Spastic Dystonia Research Articles

(232) CG100649, a novel dual-acting COX-2 and carbonic anhydrase inhibitor: Ascending single dose and multi-dose pharmacokinetics and safety evaluation in healthy male subjects

Stroke can be a condition causing damage to the descending corticospinal fibers that may result in symptoms of the Upper Motor Neuron Syndrome. This syndrome can include signs of abnormal antagonist cocontraction; abnormal cutaneomotor reflexes, spastic dystonia and synergistic motor patterning. Management of these abnormal motor behaviors will be determined by how they impact a patient’s life style, regardless of the etiology. When considering treatment options, the following should be considered: duration, severity and location of spasticity along with functional status and goals. Management strategies often include a combination of interventions such as reducing noxious stimuli, stretching, oral or intrathecal medications or neurolysis with phenol. Neurolytic procedures including nerve blocks and motor branch blocks reduce focal or regional muscular over activity. Side effects of phenol nerve blocks can include parasthesia, yet vary rarely cause musculoskeletal pain. The following case report describes two patients with lower extremity spasticity that resulted in equinovarus deformity. This deformity can prevent and limit functional ambulation and transfers. The two patients in the study were treated with posterior tibial nerve blocks for the equinovarus deformity. Both patients developed musculoskeletal foot pain, which is unusual after posterior tibial nerve blocks. Each patient responded well to a combination treatment of a two week course of NSAIDS as well as foot plate brace padding to enhance arch support. Dysesthesia is a well known complication of phenol nerve blocks. This case study describes two cases of musculoskeletal foot pain as a novel complication of posterior tibial nerve blocks that was successfully treated with NSAIDs and foot orthoses. (234) CG100649, a novel dual-acting COX-2 and carbonic anhydrase inhibitor: Multi-dose pharmacokinetics and safety evaluation in healthy male and female subjects

A MELAS-Associated ND1 Mutation Causing Leber Hereditary Optic Neuropathy and Spastic Dystonia

To report a novel mutation that is associated with Leber hereditary optic neuropathy (LHON) within the same family affected by spastic dystonia. Leber hereditary optic neuropathy is a mitochondrial disorder characterized by isolated central visual loss. Of patients with LHON, 95% carry a mutation in 1 of 3 mitochondrial DNA-encoded complex I genes. The complete mitochondrial DNA was screened for mutations in a patient with LHON without 1 of these 3 primary mutations. The heteroplasmy level and biochemical consequence of the mutation were determined. A pathogenic 3697G>A/ND1 mutation was detected and seemed associated with an isolated complex I deficiency. This family has similar clinical characteristics as the previously described families with LHON and dystonia with an ND6 mutation. The 3697G>A/ND1 mitochondrial DNA mutation causes the LHON and spastic dystonia phenotype in the same family. This mutation can also cause MELAS syndrome (which encompasses mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke), and other genetic factors may contribute to the clinical expression.

Successful Treatment of Posttraumatic Hemiballismus with Intrathecal Baclofen Therapy

Intrathecal baclofen (ITB) therapy is widely used in the management of spastic hypertonia and dystonia resulting from a multitude of conditions that present with upper motor neuron syndrome signs, such as cerebral palsy, stroke, brain and spinal injuries, and multiple sclerosis. We report successful management of posttraumatic hemiballismus and dystonia with ITB in a 43-yr-old man who sustained a traumatic brain injury secondary to an assault in 1978. He subsequently developed hemiballismus in the right lower limb and dystonia of the distal right upper limb spreading proximally to involve the shoulder. The ballistic movement of the lower limb was severe enough to cause the patient to fall out of his chair and limit his ability to perform activities of daily living safely. He had been on various oral medications and received botulinum toxin and phenol injections, but none alleviated the symptoms. The patient elected to receive the ITB pump. Before ITB, he had an average of 10-12 ballism episodes of the right lower limb per hour. During observed episodes, the right hip would flex up to about 90 degrees, with a fully extended knee. After ITB pump implantation and upward dose titration, the frequency of ballistic right leg movements decreased to about three per day, and the right hip flexed to only 30 degrees. In addition, there was increased ability to isolate individual distal joint movements in the right lower limb. The patient currently receives 202.4 microg/day ITB and continues to benefit almost 6 yrs after ITB pump implantation. This report highlights the emerging role of ITB in managing movement disorders other than dystonia spastic hypertonia and dystonia.

The construct validity of a spasticity measurement device for clinical practice: An alternative to the Ashworth scales

Introduction. Spasticity is a significant cause of disability in people with an upper motor neurone lesion, but there is a paucity of appropriate outcome measures to evaluate this phenomenon. The aim was to test the construct validity of a clinically relevant, non-invasive measure of spasticity.Methods. A cross-section study design in which participants with elbow flexor spasticity and capable of providing written informed consent were recruited.Results. Fourteen stroke patients participated (six female and eight male). Median age was 61 years and the median time post stroke was 48 months. Six patients had a MAS grading of ‘1+’, three a grade of ‘2’ and five a grade of ‘3’. The velocity of the brisk stretch was significantly higher than that of the slow stretch (p < 0.05: median difference, 34°/s: IQR, 20 – 46). Flexor muscle activity during the brisk stretch was significantly higher than that of the slow stretch (p < 0.05: median difference, 2.0 μV; IQR, 0.4 – 8.4). In contrast the RPE was not significantly different between the slow and the fast stretches (p > 0.1: median difference, 0.07 N/deg; IQR, – 0.09 – 0.16). There were no patterns of association between the MAS, elbow flexor muscle activity and RPE. Other important observations, in some patients, were: continuous background muscle activation consistent with descriptions of spastic dystonia; muscle activity at the slow velocity stretch; muscle activation patterns consistent with the clasp-knife phenomenon.Conclusions. The measurement system was capable of measuring spasticity as defined by Lance (; In: Lance et al., editors. Spasticity: disordered motor control. Chicago, IL: Year Book. p 185 – 204). In addition, it enabled various other clinical phenomena associated with spasticity to be measured. Assessing spasticity by measuring changes in resistance to passive movement only may not be sufficient, as the latter is influenced by many factors of which spasticity may only be one. Further work is now required to investigate repeatability and sensitivity.

Botulinum toxin as a novel treatment for self‐mutilation in Lesch—Nyhan syndrome

Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder resulting from a deficiency of the metabolic enzyme hypozanthine-guanine phosphoribosyltransferase (HPRT). This syndrome presents with abnormal metabolic and neurological manifestations including hyperuricemia, mental retardation*, spastic cerebral palsy (CP), dystonia, and self-mutilation. The mechanism behind the severe self-mutilating behavior exhibited by patients with LNS is unknown and remains one of the greatest obstacles in providing care to these patients. This report describes a 10-year-old male child with confirmed LNS who was treated for self-mutilation of his hands, tongue, and lips with repeated botulinum toxin A (BTX-A) injections into the bilateral masseters. Our findings suggest that treatment with BTX-A affects both the central and peripheral nervous systems, resulting in reduced self-abusive behavior in this patient.

Botulinum toxin as a novel treatment for self-mutilation in Lesch–Nyhan syndrome

Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder resulting from a deficiency of the metabolic enzyme hypozanthine-guanine phosphoribosyltransferase (HPRT). This syndrome presents with abnormal metabolic and neurological manifestations including hyperuricemia, mental retardation*, spastic cerebral palsy (CP), dystonia, and self-mutilation. The mechanism behind the severe self-mutilating behavior exhibited by patients with LNS is unknown and remains one of the greatest obstacles in providing care to these patients. This report describes a 10-year-old male child with confirmed LNS who was treated for self-mutilation of his hands, tongue, and lips with repeated botulinum toxin A (BTX-A) injections into the bilateral masseters. Our findings suggest that treatment with BTX-A affects both the central and peripheral nervous systems, resulting in reduced self-abusive behavior in this patient.

Physiological effects of botulinum toxin in spasticity.

There is considerable evidence that injection of botulinum toxin (BTX) into muscles with spastic overactivity reduces resistance to passive movement in joints supplied by the injected muscles. The demonstration of improvement in active performance of the paretic limbs has been only anecdotal to date, and represents the most difficult challenge in research on BTX therapy in spastic paralysis. Data are reviewed that indicate several neurophysiological actions of BTX, other than the blocking of acetylcholine release at the neuromuscular ending: effects on the central nervous system, including retrograde axonal transport, reduced motoneuronal excitability, action on central synapses such as decreased Renshaw inhibition and increased presynaptic inhibition; action on gamma motoneuronal endings; action on most active terminals; spread of BTX to neighboring muscles; spread of BTX effects to remote muscles. Several of these neurophysiological actions are likely to contribute to improvement in active movements, as they may antagonize the primary mechanisms of functional impairment in patients with spastic paralysis: weakness, spastic cocontraction, spastic dystonia, and muscle shortening. We review the evidence for reduction of spastic cocontraction in both the injected muscle and its antagonist, and for improvement of antagonist weakness after BTX injection. The capacity of intramuscular BTX to reduce spastic dystonia and lengthen shortened muscles is also discussed based on prior literature. When injected into the more overactive of a pair of spastic antagonists around a joint, BTX should affect all the main mechanisms impairing active function around the joint.

Poster 195: Focal dystonia after stroke leading to trismus: a case report.

Setting: Midwest acute inpatient rehabilitation hospital. Patient: A 58-year-old woman. Case Description: The patient was diagnosed with a middle cerebral artery and lacunar stroke on January 9, 2002. She was admitted to acute inpatient rehabilitation on February 14, 2002, and was found to have trismus on the second day of admission. Differential diagnoses included: tetanus, abscess, dislocation, slipped disk, fracture, volitional noncooperation, and dystonia. Plain films followed by facial computed tomography with thin cuts did not reveal pathologic findings. Manipulation at bedside with sedation and bilateral masseter muscle block did not result in resolution of trismus. Treatment for tetanus was initiated while titer results were pending. The patient subsequently underwent exam under anesthesia, where her jaw was opened fully and no evidence of fractures, abscess, or dislocation was noted. Facial electromyography revealed increased activity in the left temporalis muscle, consistent with spastic dystonia. The tetanus titers were negative and the most likely diagnosis was focal spastic dystonia. Aggressive treatment was pursued because the patient was unable to accept oral intake and had been at severe nutrition risk since the onset of trismus. Tizanidine was started, and she received adjunctive treatment with 10U of botulinum toxin type A (BTX) by electromyographic guidance to the left temporalis muscle. 6 days later, she had partial resolution of her trismus and was able to tolerate oral intake. Assessment/Results: Focal dystonia of the left temporalis muscle. Discussion: Alterations in muscle tone are a common finding after acute stroke. However, this case demonstrates an unreported complication of stroke, and the importance of dystonia in the differential diagnosis of trismus. We demonstrate the use of BTX for focal spastic dystonia in the acute rehabilitation setting. Conclusions: Focal dystonia of the temporalis muscle is a rare complication of stroke, and must be considered in the differential diagnosis of trismus.

The pathophysiology of spasticity.

Spasticity is only one of several components of the upper motor neurone (UMN) syndrome, known collectively as the 'positive' phenomena, that are characterized by muscle overactivity. Other components include tendon hyper-reflexia, clonus, the clasp-knife phenomenon, flexor and extensor spasms, a Babinski sign, and spastic dystonia. Spasticity is a form of hypertonia due to hyperexcitable tonic stretch reflexes. It is distinguished from rigidity by its dependence upon the speed of the muscle stretch and by the presence of other positive UMN signs. Hyperactive spinal reflexes mediate most of these positive phenomena, while others are due to disordered control of voluntary movement or abnormal efferent drive. An UMN lesion disturbs the balance of supraspinal inhibitory and excitatory inputs, producing a state of net disinhibition of the spinal reflexes. These include proprioceptive (stretch) and nociceptive (flexor withdrawal and extensor) reflexes. The clinical syndrome resulting from an UMN lesion depends more upon its location and extent, and the time since it occurred, than on the pathology of the lesion. However, the change in spinal reflex excitability cannot simply be due to an imbalance in supraspinal control. The delayed onset after the lesion and the frequent reduction in reflex excitability over time, suggests plasticity in the central nervous system. Knowledge of the electrophysiology and neurochemistry of spinal reflexes, together with the action of antispasticity drugs, helps us to understand the pathophysiology of spasticity.

BOTULINUM TOXIN THERAPY

BACKGROUND- Muscle overactivity (e.g., spastic dystonia and pathologic antagonistic cocontraction), in addition to motor weakness and muscle shortening, is one of the three cardinal disabling features in patients with damage to central motor pathways. Muscle overactivity is usually not distributed equally throughout the body; instead, it predominates in certain muscles. As a result, imbalance often exists between hypoactive agonists and relatively hyperactive antagonists. Treatments targeting overactivity in specific muscles (local treatments) may therefore be preferable to generalized therapies. This article reviews the physiological action, pharmacology, risks, and indications of the most promising of these local treatments, botulinum toxin (BTX). REVIEW SUMMARY- BTX is a neurotropic protein that blocks acetylcholine release from all cholinergic terminals, including peripheral motor nerves, which results in flaccid paralysis when injected into muscle. Seven serotypes of BTX are produced by several species of Clostridium, and some have been purified for therapeutic purposes. The paralyzing action of BTX is temporary, and recovery of function occurs after terminal nerve sprouting and reformation of neuromuscular junctions. No muscle or nerve destruction occurs after BTX injection into muscle, as opposed to neurolytic agents (e.g., alcohol and phenol), and clinical tolerance is usually excellent. To target specific muscles, the stimulation technique seems more effective than passive EMG monitoring. Because BTX blocks all cholinergic synapses, it has also been used in autonomic disorders as an antimuscarinic agent. CONCLUSIONS- BTX is a well-tolerated, local pharmacologic treatment for muscle overactivity, and its range of licensed indications will likely increase, particularly among spastic conditions. However, pharmaco-economic considerations mandate that controlled comparative studies between BTX and other neurolytic agents are performed. The genetic synthesis of a biologically active BTX may render this treatment more cost-effective in the future. (THE NEUROLOGIST 6:98-115, 2000)

Treatment of spastic dystonia with transdermal nicotine

Nicotine has been shown to relieve some neurological disorders and a negative correlation between smoking and Parkinson's disease has been described. 1 Jarvik ME Beneficial effects of nicotine. Br J Addiction. 1991; 86: 571-575 Crossref PubMed Scopus (82) Google Scholar We investigated a patient with a long-standing spastic dystonia who noted an improvement in symptoms after smoking cigarettes.

Traditional pharmacological treatments for spasticity part I: Local treatments

Spasticity is a velocity-dependent increase in stretch reflex activity. It is one of the forms of muscle overactivity that may affect patients with damage to the central nervous system. Spasticity monitoring is relevant to function because the degree of spasticity may reflect the intensity of other disabling types of muscle overactivity, such as unwanted antagonistic co-contractions, permanent muscle activity in the absence of any stretch or volitional command (spastic dystonia), or inappropriate responses to cutaneous or vegetative inputs. In addition, spasticity, like other muscle overactivity, can cause muscle shortening, which is another significant source of disability. Finally, spasticity is the only form of muscle overactivity easily quantifiable at the bedside. Under the name pharmacological treatments of spasticity, we understand the use of agents designed to reduce all types of muscle overactivity, by reducing excitability of motor pathways, at the level of the central nervous system, the neuromuscular junctions, or the muscle. Pharmacologic treatment should be an adjunct to muscle lengthening and training of antagonists. Localized muscle overactivity of specific muscle groups is often seen in a number of common pathologies, including stroke and traumatic brain injury. In these cases, we favor the use of local treatments in those muscles where overactivity is most disabling, by injection into muscle (neuromuscular block) or close to the nerve supplying the muscle (perineural block). Two types of local agents have been used in addition to the newly emerged botulinum toxin: local anesthetics (lidocaine and congeners), with a fully reversible action of short duration, and alcohols (ethanol and phenol), with a longer duration of action. Local anesthetics block both afferent and efferent messages. The onset of action is within minutes and duration of action varies between one and several hours according to the agent used. Their use requires resuscitation equipment available close by. When a long-lasting blocking agent is being considered, we favor the use of transient blocks with local anesthetics for therapeutic tests or diagnostic procedures to answer the following questions: Can function be improved by the block? What are the roles played by overactivity and contracture in the impairment of function? Which muscle is contributing to pathologic posturing? What is the true level of performance of antagonistic muscles? A short-acting anesthetic can also serve as preparation to casting or as an analgesic for intramuscular injections of other antispastic treatment. Alcohol and phenol provide long-term chemical neurolysis through destruction of peripheral nerve. Experience with ethanol is more developed in children using intramuscular injection, while experience with phenol is greater in adults with perineural injection. In both cases, there are anecdotal reports of efficacy but studies have rarely been controlled. Side effects are numerous and include pain during injection, chronic dysesthesia and chronic pain, and episodes of local or regional vascular complications by vessel toxicity. In the absence of controlled studies, a theoretical comparison of neurolytic agents with botulinum toxin is proposed. Neurolytic agents may be preferred to botulinum toxin on a number of grounds, including earlier onset, potentially longer duration of effect, lower cost, and easier storage. Conversely, pain during injection, tissue destruction with chronic sensory side effects, and lack of selectivity on motor function with neurolytic agents may favor the use of botulinum toxin. Neurolytic agents and botulinum toxin may be used in combination, the former for larger proximal muscles and the latter for selective injection into distal muscles. In the future, neurolytic agents may prove more appropriate in very severely affected patients for whom the purposes of the block are comfort and hygiene. (ABSTRACT TRUNCATED)

Simultaneous bilateral pallidoansotomy for idiopathic dystonia musculorum deformans

A 17-year-old Russian male with a 9-year diagnosed history of dystonia musculorum deformans manifested as severe tortipelvis, lordosis, and axial and appendicular spastic dystonia, refractory to medical therapy, is reported. This patient underwent a simultaneous bilateral pallidoansotomy with dramatic results. Postoperative evaluation revealed sustained alleviation of all dystonic symptoms and abnormal movements. Rapid recovery of useful strength in all limbs as well as dramatic improvement in coordination occurred. Bilateral posteroventral pallidotomy and pallidoansotomy in the past have proven effective in alleviation of all parkinsonian symptoms, including dyskinesia and dystonia, without the concurrent risk of intransigent side effects associated with bilateral thalamotomy or other stereotactic surgical procedures. Pallidoansotomy may prove to be the treatment of choice for idiopathic torsion dystonia and merits further investigation.

Neurological disorders in members of families with Leber's hereditary optic neuropathy (LHON) caused by different mitochondrial mutations.

Neurological abnormalities have been occasionally associated with Leber's hereditary optic neuropathy (LHON). We describe four patients with spastic dystonia from two of our 35 LHON families. Magnetic resonance imaging revealed signal alterations of globus pallidus, putamen, internal capsula, and substantia nigra. Neuropathological findings in one of the patients with dystonia are described. Each of the dystonia families carries a different mtDNA mutation; one at np 3460 and one at np 11778. Periventricular multiple sclerosis-like white matter lesions were observed in one individual from a third family with the mtDNA 3460 mutation. Neurological disorders are probably underestimated in association with LHON.

Hereditary spastic dystonia with Leber's hereditary optic neuropathy: Neuropathological findings

Neuropathological findings in a 59-year-old male case of hereditary spastic dystonia with Leber's hereditary optic atrophy included: marked depletion of myelinated nerve fibres in the posterior funiculi, corticopontine tracts and striatum: practically complete neuronal depletion in the putamen and lateral part of the caudate, and mild cell loss in the substantia nigra. The putamina had changed into a spongy fibrillary scar, the pallidal fibres and laminae were practically all degenerated. Moreover, there was generalised mild fibre degeneration of the white matter. The optic nerve showed marked, predominantly central, loss of nerve fibres with demyelination.

Hereditary spastic dystonia: A new mitochondrial encephalopathy?: Putaminal necrosis as a diagnostic sign

A large kindred, in which either Leber's hereditary optic atrophy, or a hereditary spastic dystonia, or a combination of both manifested over many generations was restudied after the first report on it in 1964. NMR scans revealed bilateral, and, in two patients with hemidystonia, unilateral necrosis with shrinkage of the putamen, in one case associated with total disappearance of the head of the caudate nucleus. Except for age-appropriate cortical atrophy in one instance, no other changes were observed in the brain, brainstem, and cerebellum. The putaminal necrosis appears as typical “striatal slits” on the NMR scans. It is argued that this rare disease, since the princeps description in 1964 only reported in England (1986) and the U.S.A (1986), is most likely a singular type of mitochondrial encephalopathy: it is associated with Leber's optic atrophy, and the NMR changes observed have been signalled in other mitochondrial encephalomyelopathies, such as Leigh's disease and MELAS.

Pigmentary Degeneration of the Retina in the Hallervorden-Spatz Syndrome

Dizygotic twins developed a progressive neurologic disorder at age 6 months. When examined at age 7 1/2 years each had spastic quadriparesis and dystonia. Neither had ever spoken a complete sentence. The fundi showed bone spicule formation, a conspicuous choroidal circulation, and a striking accumulation of yellowish-white globular masses of varying sizes and shapes. Because our patients developed both the pigmentary degeneration and clinical signs of Hallervorden-Spatz syndrome at a much younger age than patients without retinopathy, we believe this case demonstrated a distinct nosologic entity.