4-Phenylbutyrate attenuates the ER stress response and cyclic AMP accumulation in DYT1 dystonia cell models.

Dystonia is a neurological disorder in which sustained muscle contractions induce twisting and repetitive movements or abnormal posturing. DYT1 early-onset primary dystonia is the most common form of hereditary dystonia and is caused by deletion of a glutamic acid residue (302/303) near the carboxyl-terminus of encoded torsinA. TorsinA is localized primarily within the contiguous lumen of the endoplasmic reticulum (ER) and nuclear envelope (NE), and is hypothesized to function as a molecular chaperone and an important regulator of the ER stress-signaling pathway, but how the mutation in torsinA causes disease remains unclear. Multiple lines of evidence suggest that the clinical symptoms of dystonia result from abnormalities in dopamine (DA) signaling, and possibly involving its down-stream effector adenylate cyclase that produces the second messenger cyclic adenosine-3', 5'-monophosphate (cAMP). Here we find that mutation in torsinA induces ER stress, and inhibits the cyclic adenosine-3', 5'-monophosphate (cAMP) response to the adenylate cyclase agonist forskolin. Both defective mechanins are corrected by the small molecule 4-phenylbutyrate (4-PBA) that alleviates ER stress. Our results link torsinA, the ER-stress-response, and cAMP-dependent signaling, and suggest 4-PBA could also be used in dystonia treatment. Other pharmacological agents known to modulate the cAMP cascade, and ER stress may also be therapeutic in dystonia patients and can be tested in the models described here, thus supplementing current efforts centered on the dopamine pathway.

Pallidal deep brain stimulation for DYT6 dystonia.

BACKGROUND: Mutations of the THAP1 gene were recently shown to underlie DYT6 torsion dystonia. Little is known about the response of this dystonia subtype to deep brain stimulation (DBS) at the internal globus pallidus (GPi). METHODS: Retrospective analysis of the medical records of three DYT6 patients who underwent pallidal DBS by one surgical team. The Burke-Fahn-Marsden Dystonia Rating scale served as the primary outcome measure. Comparison is made to 23 patients with DYT1 dystonia also treated with GPi-DBS by the same team. RESULTS: In contrast with the DYT1 patients who exhibited a robust and sustained clinical response to DBS, the DYT6 patients exhibited more modest gains during the first 2 years of therapy, and some symptom regression between years 2 and 3 despite adjustments to the stimulation parameters and repositioning of one stimulating lead. Microelectrode recordings made during the DBS procedures demonstrated no differences in the firing patterns of GPi neurons from DYT1 and DYT6 patients. DISCUSSION: Discovery of the genetic mutations responsible for the DYT6 phenotype allows for screening and analysis of a new homogeneous group of dystonia patients. DYT6 patients appear to respond less robustly to GPi-DBS than their DYT1 counterparts, most likely reflecting differences in the underlying pathophysiology of these distinct genetic disorders. CONCLUSIONS: While early results of pallidal DBS for DYT6 dystonia are encouraging, further research and additional subjects are needed both to optimise stimulation parameters for this population and to elucidate more accurately their response to surgical treatment.

An anticholinergic reverses motor control and corticostriatal LTD deficits in Dyt1 ΔGAG knock-in mice.

DYT1 early-onset generalized torsion dystonia is an inherited movement disorder associated with mutations in DYT1 that codes for torsinA protein. The most common mutation seen in this gene is a trinucleotide deletion of GAG. We previously reported a motor control deficit on a beam-walking task in our Dyt1 ΔGAG knock-in heterozygous mice. In this report we show the reversal of this motor deficit with the anticholinergic trihexyphenidyl (THP), a drug commonly used to treat movement problems in dystonia patients. THP also restored the reduced corticostriatal long-term depression (LTD) observed in these mice. Corticostriatal LTD has long been known to be dependent on D2 receptor activation. In this mouse model, striatal D2 receptors were expressed at lower quantities in comparison to wild-type mice. Furthermore, the mice were also partially resistant to FPL64176, an agonist of L-type calcium channels that have been previously reported to cause severe dystonic-like symptoms in wild-type mice. Our findings collectively suggest that altered communication between cholinergic interneurons and medium spiny neurons is responsible for the LTD deficit and that this synaptic plasticity modification may be involved in the striatal motor control abnormalities in our mouse model of DYT1 dystonia.

Dystonia.

INTRODUCTION: Dystonia is usually a lifelong condition with persistent pain and disability. Focal dystonia affects a single part of the body; generalised dystonia can affect most or all of the body. It is more common in women, and some types of dystonia are more common in people of European Ashkenazi Jewish descent. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, surgical treatments, and physical treatments for focal, and for generalised dystonia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 15 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acetylcholine release inhibitors (botulinum toxin), acupuncture, anticholinergic/antihistaminic drugs, anticonvulsants, atypical antipsychotic drugs, benzodiazepines, biofeedback, chiropractic manipulation, deep brain stimulation of thalamus and globus pallidus, dopaminergic agonists and antagonists, gamma-aminobutyric acid (GABA) analogues, microvascular decompression, muscle relaxants, myectomy, occupational therapy, osteopathy, pallidotomy, physiotherapy, selective peripheral denervation, serotonergic agonists and antagonists, speech therapy, and thalamotomy.

Status dystonicus a rare complication of dystonia.

A severe episode of dystonia refractory to standard drug therapy has been labeled as status dystonicus or dystonic storm. We report the development of this complication in a 10-year old boy with idiopathic torsion dystonia, the probable precipitating factor being either an infection or introduction of clonazepam.

[Case of DYT1 dystonia (early-onset torsion dystonia) showing long-term focal dystonia in the arm].

DYTI dystonia (DYT1-D, early-onset torsion dystonia) is caused by a GAG deletion in the DYTI gene. Here we report a girl with child-onset familial DYT1-D showing localized arm involvement. The patient developed postural and action dystonia in the right and left arms at 7 and 9 years, respectively. She was misdiagnosed as hysteria due to lack of abnormalities on laboratory tests. At 11 years of age she was introduced to our clinic. Increased muscle tonus and dystonic discharges seen on surface electromyogram in the right arm and the sternocleidomastoid muscle led to the diagnosis of dystonia. A GAG deletion in the DYTI gene was confirmed in the patient, her healthy father and paternal grandfather with torsion dystonia. Titration of levodopa resulted in the fluctuation of her arm dystonia. Combined therapy by levodopa and trihexyphenidyl relieved postural dystonia in the right arm but not action dystonia in the left. Both types of dystonia in the right and left arms were well ameliorated by the additional increase of levodopa. Somatosensory evoked potentials demonstrated abnormal premovement gating. The latency and accuracy of the amplitude were disturbed in visually guided saccadic eye movement. Now at more than 11 years after onset, the patient has not shown torsion or involvement of the lower extremities. Most DYT1-D patients are refractory to medication and early surgical intervention is recommended. However, the presence of DYT1-D patients showing a milder disease course should also be considered.

[Continuous infusion of baclofen and an antibiotic for treating meningitis related to refilling of an intrathecal infusion pump reservoir]. / Infusión continua de baclofeno con antibiótico para el tratamiento de meningitis asociada a relleno del reservorio de la bomba de perfusión intratecal.

Baclofen via intrathecal infusion pump is a widely used treatment severe spasticity. Complications are rare and usually mild, though they can also be serious. The sudden discontinuation of intrathecal baclofen may have significant adverse effects. We report the case of a 59-year-old man with chronic spasticity and torsion dystonia who developed meningitis due to Staphylococcus epidermidis due to contamination of the intrathecal, infusion pump reservoir during refilling. It was decided to treat the patient by administering vancomycin through the pump, together with the baclofen. We believe that changing the intrathecal perfusion pump is not necessary as the first measure to take in these cases. Combined infusion of baclofen and an antibiotic through the pump makes it possible to maintain antispastic treatment, sterilize the pump reservoir and tubes, and effectively treat infections that develop during use of these systems.

Dystonia.

INTRODUCTION: Dystonia is usually a lifelong condition with persistent pain and disability. Focal dystonia affects a single part of the body; generalised dystonia can affect most or all of the body. It is more common in women, and some types of dystonia are more common in people of European Ashkenazi Jewish descent. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, surgical treatments, and physical treatments for focal, and for generalised dystonia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 13 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acetylcholine receptor inhibitors, acupuncture, anticholinergic drugs, anticonvulsants, atypical antipsychotic drugs, benzodiazepines, biofeedback, botulinum toxin, chiropractic manipulation, deep brain stimulation of thalamus and globus pallidus, dopaminergic agonists and antagonists, gamma-aminobutyric acid (GABA) inhibitors, microvascular decompression, myectomy, occupational therapy, osteopathy, pallidotomy, physiotherapy, selective peripheral denervation, serotonergic agonists and antagonists, speech therapy, and thalamotomy.

Distonía focal del pie de inicio en el adulto / Adult-onset primary focal foot dystonia

Introducción. La distonía focal idiopática del pie de inicioen el adulto es una entidad rara de la que hasta la fechasólo se han encontrado siete casos publicados en la literatura.Dado que las formas idiopáticas en el adulto son excepcionales,su presentación obliga siempre a descartar formassecundarias. Caso clínico. Mujer de 51 años con distonía focal delpie de 3 años de evolución. La paciente presentaba posturaen flexión plantar e inversión del pie que empeoraba con laacción. Las exploraciones complementarias dirigidas a descartarcausas secundarias fueron negativas. A lo largo de suevolución el fenómeno distónico permaneció limitado al piey no desarrolló otra sintomatología neurológica. La pacientese benefició de tratamiento con toxina botulínica. Conclusiones. La distonía focal primaria idiopática delpie en el adulto es excepcional. El patrón más común es laflexión plantar y de los cinco dedos. El dolor asociado es unsíntoma relativamente frecuente. La patogenia es sólo parcialmenteconocida, los estudios neurofisiológicos y de resonanciafuncional demuestran que existe una pérdida delcontrol inhibitorio a nivel espinal y troncoencefálico, unaplasticidad cortical anómala y una integración sensitivomotoradefectuosa. La respuesta al tratamiento con fármacosorales es escasa, pero los pacientes pueden beneficiarsede la infiltración con toxina botulínica en los músculos implicados

Introduction. Adult-onset primary focal foot dystoniais a rare event. Up to now, only 7 cases have been reportedin the literature. Since the idiopathic-type fooddystonia is uncommon in adults, secondary types mustbe ruled out. Clinical report. We present the case of a 51 yearwoman with a 3 year history of focal food dystonia. Shehad abnormal posture of the foot with plantar flexionand inversion, which worsened with action. Complementarystudies aimed at ruling out secondary causes wereall negative. The dystonia remained limited to her foodand she did not develop any other neurological symptoms.She benefited from botulinum toxin treatment. Conclusions. Primary focal foot dystonia is uncommonin adults. The most common pattern is plantar andfive toes flexion. Associated pain is common. Its pathogenesisis only partially understood, the neurophysiologicstudies and functional resonance showing a loss ofinhibitory control at spine and brainstem levels, abnormalcortical plasticity and altered sensorimotor integration.The response of this disorder to drugs is poor, however,the patients may benefit from botulinum toxininfiltrations of the muscles involved

Dystonia: genetics and treatment update.

BACKGROUND: Dystonia refers to a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. Although age at onset, anatomic distribution, and family history are essential elements in the evaluation of dystonia, new classification increasingly relies on etiologic and genetic data. In recent years, much progress has been made on the genetics of various forms of dystonia and its pathophysiology underlying the clinical signs. The treatment of dystonia has continued to evolve to include newer medications, different forms of botulinum toxin, and various surgical procedures. REVIEW SUMMARY: In this article, the author reviewed and summarized the history of dystonia, its evolving classification, and recent genetic data, as well as its clinical investigation and treatment. CONCLUSIONS: Recent advances in molecular biology have led to the discovery of novel dystonia genes and loci, updating classification schemes, and better understanding of underlying pathophysiology. Treatment strategies for dystonia have significantly been updated with the introduction of different forms of botulinum toxin therapy, new pharmacologic agents, and most recently pallidal deep brain stimulation. A systematic approach to the diagnosis and treatment evaluation of dystonic patients provides optimal care for long-term management.

[Some pathophysiological mechanisms of muscular tone impairment]. / Nekotorye patofiziologicheskie mekhanizmy narusheniia myshechnogo tonusa.

Pathophysiological mechanisms of the muscular tone was studied clinicoelectrophysiologically (the method of stimulating electromyography with evoked H-reflex) in 130 healthy subjects and 63 patients with dystonia musculorum deformans (23 patients of the latter were examined before and after intake of a therapeutic dose of L-DOPA). It was found that patients with impaired muscular tone have low activity of spinal motoneurons on both sides of the body especially the activity of phasic motoneurons and on the right side of the body. L-DOPA activates motoneurons, higher activation seen for the phasic motoneurons and on the right side of the body.

Adverse effects of dopamine potentiation by long-term treatment with selegiline.

A patient with triosephosphate isomerase (TPI) deficiency exhibited worsening of abnormal involuntary movements of the dystonic type and developed psychiatric symptoms while on selegiline. When selegiline was stopped after 9 years of treatment, abnormal involuntary movements improved to pretreatment level and psychiatric behaviour returned to normal. Monoamine oxidase-B platelet activity was low in this patient.

[Chronic high frequency deep brain stimulation of the globus pallidus internus for torsion dystonia]. / Chronische Tiefenhirnstimulation des Globus pallidus internus bei Torsionsdystonie.

Deep Brain Stimulation (DBS, chronic high frequency stimulation) is well established for Parkinson's disease and tremordominant movement disorders. Generalized dystonia is known as a type of movement disorder in which therapeutic options are very limited. A case of generalized dystonia is reported which was successfully treated by DBS in the Globus pallidus internus (GPI). A 26 years old male suffered from severe torsion dystonia of the lower limbs. The onset of symptoms was at age 7. It started with dystonia of the left foot. He very fast developed severe dystonia of the lower limbs. These complaints were initially treated by diazepam, later by baclofen (Lioresal ((R))) p.o em leader There was no L-DOPA response. Because of the rapid progression of the disease a cervical spinal cord stimulator was implanted with a transient success. Due to further progression of the disease the patient became wheelchair bounded and resistant for oral medication. Limited improvement of symptoms was achieved using continuous intrathecal administration of baclofen. Finally the patient was treated with 980 microgram intrathecal Baclofen (Lioresal ((R))) daily and up to 100 mg diazepam. Under these conditions the patient remained wheelchair bounded with severe lower limb dystonia. As an ultima ratio it was decided to treat the patient with stereotactic implantation of two electrodes (Medtronic 3387) and two neurostimulators (Medtronic ITREL ((R))II). The GPI was the bilateral target point. Intraoperative computerized tomography and ventriculography were used for target setting. Furthermore microrecordings were helpful to ensure the exact electrode positioning. Surgery was performed under sedation. Two weeks after surgery first improvement of symptoms was observed. Patient was able to stand with assistance. At the three months follow-up he could walk without assistance. Slight dystonic movement of the left ankle was the only remaining symptom under stimulation. The oral medication has been continuously reduced. After 6 months it was stopped. The intrathecal administered baclofen was diminished to 250 microgram daily. At the 24 months follow-up the effect of stimulation remained unchanged. However high stimulation parameters are required to maintain an optimal effect (3,5 V, 400 microseconds 145 Hz for both sides). Deep Brain Stimulation of the Globus Pallidus internus is an alternative approach for severe cases of generalized dystonia.

Alcohol with xylocaine for treatment of eyelid dystonia.

Eyelid dystonia represents a form of idiopathic torsion dystonia, and it is considered as a rare disorder. Although botulinum toxin injections into the eyelids and eyebrows are considered by many neurologists as the treatment of choice for this, its cost limit its use in our community. A study was conducted at the King Hussein Medical Center between January 1995 and January 1998 using 1-2 ml of 0.5% xylocaine added to 99.5% ethanol in one-tenth of the volume of xylocaine, made injectable into the eyelids and eyebrows muscles in patients with blepharospasm. The treatment was aimed at reducing muscle spindle afferent activity. Twenty-one patients were given this modality of treatment in at least 8-12 separate sessions, with two weeks elapsing between any two sessions. Mild to moderate improvement was observed in 47.6% of our patients. The average latency from the time of the injection to the onset of improvement was 30-60 min and the average duration of improvement was 5-7 days. The commonest encountered side-effect was bruising at the site of injection that resolved spontaneously in less than 5 days. It is obvious that the usefulness of this treatment is limited by the substantially shorter duration of benefit, thus it cannot be considered as an alternative to Botox treatment. It may be useful to investigate whether a higher alcohol concentration is more effective.

Post-traumatic cervical dystonia: a distinct entity?

BACKGROUND/OBJECTIVE: The incidence of head/neck trauma preceding cervical dystonia (CD) has been reported to be 5-21%. There are few reports comparing the clinical characteristics of patients with and without a history of injury. Our aim was to compare the clinical characteristics of idiopathic CD (CD-I) to those with onset precipitated by trauma (CD-T). METHODS: We evaluated 114 consecutive patients with CD over a 9-month period. All patients were interviewed using a detailed questionnaire and had a neurological examination. Their clinical charts were also reviewed. RESULTS: Fourteen patients (12%) had mild head/neck injury within a year preceding the onset of CD. Between the two groups (CD-I and CD-T), the gender distribution (F:M of 3:2), family history of movement disorders (32% vs. 29%), the prevalence of gestes antagonistes (65% vs. 64%), and response to botulinum toxin were similar. There were non-specific trends, including an earlier age of onset (mean ages 43.3 vs. 37.6), higher prevalence of neck pain (86% vs. 100%), head tremor (67% vs. 79%), and dystonia in other body parts (23% vs. 36%) in CD-T. CONCLUSIONS: CD-I and CD-T are clinically similar. Trauma may be a triggering factor in CD but this was only supported by non-significant trends in its earlier age of onset.

Dystonia update.

Dystonia is a syndrome of sustained muscle spasms of presumed central nervous system origin. Recent advances in molecular biology have permitted clearer understanding of the genetics of various forms of dystonia and suggest pathophysiological deficits at the origin of the clinical signs. Treatment has involved centrally-acting drugs, specifically the anticholinergic medications, as well as peripherally acting agents that block neuromuscular transmission (botulinum toxin). Some forms of dystonia are particularly responsive to levodopa. A systematic approach to the diagnostic and treatment evaluation of dystonic patients permits optimal care for long-term management.

[Recessive dopa-responsive form of dystonia due to a mutation of the tyrosine hydroxylase gene]. / Dystonie dopa-sensible forme récessive mutation du gène de la tyrosine-hydroxylase.

The cause of Dystonia Musculorum Deformans (DMD) is most frequently unknown, therefore the treatment can only be symptomatic and often disappointing. In 1971 we reported the first two cases of recessive dopa-responsive dystonia, simulating a severe form of idiopathic DMD, however remarkably well reacting to levodopa treatment. We found that the first above mentioned two cases are related to mutations in the tyrosine hydroxylase gene itself in the chromosome 11p. An other variety which is dominant, with marked diurnal fluctuation, is due to mutations of a cofactor of the tyrosine hydroxylase, located in chromosome 14q. Consequently a trial of dopa treatment should be given in all diseases evoking a DMD diagnosis. Further more it is possible to confirm the diagnosis by a genetic inquiry.

[Movement disorders: dystonias which are apparently psychosomatic. Torsion dystonias]. / Movimientos anormales: distonías aparentemente psicosomáticas. Distonías de torsión.

In neuropediatric clinical practice, disorders of movement include a wide diversity of conditions, amongst which the dystonias are uncommon in our practice, although they have to be considered amongst the possible diagnoses in some cases. The great variety of clinical symptoms and age of onset together with the nonspecific, erratic clinical course make diagnosis difficult. Some clinical pictures of genuine torsion disorders may be confused with hysterical conversion disorders, somatizations or Munchausen's syndrome. Diagnosis requires clinical knowledge of both conditions--torsion dystonia as opposed to hysteria or a conversion reaction--and considerable ability and experience. Genetics and molecular studies have helped to clarify some difficult diagnostic problems and facilitated both diagnosis and treatment. In a diagnostic video session we show the case of a seven year old boy who initially presented with a dystonic disorder. There was some doubt as to the aetiology and different types of treatment were given by different specialists. The true diagnosis was reached after molecular genetic studies.