Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to evaluate the effects of intrathecal bacolfen (ITB) on patients with severe generalized dystonia. Eighty-six participants ranging in age from 3 to 42 years (median age 13 years) with generalized dystonia refractory to oral medications were offered treatment with ITB. Dystonia was associated with cerebral palsy in 71% of participants. Response to ITB was tested by continuous infusions in 72%, and by bolus injections in 17% of participants who had both dystonia and spasticity. Ninety-one percent of participants responded to the screening infusion and 93% to the bolus injections. Pumps were implanted in 77 participants. Dystonia scores at 3, 6, 12, and 24 months were significantly decreased (p<0.005) compared with baseline scores. Dystonia scores were significantly lower in those with intrathecal catheters positioned at T4, or higher than in those with catheters at T6 or lower (p=0.005). Ninety-two percent of participants implanted with a pump retained their responses to ITB during a median follow-up of 29 months. Patient questionnaires indicated that quality of life and ease of care improved in 86% and speech improved in 33%. Side effects of ITB occurred in 26% of participants. Surgical complications occurred in 38% and included CSF leaks, infections, and catheter problems. ITB is probably the treatment of choice for generalized dystonia if oral medications are ineffective.
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PMID:Intrathecal baclofen for generalized dystonia. 1166 21

Baclofen, the most effective drug to treat spasticity, is a specific agonist of gamma-aminobutyric acid-B receptors, and is very abondant in the superficial layers of the spinal cord. Given orally, baclofen does not easily penetrate the blood-barrier, and is distributed equally to the brain and spinal cord. After oral administration of baclofen, the drug is resorbed by more than 80-90% in the stomach and bowel and is eliminated by urinary excretion. Failure of oral medication to produce sufficient relief of spasticity is due to the poor passage of the drug across the blood-brain barrier. In animals the concentration in brain is less than 1/10 of the blood levels. The problem of insufficient anti-spastic efficacy (in relation to the rate of side-effects) after systemic medication may be overcome by local application in spinal CSF. Direct intrathecal administration of baclofen in the treatment of severe spasticity was proposed in 1984 by Richard Penn with the objective to carry out a selective spinal distribution of the active principle thus avoiding supraspinal side effects. The pharmacokinetics of baclofen in animal and man after intrathecal administration have been investigated to determine the CSF pharmacokinetic parameters.
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PMID:[Intrathecal baclofen. Experimental and pharmacokinetic studies]. 1274 2

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) that is increasingly recognized as a disease that affects children. Similar to adult-onset MS, children present with visual and sensory complaints, as well as weakness, spasticity, and ataxia. A lumbar puncture can be helpful in diagnosing MS when CSF immunoglobulins and oligoclonal bands are present. White matter demyelinating lesions on MRI are required for the diagnosis; however, children typically have fewer lesions than adults. Many criteria have been proposed to diagnose MS that have been applied to children, mostly above 10 years of age. The recent revisions to the McDonald criteria allow for earlier diagnosis, such as after a clinically isolated event. However, children are more likely than adults to have monosymptomatic illnesses. None of the approved disease-modifying therapies used in adult-onset MS have been approved for pediatrics; however, a few studies have verified their safety and tolerability in children. Although children and adults with MS have similar neurological symptoms, laboratory (cerebrospinal fluid) data, and neuroimaging findings, the clinical course, pathogenesis, and treatment of childhood onset MS require further investigation.
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PMID:Childhood multiple sclerosis: a review. 1680 11

Neuraxial drug administration describes techniques that deliver drugs in close proximity to the spinal cord, i.e. intrathecally into the CSF or epidurally into the fatty tissues surrounding the dura, by injection or infusion. This approach was initially developed in the form of spinal anaesthesia over 100 years ago. Since then, neuraxial drug administration has evolved and now includes a wide range of techniques to administer a large number of different drugs to provide anaesthesia, but also analgesia and treatment of spasticity in a variety of acute and chronic settings. This review concentrates on the pharmacological agents used and the clinical basis behind currently utilised approaches to neuraxial drug administration. With regard to local anaesthetics, the main focus is on the development of the enantiomer-specific compounds ropivacaine and levobupivacaine, which provide similar efficacy to bupivacaine with a reduced risk of severe cardiotoxicity. Opioids are the other group of drugs widely used neuraxially, in particular to provide analgesia alone or more commonly in combination with other agents. The physicochemical properties of the various opioids explain the main differences in efficacy and safety between these drugs when used intrathecally, of which morphine, fentanyl and sufentanil are most commonly used. Another group of drugs including clonidine, dexmedetomidine and epinephrine (adrenaline) provide neuraxial analgesia via alpha-adrenergic receptors and are used mainly as adjuvants to local anaesthetics and opioids. Furthermore, intrathecal baclofen is in routine clinical use to treat spasticity in a number of neurological conditions. Beside these established approaches, a wide range of other drugs have been assessed for neuraxial administration to provide analgesia; however, most are in various early stages of investigation and are not used routinely. These drugs include neostigmine, ketamine, midazolam and adenosine, and the conotoxin ziconotide. The latter is possibly the most unusual compound here; it has recently gained registration for intrathecal use in specific chronic pain conditions.
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PMID:Neuraxial drug administration: a review of treatment options for anaesthesia and analgesia. 1704 29

Spasticity is a predominant clinical sign appearing in different neurological diseases. It is always flanked by various degrees of muscle weakness. The clinical evaluation of a spastic patient is score according to varius internationally approved evaluation scales (Ashworth scale, muscle spasms scale, and FIM disability scale). The treatment of spasticity is mostly a symptomatic treatment aimed to relief muscle hypertonus thus increasing both motor performance and improving nursing. Many molecules are frequently being used orally with poor results or with the onset of undesired side effects. In fact oral baclofen, diazepam and tizanidine often have poor effect on spasticity and bring frequently to the appearance of undesired side effects caused by the concentration of these molecule at the brain level. Intrathecal baclofen is a good option to treat diffuse spasticity through the infusion of baclofen into the spinal CSF space. When baclofen is administered intrathecally at the spinal level it distributes with a concentration-gradient between caudal and rostral level of the spine that was calculated as 4:1 thus avoiding its concentration at the brain level when given at a therapeutical dosage. This fact avoids any undesired side effect due to the action of baclofen at the brain level. Botulinum toxin as well as peripheral neurotomies are very helpful in those cases in whom spasticity is mainly restricted to few muscular groups. A correct flow-chart to diagnose and treat the patient is mandatory to achieve the best results for each patient according to his spasticity and residual motor ability.
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PMID:The guidelines for the diagnosis and treatment of spasticity. 1710 87

Baclofen (beta-p-chlorophenyl-GABA) binds to a number of spinal and cerebral sites and depresses the excitability of motor neurons. Intrathecal administration induces much higher CSF concentrations compared to the limited passage through the blood-brain barrier after oral administration. The development of reliable implanted pumps allows long-term intrathecal baclofen treatment (ITB). Baclofen is mainly an antispastic drug and the main indication of ITB is generalized lower limb spasticity in spinal cord injury and multiple sclerosis. The side-effects are due to either drug over-dose or withdrawal and to malfunctions of the implanted device (disconnections of the catheter, infections, etc.). Large numbers of patients have been treated over the past twenty years. More recently, baclofen has been used in the treatment of spasticity of cerebral origin, and in the treatment of other motor disorders, mainly dystonia. The results in cerebral palsy are promising and ITB's role will probably grow in the management of the movement disorders of these children. Further studies are required on the exact site of action, on the possible association with other drugs, especially clonidine and on the development of sustained release formulations.
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PMID:Intrathecal baclofen in the treatment of spasticity, dystonia and vegetative disorders. 1769 79

GLUT1 deficiency syndrome (GLUT1DS, OMIM 606777) is a treatable epileptic encephalopathy resulting from impaired glucose transport into the brain. The essential biochemical finding is a low glucose concentration in the cerebrospinal fluid (CSF; hypoglycorrhachia; mean 1.7 [SD 0.3mmol/L]) in the setting of normoglycaemia. CSF lactate is normal. Patients present with an early-onset epilepsy resistant to anticonvulsants, developmental delay, and a complex movement disorder. Hypotonic, ataxic, and dystonic features are most prominent. Speech is often severely affected. Some patients develop spasticity and secondary microcephaly. The phenotype is highly variable ranging from severe impairment to children without seizures. Electroencephalography (EEG) may show 2.5-4Hz spike-waves improving on food intake. Neuroimaging is uninformative. Most patients carry heterozygous de novo mutations in the GLUT1 gene (OMIM 138140, gene map locus 1p35-31.3). Autosomal dominant transmission and several mutational hot spots have been identified, but phenotype-genotype correlations are not yet apparent. Homozygous GLUT1 mutations presumably are lethal. The ketogenic diet is the treatment of choice as it provides an alternative fuel to the brain. It should be introduced early and maintained into puberty. Seizures are effectively controlled with the onset of ketosis, but might recur and require comedication. The effect on neurodevelopment appears less impressive. The increasing number of patients, molecular and biochemical analysis, recent research into ketogenic diet mechanisms, and the development of animal models for GLUT1DS have brought substantial insights in disease manifestations and mechanisms. This review summarizes data on 84 published cases and highlights recent advances in understanding this entity.
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PMID:GLUT1 deficiency syndrome--2007 update. 1771 30

Hereditary movement disorders comprise a group of genetically defined diseases characterized by an impaired control of movements, ataxia and/or spasticity. Affected individuals are disabled, their quality of life significantly reduced and their life expectancy shortened. One or more genetic causes have been identified for many of these diseases, including Huntington's disease, Wilson's disease, spinocerebellar ataxias, recessive ataxias, hereditary spastic paraplegia and hereditary dystonias. Due to their characteristic molecular and biochemical pathogenesis, these rare diseases can often serve as models for more common disorders such as Alzheimer's disease or Parkinson's disease. The primary tasks of the German Network of Hereditary Movement Disorders (GeNeMove), funded by the German Ministry for Education and Research (BMBF), are to co-ordinate basic scientific research and clinical research into rare hereditary movement disorders and to improve the cooperation between the German centers specializing in hereditary movement disorders. For each of the diseases in its scope, GeNeMove works at creating standardized documentation of symptoms and the disease's progressive course over time; developing rating scales for clinical examinations and guidelines for therapy; improving genetic testing; fostering genetic research; and collecting samples of DNA, tissue, CSF and blood from sufferers of the disease for biobanks.
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PMID:[Hereditary movement disorders]. 1805 48

We describe a unique presentation of autosomal recessive (AR) GTP cyclohydrolase I (GTPCH) deficiency, with severe CNS involvement but without hyperphenylalaninemia. A male infant presented with progressive spasticity, dystonia and oculogyric episodes. Blood phenylalanine levels were persistently normal: whereas an oral phenylalanine loading test revealed impaired phenylalanine clearance. CSF neopterin and tetrahydrobiopterin (BH(4)) were low, homovanillic acid marginally low and 5-hydroxyindoleacetic acid normal. Fibroblasts showed decreased GTPCH enzyme activity. A homozygous novel mutation of GCH1, p.V206A, was identified. On treatment (BH(4), L-Dopa/Carbidopa and 5-hydroxytryptophan), motor development improved. Mutational analysis provided neonatal diagnosis of a younger brother who, after 18 months on treatment, shows normal development. AR GTPCH I deficiency can present without hyperphenylalaninemia and with normal or subtle CSF neurotransmitter profiles. Testing for GTPCH deficiency should be considered for patients with unexplained neurological symptoms and extrapyramidal movement disorder.
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PMID:Autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia: evidence of a phenotypic continuum between dominant and recessive forms. 1827 79

GLUT-1 protein is the principal glucose transporter across the blood-brain barrier. GLUT-1 deficiency results in a syndrome of infantile seizures refractory to anticonvulsive drugs, developmental delay, acquired microcephaly and neurologic manifestations including spasticity, hypotonia, and ataxia. A low cerebrospinal fluid glucose concentration in the absence of hypoglycaemia is pathognomonic of glucose transporter deficiency syndrome. Ketogenic diet is an effective treatment of epileptic manifestations but it has less effect on the cognitive symptoms. We report on a child who presented with paroxistical events often occurring prior to meals, developmental delay, microcephaly and spasticity. CSF and serum glucose levels measured simultaneously showed a CSF/serum glucose ratio of 0.39. Molecular analysis identified a heterozygous novel mutation.
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PMID:[GLUT-1 deficiency syndrome or De Vivo disease: a case report]. 1855 84


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