality of life as also seen in our patient. Complications include device related adverse effects such as electrode displacement, fracture and rebound dystonia resulting from depletion of the stimulatory source or stimulation related extrapyramidal side-effects. Cognition and mood remains unaffected unlike with ablative surgeries carried out in the past.[12] In a multi-centric study from Germany, 23 confirmed cases of PKAN who failed medical management for dystonia were subjected to DBS with amelioration of dystonia. The mean age at the onset of symptoms was 7.8 ± 4.8 years, mean age at diagnosis was 12.7 ± 8.0 years while the mean age at surgery was 18.0 ± 8.8 years with the youngest patient being 6 years old at the time of surgery. Post-operative improvement in the dystonia was 28.5% at 2-6 months, 25.7% at 9-15 months with 15.8% improvement in the disability. French group reported sustained benefit of the DBS in improving incapacitating dystonia in 7 children suffering from PKAN followed over a period of twenty months. Near normal functional improvement in an independent walking and writing was noted in 5 patients, with substantial improvement in speech and pain in the majority without any untoward therapy related adverse effects.[17] The degree of improvement in dystonia is directly proportional to the severity of dystonia pre-operatively. Prolonged disease duration and fixed skeletal deformities are associated with unfavorable outcome post-operatively. Timely consideration of the DBS is critical for maximizing the benefits of the surgery.[9]