Fourth International Symposium on Neuroacanthocytosis

Abstracts from the Fourth International Symposium on Neuroacanthocytosis

July 1-2, 2008
London and Oxford

Chairs: Prof. Kailash Bhatia, MD, FRCP, Institute of Neurology, University College London; Prof. Anthony P. Monaco, MD, PhD, Wellcome Trust Centre for Human Genetics, University of Oxford

Organizers: Antonio Velayos-Baeza, PhD; Susanne Schneider, MD; Glenn Irvine

2-4 Deep brain stimulation for NA patients - forum

a) Deep Brain Stimulation in Pantothenate Kinase Associated Neurodegeneration
L. Cif, V. Gonzalez, X. Vasques, and P. Coubes
CHRU Montpellier, Hôpital Gui de Chauliac, Service de Neurochirurgie; INSERM, U661; Université de Montpellier 1; CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, F-34000 France

Background: Pantothenate kinase-associated neurodegeneration (PKAN, OMIM 234200) is a progressive autosomal recessive disorder due to mutations in the pantothenate kinase 2 gene (PANK2). PKAN patients generally fall into 2 clinical categories: early onset, rapidly progressive (classic) disease or late onset, slowly progressive (atypical) disease. Motor involvement with gait disturbances due to dystonia, rigidity, and spasticity are present in both forms. Psychiatric symptoms (more prominent in atypical disease) include depression, emotional lability, and impulsivity. Repetitive actions, freezing, and palilalia are all common features of the syndrome. Pharmacologic and surgical interventions aim at improvement of psychiatric and motor symptoms.
Objective: Deep brain stimulation of the internal globus pallidus (GPi) has been proposed for treating progressive generalized dystonia and dyskinesia sometimes resulting in life threatening conditions in PKAN. We studied the results of GPi stimulation in PKAN.
Population and method: Eleven consecutive genetically proven PKAN patients (6 male) underwent surgery for DBS. Eight patients presented classic form of PKAN. Bilateral GPi implantation has been performed in all patients. The patients were assessed before and after surgery using the Burke-Fahn-Marsden's dystonia rating scale (BFMDRS) which includes a motor scale and a disability scale.
Results: At onset, the mean age of the patients was of 9.4 years (range, 1-17). At surgery, the mean age was 18.5 years (range, 8-39). Postoperatively, there was a sustained decrease of the dystonia in all but one patient with a mean global motor improvement of 60.5% (range, 6.5 to 91.5) and a mean global disability improvement of 42% (range, 4-82). Two patients presenting with classic forms of PKAN died after 56 and 14 months follow-up. The three atypical and four classic PKAN patients preserved autonomous gait at last assessment. Three patients experienced improvement of dysarthria. Hardware related complications occurred in one patient.
Discussion: Since our first publication reporting on the effect of GPi DBS in 6 PKAN patients, several case reports described sustained efficacy of GPi stimulation in PKAN. Two patients in life-threatening condition previous to DBS survived for more than five years with a satisying quality of life. If the mean motor improvement is satisfying, the outcome for walking capacities can be limited by freezing (common feature of the disease), sometimes increased by high frequency GPi stimulation. Speech involvement with severe dysarthria is rarely improved by DBS. Psychiatric symptoms were not modified by GPi DBS.
Conclusion: Since no curative therapy exists to date, we consider that DBS should be considered in the treatment of the severe generalized dystonia of PKAN. Pallidal stimulation reduces the dystonia along with the painful spasms and subsequently improves the functional autonomy of the patients in daily living.

b) Deep brain stimulation for neuroacanthocytosis. Lessons from three cases
P. Burbaud
Department of Clinical Neurophysiology, Bordeaux Hospital, Bordeaux, France

Neuroacanthocytosis (NA) is a group of neurodegenerative diseases characterized by various types of involuntary movements resistant to medical treatment. We report data concerning three NA patients who benefited from deep brain stimulation (DBS) with different targets: one in the posterior ventral oral nucleus of the thalamus (Vop) and the other two in the internal pallidum (GPi).
Patient 1 had a severe form of chorea-acanthocytosis, with violent truncal spasms, head banging, hypotonia and dysarthria. The frequency of trunk spasms and head banging dramatically decreased with Vop stimulation and the clinical benefit remained stable 1 year later but no clear effect was observed on dysarthria nor on hypotonia, which always impaired gait.
Patient 2 was a 32-year-old man with an 8-year history of choreatic-dystonic syndrome, dysarthria, recurrent distressing tasteless belching and dramatic tongue-biting. Walking was disturbed by intermittent dystonia of the left foot and bilateral choreatic movements causing a jerky gait. Trunk flexion movements and a moderate back-arching dystonia were occasionally observed. Patient 3 exhibited a severe generalized chorea predominating on the left side with hypotonia, postural instability causing him to fall repeatedly and a moderate cognitive deterioration. In these two patients 40Hz stimulation applied to the GPi gave the best clinical benefit, improving chorea without effect upon hypotonia. Higher frequency stimulation (120Hz) was effective for dystonia but increased chorea, worsened dysarthria and induced drooling. Low frequency (10Hz) GPi stimulation was ineffective.
These preliminary data show that pallidal stimulation is effective on choreatic and dystonic symptoms in NA. However, it should be kept in mind that this evolutive disease has a wide spectrum of symptoms. The decision to perform surgery involves full assessment of the risk of side-effects and the clinical features of each patient. The latter must also guide the choice of target and stimulation parameters.

c) DBS frequency screening for programming optimization in a patient with chorea-acanthocytosis
F. Gupta, N. Chan, R. Alterman, R. Walker, and M. Tagliati
Mount Sinai Health Center, New York, NY, USA

Objective: To explore the optimal frequency of therapeutic pallidal stimulation in a patient with genetically confirmed neuroacanthocytosis (NA).
Background: Pharmacological treatment of NA, including antipsychotics, tetrabenazine, tiapride and levitiracetam, has often been proven ineffective. The use of pallidal deep brain stimulation (DBS) has been reported in five previous medication-resistant NA patients. A superior efficacy of lower stimulation frequencies (40Hz) has been reported, while classical high frequency stimulation (130 Hz) either failed to provide benefits or worsened NA symptoms.
Methods: Bilateral pallidal DBS was performed on a 49 year-old male with a two year history of medically resistant, progressive orobuccal dyskinesia with recurrent tongue biting associated with distressful, tasteless belching. Choreiform movements involving the lower extremities caused a mild gait disturbance. Diagnosis was confirmed by peripheral blood smear positive for acanthocytes, elevated CPK and genetic testing. Instead of applying a routine voltage screening during initial programming, we adopted a new paradigm maintaining constant voltage (3.0V) and pulse width (210 microsec) while performing a frequency screening with systematic changes every 24 hours. Tested frequencies ranged from 10 to 130 Hz. Results were evaluated using the Unified Huntington's Disease Rating Scale (UHDRS).
Results: We observed best clinical results, as measured by the UHDRS, at 40 and 50 Hz stimulation using a single monopolar configuration and at 40 Hz using a double monopolar configuration. At 40Hz, maximum UHDRS score improvement from baseline of 64% (single monopolar) and 73% (double monopolar) was recorded. Stimulation at frequencies higher than 100 Hz were not effective and poorly tolerated.

Table 1: UHDRS scores following DBS programming screening at different stimulation frequencies
Frequency (Hz) UHDRS Score
  Single Monopolar (1-C+) Double Monopolar (1-2-C+)
Baseline 33 33
20 15 12
30 15 11
40 13 9
50 12 17
> 50 Not Tolerated Not Tolerated

Conclusions: Pallidal DBS is a safe and effective treatment for patients with advanced NA resistant to currently available medications. Our data confirm that lower stimulation frequencies (40-50 Hz) are more effective to treat NA than high frequencies typically used for tremor and Parkinson's disease treatment. New programming paradigms, highlighting the importance of frequency screening, should be further investigated to optimize DBS results in NA and other movement disorders.

d) Bilateral Deep Brain Stimulation of internal Globus pallidus in Chorea-acanthocytosis: New Neurological and Psychiatric Findings
L. Burghaus¹, J. Kuhn², M. Barbe¹, A. Pauls¹1, J. Klosterkötter², V. Sturm³, G. R. Fink¹, and L. Timmermann¹
¹Department of Neurology, University Hospital Cologne, Cologne, Germany
²Department of Psychiatry, University Hospital Cologne, Cologne, Germany
³Department of Neurosurgery, University Hospital Cologne, Cologne, Germany

Neuroacanthocytosis syndromes are a group of rare neurodegenerative disorders with co-occurring neurological deficits and peripheral blood acanthocytosis. Although pharmacological treatment strategies have positive effects, in many cases there is loss of efficacy with longer disease duration. Deep brain stimulation, employed in other movement disorders, has been tested as a therapeutic option in neuroacanthocytosis syndromes. We describe the effects of bilateral internal globus pallidus deep brain stimulation on the neurological and psychiatric symptoms of two patients suffering from pharmaco-resistant chorea-acanthocytosis. The data presented here, including a detailed neurological and psychiatric evaluation of disease course under conditions of low and high frequency deep brain stimulation, are of considerable value in this regard. We claim that deep brain stimulation should be included as a potential therapeutic option in the treatment of neuroacanthocytosis syndromes, particularly in cases with drug-resistant motor disturbances.