Long-term follow-up of pallidal Deep Brain Stimulation in teenagers with refractory Tourette syndrome and comorbid psychiatric disorders: About three cases.

OBJECTIVES: Tourette syndrome (TS) is a complex neuropsychiatric disorder associated with comorbid psychiatric disorders. Peak of tic severity typically occurs in early adolescence and impacts quality of life. Since 1999, promising therapeutic effects of Deep Brain Stimulation (DBS) have been reported in tic reduction for adults with refractory TS. The aim of the study was to assess the long-term risk-benefit ratio of pallidal DBS for young patients with refractory TS and severe comorbid psychiatric disorders. METHODS: We retrospectively assessed the long-term clinical outcomes of three adolescents who underwent pallidal DBS for the treatment of refractory TS. RESULTS: The mean duration of follow-up was 52 months in our case series. We observed that motor tics decreased with posteroventral GPi DBS in all patients, without reaching a continuous significance over the long-term follow-up. Self-reported social inclusion was globally improved, despite lack of efficacy of DBS on comorbid conditions. CONCLUSIONS: These findings suggest a long-term therapeutic benefit of early DBS intervention for highly socially impaired young patients suffering from intractable TS with severe comorbid psychiatric conditions. Further studies are needed to determine the most effective targets of DBS on both tics and comorbid psychiatric profile of TS.

Extragenetic factors and clinical penetrance of DYT1 dystonia: an exploratory study.

Factors modifying the clinical penetrance of DYT1 dystonia are incompletely defined. Particularly, the contribution of extragenetic factors has been subject to only limited investigation and remains largely unexplored. A possible effect of childhood infections has been proposed, and the effect of other factors, such as perinatal adversity and trauma, has not been systematically investigated. We performed an exploratory analysis of the exposure to perinatal adversity, childhood infections, general anaesthesia and trauma comparing 39 manifesting carriers of the ∆GAG mutation, 23 non-manifesting carriers and 48 non-carriers from a multi-centre European series of 28 families with DYT1 dystonia, by means of a self-completed questionnaire and clinical interview. Detailed information on perinatal adversities (pre-term birth, complications at natural delivery, urgent caesarean section), previous childhood infections, and prior general anaesthesia or physical trauma was recorded. A positive association between a history of complications of vaginal delivery and manifestation of dystonia was detected, which was not confounded by age, gender, or education level (odds ratio 8.47, 95 % confidence interval 1.45-49.4, p = 0.02). We could not observe any significant association between presence of dystonia and the other investigated variables. Comparing non-manifesting carriers to non-carriers, the presence of the ∆GAG mutation per se was not associated with any of the environmental exposures explored. Perinatal adversities might modulate the clinical penetrance of DYT1 dystonia; their interaction with known genetic factors modifying penetrance of this condition should be investigated in new, larger collaborative studies.

Stereotactic MRI in DYT1 dystonia: focal signal abnormalities in the basal ganglia do not contraindicate deep brain stimulation.

AIMS: To study stereotactic magnetic resonance imaging (MRI) features of the basal ganglia in DYT1 primary dystonia. METHODS: Twenty-five genetically confirmed DYT1 dystonia patients (age range, 8-66 years; mean age, 22 years) underwent brain MRI under general anesthesia at the time of globus pallidus internus (GPi) deep brain stimulation (DBS) surgery. MR images were retrospectively reviewed for signal intensity alterations. Clinical improvement of patients was assessed by comparing pre- and postoperative Burke-Fahn-Marsden Dystonia Rating Scale scores. RESULTS: Seventeen patients out of 25 (68%) exhibited T(1)-weighted hypointense/T(2)-weighted hyperintense signal abnormalities in the putamen and globus pallidus on MR images. Signals were isointense with cerebrospinal fluid in all sequences. The mean volume of focal signal abnormalities was 15 mm(3) (maximum, 154.5 mm(3)). The total volume of focal signal abnormalities in the basal ganglia was correlated with the duration of the disease (p = 0.01). Although clinical outcome did not differ as a function of the presence of focal signal abnormalities overall, patients with signals within the GPi tended to show lesser improvement (p = 0.04). CONCLUSIONS: T(1)-hypointense/T(2)-hyperintense signal abnormalities are common findings in the putamen and globus pallidus of DYT1 patients but do not contraindicate DBS. However, their presence within the GPi may reduce the efficacy of DBS treatment.

Is the early-onset torsion dystonia (EOTD) linked to TOR1A gene as frequent as expected in France?

Early onset torsion dystonia are rare movement disorders. Molecular defect is known for only a subgroup, consisting of a unique and recurrent mutation in the TOR1A gene. We undertook a nationwide census of French TOR1A-mutation carriers and the assessment of clinical associated signs. Overall, 53 index cases and 104 relatives were studied and haplotypes linked to the mutation constructed. The previously reported Ashkenazi-Jewish haplotype was found in 11 families with the remainder carrying distinct haplotypes suggesting independent mutation events. This study demonstrates the scarcity of this disease in France with estimated disease frequency of 0.13:100,000 and mutation frequency of 0.17:100,000.

[Neurosurgical treatment in childhood dystonias and dyskinesias]. / Tratamientos neuroquirúrgicos en las distonías y discinesias de la infancia.

AIM: To present the post-surgery clinical results of deep brain stimulation of the internal globus pallidus (GPi) in a group of paediatric patients with primary and secondary dystonic-dyskinetic syndrome. PATIENTS AND METHODS: Between November 1996 and May 2006, 121 patients were submitted to interventions with bilateral deep brain stimulation of the GPi, 58 of whom were children (age range: 5-16 years); 35 were cases of primary dystonia, of which 17 were carriers of the DYT1 mutation and 10 were not. A further 8 cases were myoclonic dystonias, 3 of whom presented the DYT11 mutation. With regard to the secondary dystonias, 4 were carriers of PKAN (pantothenate kinase-associated neurodegeneration) syndrome and 9 were cases of post-anoxic encephalopathies. RESULTS: Percentage improvements were as follows: in the case of DYT1+ primary dystonias, 80% at one year maintained at 3 years; in cases of DYT1-, 70% at one year maintained at 3 years, and in the myoclonic dystonias, 50% at one year and 85% at 3 years. In the group of patients with secondary dystonias due to post-anoxic encephalopathies, we found an improvement of 30% at one year and 40% at 3 years; in the group with PKAN syndrome, the figures were 60% at one year and 50% at two years. CONCLUSIONS: Treatment involving bilateral deep brain stimulation of the GPi nuclei in childhood cases of generalised dystonias is highly effective, the best prognoses being those offered by the group with primary dystonias and especially those related to the DYT1 mutation. Treatment also proved to be effective in the case of secondary dystonias, although with lower degrees of improvement.

Tratamientos neuroquirúrgicos en las distonías y discinesias de la infancia / Neurosurgical treatment in childhood dystonias and dyskinesias

Objetivo. Presentar los resultados clínicos poscirugíade estimulación cerebral profunda del globo pálido interno (Gpi)en un grupo de enfermos pediátricos con síndrome distonodiscinéticoprimario y secundario. Pacientes y métodos. Desde noviembrede 1996 hasta mayo de 2006 se operaron con estimulación cerebralprofunda del Gpi, de forma bilateral, 121 enfermos, de los cuales58 eran niños (rango de edad: 5-16 años): 35 eran distonías primarias,de los que 17 eran portadores de la mutación DYT1, 10 no y 8eran distonías mioclónicas, tres de ellas con la mutación DYT11.En cuanto a las distonías secundarias, 4 eran portadores del síndromePKAN (pantothenate kinase-associated neurodegeneration) y9 eran encefalopatías postanóxicas. Resultados. La mejoría porcentualfue la siguiente: en el caso de las distonías primariasDYT1+, 80% al año mantenida a los 3 años; en los DYT1–, 70% alaño mantenida a los 3 años, y en las distonías mioclónicas, 50%al año y 85% a los 3 años. En el grupo de enfermos con distoníassecundarias por encefalopatías postanoxicas encontramos una mejoríadel 30% al año y 40% a los 3 años, y en el grupo con síndromePKAN, 60% al año y 50% a los dos años. Conclusiones. El tratamientopor estimulación cerebral profunda bilateral de los núcleosdel Gpi en los casos de distonías generalizadas de la infanciaes altamente eficaz, siendo el grupo de las distonías primarias y especialmentelas relacionadas con la mutación DYT1 las de mejorpronóstico. En el caso de las distonías secundarias, la eficaciatambién se ha probado, aunque con grados de mejoría inferiores

Aim. To present the post-surgery clinical results of deep brain stimulation of the internal globus pallidus (GPi) ina group of paediatric patients with primary and secondary dystonic-dyskinetic syndrome. Patients and methods. BetweenNovember 1996 and May 2006, 121 patients were submitted to interventions with bilateral deep brain stimulation of the GPi,58 of whom were children (age range: 5-16 years); 35 were cases of primary dystonia, of which 17 were carriers of the DYT1mutation and 10 were not. A further 8 cases were myoclonic dystonias, 3 of whom presented the DYT11 mutation. With regardto the secondary dystonias, 4 were carriers of PKAN (pantothenate kinase-associated neurodegeneration) syndrome and 9were cases of post-anoxic encephalopathies. Results. Percentage improvements were as follows: in the case of DYT1+primary dystonias, 80% at one year maintained at 3 years; in cases of DYT1–, 70% at one year maintained at 3 years, and inthe myoclonic dystonias, 50% at one year and 85% at 3 years. In the group of patients with secondary dystonias due to postanoxicencephalopathies, we found an improvement of 30% at one year and 40% at 3 years; in the group with PKAN syndrome,the figures were 60% at one year and 50% at two years. Conclusions. Treatment involving bilateral deep brain stimulation ofthe GPi nuclei in childhood cases of generalised dystonias is highly effective, the best prognoses being those offered by thegroup with primary dystonias and especially those related to the DYT1 mutation. Treatment also proved to be effective in thecase of secondary dystonias, although with lower degrees of improvement

The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal-recessive disorder caused by mutations in the PANK2 gene. The authors report clinical and genetic findings of 16 patients with PKAN. The authors identified 12 mutations in the PANK2 gene, five of which were new. Only nine patients could be classified as classic or atypical PKAN, and intermediate phenotypes are described. Two patients presented with motor tics and obsessive-compulsive behavior suggestive of Tourette syndrome.

Accelerometric measurement of involuntary movements during pallidal deep brain stimulation of patients with generalized dystonia.

Accelerometric activity during rest and posture was quantified in the upper dominant limb of 14 patients with primary or secondary dystonia and five healthy control subjects. Data were recorded before and after bilateral implantation of the stimulating electrodes in the Globus Pallidus internus. Clinical evaluation was based on the Burke-Marsden-Fahn's Dystonia Rating Scale (BMFDRS). For the patient group, I(t), the integral (i.e. area) of the acceleration power spectrum over the total frequency range (0.6-16 Hz) decreased as the clinical state of the patients improved following deep brain stimulation (p < 0.01) during rest and posture. Ten days after surgery, there were no I(t) differences between control subjects and patients (p > 0.05). A significant correlation was found between the global BMFDRS scores and I(t) for rest (p < 0.01) but not for posture. No significant correlation was found between I(t) and a partial BMFDRS score for the right arm for rest or posture. The integral I(t) provides a valid indicator of the motor activity generated by the arm of the patient but further analyses are needed to monitor patients' progress not only during their hospitalization but also after they are released from the hospital, and to understand why this measure does not correlate with partial BMFDRS scores.

[Kinematic evaluation of dystonic syndromes in patients treated with deep brain stimulation]. / La cinématique dans l'évaluation des syndromes dystoniques sous stimulation cérébrale profonde.

INTRODUCTION: Quantification of motor functions of patients with dystonic syndromes treated by chronic high frequency stimulation of the internal globulus pallidus is a challenge. OBJECTIVE: Through a series of clinical examples this paper shows that kinematic analysis of movements in dystonic syndromes treated by deep brain stimulation (DBS) is a complement to clinical evaluation. In addition, it provides valuable information for early detection of improvement or impairment of movements associated with modifications of stimulation parameters. METHOD: Thirteen dystonic patients and eleven reference subjects completed three tests (i.e., rest: lying supine; posture: standing with arms held in front (at shoulder height); and alternative movements: bimanual finger-to-nose test). These tests were recorded with an electromagnetic system quantifying movement kinematics (position) in three-dimensional space. RESULTS: From the recorded data, several indices were developed and provided a quantitative evaluation of movements during each test. In addition, a clinical evaluation (BMFDRS) was also completed. No correlation between clinical and kinematic evaluations was found. CONCLUSION: It is shown that kinematic analysis is a useful complement of clinical evaluation and can assist clinicians in monitoring the evolution of movements in dystonic patients treated by DBS in a simple, reliable and valid fashion.

Treatment of dystonic syndromes by chronic electrical stimulation of the internal globus pallidus.

AIM: Dystonia is a medically intractable condition causing twisting or myoclonic movements and abnormal postures. There is an important heterogeneity among etiologies of dystonia. The electrical stimulation of the globus pallidus has been used successfully in primary generalized dystonia. The aim of this study was to examine the long-term efficacy and safety of deep brain stimulation (DBS) in the treatment of primary and secondary generalized dystonia in children and adults. METHODS: Fifty-three patients were included. Electrodes were bilaterally implanted under stereotactic guidance and connected to neurostimulators, subcutaneously inserted. Efficacy was evaluated by comparing scores on the clinical and functional Burke-Marsden-Fahn dystonia rating scales (BMFDRS) before and after implantation. Patients were divided into 3 groups: group 1 comprised 15 patients with DYT1 dystonia; group 2, 17 patients with dystonia of unknown etiology and group 3, 21 patients with secondary dystonia. The mean follow-up was 26.6+/-12.3 months for primary dystonia and 23.1+/-11.8 for secondary dystonia. RESULTS: After 1 year, the improvement of the clinical score is 71% in group 1, 74% in group 2 and 31% in group 3. The functional score was improved by 63% in group 1, 49% in group 2 and 7% in group 3. We did not find any significant difference between children and adults. In secondary dystonia, efficacy of the stimulation is more limited. The efficacy of the stimulation improved with time for the 3 groups. COMCLUSION: Electrical stimulation of the internal globus pallidus proved to be an effective treatment for generalized dystonia and should be considered as first-line therapy.

Magnetic resonance imaging stereotactic target localization for deep brain stimulation in dystonic children.

OBJECT: The actual distortion present in a given series of magnetic resonance (MR) images is difficult to establish. The purpose of this study was to validate an MR imaging-based methodology for stereotactic targeting of the internal globus pallidus during electrode implantation in children in whom general anesthesia had been induced. METHODS: Twelve children (mean follow up 1 year) suffering from generalized dystonia were treated with deep brain stimulation by using a head frame and MR imaging. To analyze the influence of distortions at every step of the procedure, the geometrical characteristics of the frame were first controlled using the localizer as a phantom. Then pre- and postoperative coordinates of fixed anatomical landmarks and electrode positions, both determined with the head frame in place, were statistically compared. No significant difference was observed between theoretical and measured dimensions of the localizer (Student's t-test, ¿t¿ > 2.2 for 12 patients) in the x, y, and z directions. No significant differences were observed (Wilcoxon paired-sample test) between the following: 1) pre- and postoperative coordinates of the anterior commissure (AC) (deltax = 0.3+/-0.29 mm and deltay = 0.34+/-0.32 mm) and posterior commissure (PC) (deltax = 0.15+/-0.18 mm and deltay = 0.34+/-0.25 mm); 2) pre- and postoperative AC-PC distance (deltaL = 0.33+/-0.22 mm); and 3) preoperative target and final electrode position coordinates (deltax = 0.24+/-0.22 mm; deltay = 0.19+/-0.16 mm). CONCLUSIONS: In the authors' center, MR imaging distortions did not induce detectable errors during stereotactic surgery in dystonic children. Target localization and electrode implantation could be achieved using MR imaging alone after induction of general anesthesia. The remarkable postoperative improvement in these patients confirmed the accuracy of the procedure (Burke-Marsden-Fahn Dystonia Rating Scale score delta = -83.8%).

Treatment of early-onset dystonia: update and a new perspective.

Dystonia is a rare disease of childhood, often leading to devastating functional impairment. Medical treatment is reviewed, although its efficacy is often limited. Recent advances in functional neurosurgery have opened up a new field in the management of dystonic patients, and the results of deep brain stimulation are given particular emphasis.