Cerebral palsy has always been known as a disorder of movement and posture resulting from a non-progressive injury to the developing brain; however, more recent definitions allow clinicians to appreciate more than just the movement disorder. Accurate classification of cerebral palsy into distribution, motor type and functional level has advanced research. It also facilitates appropriate targeting of interventions to functional level and more accurate prognosis prediction. The prevalence of cerebral palsy remains fairly static at 2-3 per 1000 live births but there have been some changes in trends for specific causal groups. Interventions for cerebral palsy have historically been medical and physically focused, often with limited evidence to support their efficacy. The use of more appropriate outcome measures encompassing quality of life and participation is helping to deliver treatments which are more meaningful for people with cerebral palsy and their carers.
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Chronic cough is a common symptom that can be difficult to treat. It is proposed to be part of a cough hypersensitivity syndrome characterised by troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure. Upper airway and laryngeal neural dysfunction may also be present. There is evidence that this hypersensitivity may be due to sensory nerve damage caused by inflammatory, infective and allergic factors. Antitussive therapies based on opioid medications are generally not efficacious. Antagonists of N-methyl-d-aspartate receptors in the brain stem and use of GABAB receptor agonists such as baclofen acting centrally and possibly peripherally may represent novel therapeutic approaches.
The spontaneous occurrnce of blepharospasm and dystonic movements in face muscles, particularly those of the perioral and mandibular regions, has been named Meige's disease. Other dystonic features as spasmodic torticollis, dysphagia, spasmodic dysphonia and segmental dystonia of the limbs may, eventually, be present in the same patient. There is very little knowledge about the pathology of this disease. Many hypotheses concerning the pathophysiology of this entity have been put forward, most of them correlating the clinical response to several drugs with known action on the neurotransmitter system of the brain. There are some evidences that it may exist a dopaminergic preponderance in the disease. In the nigro-striatal pathway, one of the retrograde loops in the feed-back control of dopamine synthesis by nigral neurons is dependent on GABA. Increasing GABA activity through GABA agonists that cross the blood-brain barrier could result in a decreased dopaminergic action in the nigro-striatal pathway and, thus, ameliorate the dystonic symptoms which might have been produced by its increased function. We have used baclofen, a GABA-agonist drug, to treat five patients with Meige's disease, in a single-blinded trial. These were four females and one male, with age ranging from 50 to 63 years. The drug was started at 20mg/day, being increased by 10mg each three days reaching a maximum dose of 70mg/day. One of the patients showed marked improvement of blepharospasm and orofacial dystonia and a second patient had a moderate improvement in the same symptoms. Another patient showed moderate improvement of limb dystonia, but had no benefit in the facial movements.(ABSTRACT TRUNCATED AT 250 WORDS)
Adults with methamphetamine dependence were randomized to one of three conditions for 16 weeks: baclofen (n = 25), gabapentin (n = 26) or placebo (n = 37). All participants attended clinic thrice weekly to receive study medication and psychosocial counseling, complete study assessments, and provide urine samples.
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Of the 103 people diagnosed by the neurologist, 24 had diplegic spasticity, 4 had hemiplegic spasticity, 44 had quadriplegic spasticity, and 31 had no spasticity. Functional goals identified by multidisciplinary teams were undergarment change (46.3% of the persons for whom goals were identified), splinting hands (11%), dressing (57.4%), hygiene (20.4%), wheelchair positioning (25.9%), ambulation improvement (14.8%), and transfers (9.3%). After physical and occupational therapy, the first invasive treatments indicated for people with spasticity included botulinum toxin injections (60%), intrathecal baclofen (26.4%), orthopedic surgery (5.6%), and medication (1.4%). No treatment was recommended for 25% of the spasticity patients.
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gamma-Hydroxybutyrate (GHB) is a neurotransmitter in brain and an emerging drug of abuse, although its mechanism of action is poorly understood. This study characterized the role of GABA(A), GABA(B), and other receptors in the discriminative stimulus effects of GHB. Eight rats reliably discriminated 200 mg/kg GHB from saline after a median of 35 (range: 23-41) training sessions. GHB, a metabolic precursor 1,4-butanediol (1,4-BDL), and the GABA(B) agonist (+/-)baclofen all occasioned greater than 83% responding on the GHB lever. The onset of action was similar for GHB and 1,4-BDL; however, 1,4-BDL exhibited a longer duration of action than GHB. The GHB precursor gamma-butyrolactone, the benzodiazepine diazepam, the neuroactive steroid pregnanolone, the opioid agonist morphine, and the N-methyl-d-aspartate antagonist ketamine elicited substantial GHB-appropriate responding, although none occasioned greater than 66% drug-lever responding. The barbiturate pentobarbital and the GABA(A) receptor agonist muscimol did not occasion greater than 17% drug-lever responding at any dose tested. The benzodiazepine antagonist flumazenil attenuated GHB-lever responding occasioned by diazepam, but not GHB. The GABA(B) receptor antagonist CGP 35348 antagonized GHB-lever responding occasioned by baclofen or GHB. Small doses of the purported GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a]annulen-6-ylidene ethanoic acid (NCS-382) attenuated partially the effects of GHB, whereas larger doses of NCS-382 alone occasioned partial GHB-lever responding. These results implicate GABA(B) mechanisms in the discriminative stimulus effects of GHB and further suggest that the effects of 1,4-BDL under these conditions result from its conversion to GHB. That NCS-382 shares effects with GHB could explain the lack of antagonism reported for NCS-382 in some studies.
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In an attempt to establish a relationship between food intake and fear/anxiety-related behaviours, the goal of this study was to investigate the effect of bilateral injections of GABAA (Muscimol, MUS, doses 25 and 50ng/side) and GABAB (Baclofen, BAC, doses 32 and 64ng/side) receptor agonists in the nucleus accumbens shell (AcbSh) on the level of fear/anxiety-like and feeding behaviours in 24h food-deprived rats. The antagonists of GABAA (Bicuculline, BIC, doses 75 and 150ng/side) and GABAB (Saclofen, SAC, doses 1.5 and 3μg/side) were also tested. The results indicated that the total number of risk assessment behaviour decreased after the injection of both doses of GABAA agonist (MUS) into the AcbSh of 24h food-deprived rats exposed to elevated plus maze. Similar results were obtained after treatment with both doses of GABAB (BAC) agonist in the AcbSh. These data indicated that the activation of both GABAA and GABAB receptors within the AcbSh caused anxiolysis in 24h food-deprived rats. In addition, feeding behaviour (food intake, feeding latency and feeding duration) remained unchanged after treatment with both GABA agonists. In contrast, both food intake and feeding duration decreased after injections of both doses of BIC (GABAA antagonist), while the feeding latency remained unchanged after treatment with both GABA antagonists in the AcbSh of 24h food-deprived rats. The treatment with SAC (GABAB antagonist) did not affect feeding behaviour. Collectively, these data suggest that emotional changes evoked by pharmacological manipulation of the GABA neurotransmission in the AcbSh are not linked with changes in food intake.
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A previous study from this laboratory demonstrated that ongoing GABAergic neurotransmission in the nucleus tractus solitarii (NTS) functions to maintain baseline arterial pressure (AP). In that study, bilateral microinjection of nipecotic acid into the NTS was observed to elevate AP. Since nipecotic acid is a selective GABA uptake blocker, changes in GABA release should be reflected by changes in the response to nipecotic acid. The present study utilized this approach to assess endogenous GABA activity within the NTS of the spontaneously hypertensive rat (SHR). Male SHR, 16-20 weeks of age, were anesthetized with chloralose, paralyzed and ventilated. Age-matched Wistar-Kyoto (WKY) rats were studied as controls. Bilateral microinjection of nipecotic acid (10 nmol in 100 nl; a maximally effective dose) into the NTS elicited a pressor response which was significantly greater in the SHR than the response observed in the WKY rats. Similarly, direct stimulation of GABAB receptors in the NTS with (-)-baclofen 40 pmol, a maximally effective dose) elicited an increase in AP which was significantly greater in the SHR. In contrast, bilateral microinjection of the direct acting GABAA agonist muscimol (160 pmol, a maximally effective dose) resulted in a similar elevation of AP in both the SHR and WKY rats. These results suggest that the enhanced pressor response caused by endogenous GABA in the NTS of the SHR is due to a greater response evoked by stimulation of GABAB receptors. Thus, enhanced GABAB receptor-mediated neural transmission in the NTS may contribute to the expression or maintenance of hypertension in this genetic model of hypertension.
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Subjects were observed in a CRO for 24 hours after each dose of baclofen, and were assessed for nystagmus, ataxia, and sedation. Blood samples were collected from 0 to 24 hours and analyzed for baclofen concentration using high-performance liquid chromatography-mass spectroscopy. Noncompartmental pharmacokinetic analyses were performed. Dose linearity and proportionality was assessed using 2-way repeated-measures analysis of variance and a power model analysis.
Cephalad catheter migration is a rare phenomenon. The mechanism of rostral migration remains unclear. The forces that propel a free fragment of catheter under these circumstances seem to be sufficient to cause a small vessel to rupture and bleed. Given the lack of an observed arterial injury, we postulate that venous bleeding caused this hemorrhage.
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Techniques for the placement of intrathecal baclofen (ITB) systems have been described in detail, with special consideration given to complications from hardware placement. Risks including catheter kinking and migration, hardware erosion through the skin, and lumbar CSF leak are elevated given the often-low body mass index and poor nutritional status of this patient population. The bulk of a spinal catheter and fascial connector within the lumbar wound may increase the potential for the aforementioned risks, leading to potential risks for wound infection and breakdown. The authors' experience has led them to develop a novel method of paraspinal subfascial lumbar catheter placement to address these risks. The authors describe a novel lumbar intrathecal catheter placement technique as part of the ITB system.
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The antagonism of various seizure and time-related components of the convulsions resulting after IV injection of D,L-allylglycine into male Wistar rats were assessed in a standard test procedure. Trimethadione and ethosuximide did not antagonize the seizure components, whereas clonazepam, phenobarbital, diphenylhydantoin, primidone, valproate sodium, aminoxyacetic acid, etomidate, acetazolamide, flunarizine, pipamperone and baclofen did. The allylglycine test may thus represent a relatively specific method of differentiating between drugs effective against partial or generalized convulsive seizures from those effective against absence seizures. The neuroleptics haloperidol and pimozide were completely inactive in contrast to their reported antagonism of bicuculine seizures. The spectra of the active substances are discussed with respect to Principal Component and Cluster Analysis. Noteworthy are the similarities between baclofen and etomidate; between aminoxyacetic acid, phenobarbital and valproate sodium; and between diphenylhydantoin and flunarizine.
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Unfortunately, in spite of the advances in foetal and perinatal medicine in the last twenty years, the incidence of cerebral palsy has remained unchanged (1.5-2.5 per 1000 live births). It has even possibly risen slightly in premature babies of low birth weight, in parallel with the increased survival of these babies. In spite of modern techniques of rehabilitation, 25% of these patients cannot walk and 35% are mentally retarded. This costs society 5,000 million dollars annually, not counting the loss of opportunity and the emotional and economic burden imposed on these families. The development of new preventive measures such as the use of antagonists of the cortical excitatory amino acids (which when in excess may cause irreversible cerebral damage in cases of hypoxic-ischaemic encephalopathy of the new born). Intramuscular botulinum toxin and continuous intrathecal baclofen seem to promise a reduction in the incidence and functional incapacity of cerebral palsy.
The patient was treated with selective posterior rhizotomy S1-L1. Section of 60% of the rootlets on the right side and 40% on left the side resulted in a good outcome with less spasticity and pain. Finally her contractures were treated with tenotomy and myotomy, also with good functional result.
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We have recorded the electroretinogram from 19 superfused eyecups of the Xeiiopus retina in order to assess the effects of agonists of the inhibitory neurotransmitter gamma-aminobutyric acid (GA notBA), on both oscillatory potentials and the b-wave. We found that in seven eyecups the GABA uptake blocker nipecotic acid (0.1-5 mM) reduced the amplitudes of the oscillatory potentials, without having an effect on the b-wave unless it was applied in larger doses. The GABAB agonist baclofen (0.05-3 mM) reduced the amplitude of the ERG b-wave selectively in seven eyecups tested, without any effect on the amplitude of the oscillatory potentials. The GABAA agonist aminovaleric acid (0.05-3 mM) on the other hand, selectively reduced the oscillatory potentials in five, but had no reliable effects on the Xenopus b-wave. These results suggest that GABAergic mechanisms related to both A and B receptor types induce different influence on the amplitude of the oscillatory potentials and the b-wave.
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Despite the acknowledged advantages of studying identified populations of neurons, few studies have convincingly established that fluorescent retrograde tracers do not alter the passive membrane properties, action potential characteristics, or effects of drugs on the labeled neurons. Whole-cell patch clamp recordings were made from spinally-projecting serotonergic neurons in the rostral ventromedial medulla (RVM) and spinally-projecting noradrenergic neurons in the locus coeruleus (LC) that were retrogradely labeled with 1,1'-dioactadecyl-3,3,3',3'-tetramethylindocarbodyanine perchlorate (Dil). The passive membrane and the action potential properties of Dil-labeled (0.2%) and non-labeled serotonergic neurons in the RVM did not differ. Similarly, the passive membrane and action potential properties of non-labeled noradrenergic LC neurons did not differ from neurons labeled with 0.2% or 5% Dil. Although the mu opioid receptor agonist [D-Ala(2)-NMePhe(4)-Gly-ol(5)]enkephalin (DAMGO) produced equivalent outward currents in non-labeled noradrenergic LC neurons and those labeled with 0.2% Dil, significantly smaller currents were recorded in LC neurons labeled with 5% Dil. Baclofen, a gamma-aminobutryic acid(B) receptor agonist, also produced smaller currents in RVM neurons labeled with 5% Dil compared to 0.2% Dil. These results indicate that 0.2% Dil is suitable for retrograde labeling of brainstem neurons in vivo for subsequent in vitro electrophysiological study. However, 5% Dil is likely to confound studies of the postsynaptic actions of G-protein coupled receptor ligands.
Neurosurgical procedures are indispensable in management of various types of movement disorders (MD). Stereotactic operations that have been well established include deep brain stimulation for tremor, dystonia, and Parkinsonian symptoms. Recently the actual role of stereotactic ablative procedures such as thalamotomy and pallidotomy has been re-explored, and Vo thalamotomy shows long-term improvement of task specific focal dystonia like writer's cramp and musician's dystonia. A new less invasive treatment of tremor using MR guided focused ultrasound has started and is promising. Intrathecal administration of baclofen is also an established treatment for severe spasticity, but other ablative procedures such as peripheral neurotomy and dorsal rhizotomy are also important in spasticity treatment. It seems that most neurologists are unfamiliar, at least in Japan, with such neurosurgical procedures. However, neurologists involved in management of MD should understand the important roles of neurosurgical management of intractable MD and should refer such patients to appropriate neurosurgeons before permanent contracture and deformity develop.
Many studies have demonstrated that GABAergic inhibition within the basolateral amygdala (BLA) plays an integral role in the regulation of anxiety, an important behavioral component in the etiology of alcoholism. Although ethanol has recently been shown to enhance BLA GABAergic inhibition via two distinct populations of inhibitory cells, local and lateral paracapsular (lpcs) interneurons, little is known about the mechanisms underlying ethanol potentiation of these two inhibitory pathways. Ethanol is known to enhance GABAergic inhibition in many brain regions via a complex array of pre- and postsynaptic mechanisms. In addition, ethanol's presynaptic effects are often subject to GABA(B) autoreceptor (GABA(B)-R) modulation. Therefore, in this study, we characterized GABA(B)-R function and modulation of ethanol actions at local and lpcs GABAergic synapses. At local synapses, we found significant paired-pulse depression (PPD, 250 ms inter-pulse interval) which was abated by SCH-50911 (GABA(B)-R antagonist). No significant PPD was detected at lpcs synapses, but SCH-50911 significantly potentiated lpcs-evoked IPSCs. Baclofen (GABA(B)-R agonist) had similar depressant effects on local- and lpcs-evoked IPSCs, however baclofen pretreatment only reduced ethanol potentiation at local synapses. Ethanol also significantly enhanced the frequency of spontaneous and miniature IPSCs, and these effects were also sensitive to GABA(B)-R modulators. Collectively, these data suggest that stimulus-independent inhibitory responses recorded from BLA principal neurons primarily reflect the activity of local GABAergic interneurons and provide additional evidence that ethanol potentiates local BLA inhibitory synapses primarily via a presynaptic enhancement of GABA release that is tightly regulated by GABA(B)-Rs. In contrast, ethanol potentiation of lpcs GABAergic synapses is not sensitive to GABA(B)-R activation and does not appear to involve increased presynaptic GABA release.
A DC ramp voltage was used to stimulate rabbit tooth pulps. Thresholds to elicit chewing movements were extremely stable in the absence of drug treatment. Using cumulative dosing of analgesic drugs, potency and efficacy measurements could be readily obtained. Narcotic analgesics were the most effective analgesics on this test, followed by two centrally acting non-narcotics (nefopam and baclofen). Antipyretic/anti-inflammatory analgesics and centrally acting non-analgesic drugs elevated thresholds by lesser amounts or were inactive. It is concluded that the rabbit tooth pulp assay is suitable for the qualitative and quantitative determination of analgesic activity.
In this study, the effects of atropine sulfate (atropine) on swallowing and cough reflex were evaluated in the two experimental models in conscious dogs. To evaluate the effects of atropine on swallowing, 1 mL of marker (contrast medium) was injected into the pharynx under X-ray exposure to induce swallowing. Baclofen, used as a positive control, caused marker congestion in the upper esophagus. In our experimental model, atropine (0.02 and 0.1 mg/kg, i.v.) dose-dependently increased not only the number of marker congestions but also that of the swallows. In addition, atropine significantly shortened the onset of first swallowing. In the evaluation of atropine effects on electrically evoked cough reflex induced by two electrodes implanted into the trachea, atropine strongly inhibited the number of coughs at 0.01 or 0.05 mg/kg accompanied with 0.01 or 0.05 mg/kg per hour (i.v.), respectively. These findings indicate that atropine has the potential of causing aspiration pneumonia through induction of swallowing disorder and inhibition of the cough reflex.
Intracellular recordings from adult rat dorsal root ganglion neurones were performed in vitro and the coexistence of two gamma-aminobutyric acid (GABA) receptors on the membrane of identified A delta and C primary afferents was demonstrated. Transient applications of GABA (10(-6)-10(-2) M) evoked dose-dependent depolarizations and increased membrane conductance. The responses were mimicked by muscimol, isoguvacine, THIP and 3 amino propane sulphonic acid (3 APS); they were blocked by bicuculline and picrotoxin. Pentobarbitone induced an increase of GABA-induced depolarizations. Perfusion of tetraethylammonium (TEA, 7.5 mM) and intracellular injection of Cs+ ions unmasked the Ca2+ component of action potentials, which appeared as long-lasting plateau depolarizations. Such action potentials were shortened in the presence of methoxyverapamil (D600, 5 X 10(-6)-10(-5) M) and in a medium without Ca+ ions. Prolonged (5-10 min) perfusion of GABA (10(-9)-10(-5) M) shortened the Ca2+ component of action potentials. This effect was mimicked by baclofen (10(-7)-5 X 10(-6) M) and muscimol (5 X 10(-7)-10(-5) M) and was not affected by bicuculline perfusion (5 X 10(-6)-10(-5) M). Isoguvacine (2.5 X 10(-5) M) did not affect action potential duration. It is concluded that two GABA receptors coexist on the membrane of slow conducting primary afferents: the bicuculline-sensitive GABAA receptor mediates depolarizations and the bicuculline-insensitive GABAB receptor shortens the calcium component of action potentials.
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Baclofen (Lioresal) is a derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It is used to treat spasticity particularly for the relief of flexor spasms, pain, clonus, and muscular rigidity. There have been many rare neurologic side effects reported with its use. These side effects, in particular, hallucinations and seizures, have been observed predominantly following precipitous withdrawal of the drug. We present a case demonstrating a muscular dyskinetic side effect when baclofen treatment was first initiated. The mechanism by which baclofen affects spasticity and how the resulting side effect of dyskinesia developed in our patient is not known. They are, however, most probably related to dopamine receptor hypersensitivity and the resulting imbalance of the dopaminergic/cholinergic systems. Clinicians should be aware of this additional adverse effect of muscular dyskinesia, with the use of baclofen, and its reversibility when baclofen is discontinued.
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Key points. Cocaine, the second most frequently consumed illicit substance after cannabis in both United States and Europe, remains the psychostimulant of choice for many, often mixed with other psychoactive substances. It is most frequently associated with alcohol, and a diagnosis of alcohol dependence may be made in 50%-90% of cocaine-dependent subjects. When treating cocaine addicts, it is important to characterize not only the modalities of cocaine use but also the modes of consumption of other substances, notably alcohol. Alcohol is often consumed to reduce the anxiety and discomfort resulting from cocaine withdrawal. Alcohol may also trigger an irresistible craving for cocaine, which can result in frequent relapses even after several months of cocaine abstinence. Brief intervention and motivational interview techniques can help to reduce alcohol use and prevent cocaine relapses in this context. In the absence of severe cocaine withdrawal symptoms, the guidelines for treating alcohol withdrawal syndrome may be applied for cocaine and alcohol codependence. Lower doses of benzodiazepine are needed for treating this alcohol-cocaine withdrawal syndrome. Cognitive behavioral therapies, alone or in combination with psychotropic medication, are accepted therapeutic approaches for alcohol-cocaine dependence. It is also accepted that over the long term the combination of psychotherapeutic treatments is usually more effective than any single approach. In the absence of a therapeutic consensus, four drugs (disulfiram, baclofen, topiramate and naltrexone) are most often recommended to promote and maintain abstinence; nevertheless, their efficacy has not been proven and their use remains experimental and off-label: they have not been approved by health authorities as treatment for addictions.
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Forty-one cases were identified, including 16 from the literature and 25 that were not published previously in the literature. Because of voluntary reporting and other methodological limitations, the actual number of cases must be higher than reported. All of the patients had chronic pain. The mean duration of therapy was 24.5 months. Most masses were located in the thoracic region. Intrathecal drugs included morphine or hydromorphone, either alone or mixed with other drugs, in 39 of 41 cases. No masses were reported in patients who received baclofen as the only intrathecal medication. Thirty patients underwent surgery to relieve spinal cord or cauda equina compression. Eleven patients were nonambulatory at last follow-up, and one died of a pulmonary embolus. Surgical specimens revealed noninfectious chronic inflammation, granuloma formation, and fibrosis or necrosis.