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Chronic intrathecal delivery of baclofen by a programmable pump for the treatment of severe spasticity.

The aim of this study was to determine the efficacy, safety, and cost-effectiveness of intrathecal baclofen delivered by a programmable pump for the chronic treatment of severe spasticity. Sixty-six patients with severe spasticity of spinal cord origin that was refractory to oral baclofen or who experienced intolerable side effects with this form of the drug were screened. The first nine participated in a double-blinded, randomized, placebo (normal saline)-controlled trial to determine response to a bolus dose of intrathecal baclofen. Subsequent patients were enrolled in an open-label treatment protocol without a placebo trial. All passed the screening, and the pump was implanted in 59 patients. Spasticity scores and medical costs before and after surgery were analyzed. In all patients, the mean Ashworth score for rigidity decreased from 4.3 preoperatively to 1.4 (p < 0.0005) with use of intrathecal baclofen. The spasm frequency score decreased from a mean of 3.6 to 0.5 (p < 0.0005). Activities of daily living, sleep, and skin integrity improved, and pain was eradicated in some. Constipation occurred in six patients. A reduction in dosage was necessitated by muscular hypotonia in three ambulatory patients, areflexic bladder and urinary retention in three others, and nausea, dizziness, and drowsiness in one. Catheter-related problems occurred 19 times in 15 patients. One pump was explanted because of infection in the pump pocket, and one was removed after it eroded through the skin. There were no pump failures. The use of intrathecal baclofen resulted in a decrease in the average length of subsequent hospitalizations. It is concluded that intrathecal baclofen delivered by an implanted programmable pump is a safe, effective, and cost-efficient method for treatment of severe intractable spinal spasticity.

Adolescent↗

Generation of the catalytic fragment of protein kinase C alpha in spastic canine basilar artery.

In previous studies of topical application of calphostin C, a specific inhibitor of the regulatory domain of protein kinase C (PKC), and calpeptin, a selective inhibitor of calpain, to spastic canine basilar artery (BA) researchers have suggested that the catalytic fragment of PKC (known as PKM) is probably formed by a limited proteolysis of continuously activated mu-calpain, but there has been no direct evidence for PKM formation in vasospasm. The present immunoblot study with anti-PKCalpha antibody shows a significant decrease in cytosolic 80-kD PKCalpha and a concomitantly significant increase in membrane PKCalpha in the spastic canine BA. In addition, an immunoblot study in which cleavage site-directed antibodies were used demonstrated a significant increase in immunoreactive 45-kD PKM. The changes in membrane PKCalpha and PKM were enhanced with the lapse of time after subarachnoid hemorrhage. The cleavage site-directed antibodies distinguish the proteolyzed from the unproteolyzed forms of PKC for in situ analyses of enzyme regulation mediated by proteolysis. The data indicate that PKCalpha in spastic canine BA is translocated to the cell membrane, where PKCalpha is rapidly cleaved into PKM as a result of proteolysis of the isozyme by mu-calpain but not by m-calpain. The authors hypothesize that mu-calpain is continuously activated in spastic canine BA and produces PKM by limited proteolysis of PKCalpha.

Animals↗

Spinal deformities after selective dorsal rhizotomy for spastic cerebral palsy.

OBJECT: Spinal deformities are significant problems in children with spastic cerebral palsy. The treatment of their spasticity by selective dorsal rhizotomy (SDR) may worsen or improve these problems. The purpose of this study was to determine the incidence of and change in degree of thoracolumbar scoliosis, thoracic kyphosis, and lumbar lordosis in children who have undergone SDR. METHODS: A retrospective review was conducted of children younger than 18 years of age, who had undergone SDR at British Columbia's Children's Hospital from 1987 to 2001 and in whom preoperative and postoperative spine radiographs have been obtained. Angles for thoracolumbar scoliosis, thoracic kyphosis, and lumbar lordosis were measured. The study group comprised 105 patients. The mean age at surgery was 5.2 years (range 2.7-14.6 years), with a mean time to most recent follow-up radiographs of 4.3 years (1-13.6 years). Sixty-two children had spastic diplegia (59%), 34 spastic quadriplegia (32%), and nine quadriplegia and intellectual delay (9%). A total of 104 children underwent laminoplasty with replacement of the laminae, usually from L-1 to S-1 and 54.8% of children had scoliosis at last follow up, with 25% having worsening of 10 degrees or more. The incidence of abnormal kyphosis at the last follow-up visit was 38.6%, with 31.8% having worsening of 15 degrees or more. The incidence of hyperlordosis at last follow up was 21.3%, with 36% having worsening of 15 degrees or more. The factors in this series impacting development of spinal deformities have been analyzed and are discussed. CONCLUSIONS: The relatively high incidence of spinal deformity in children who have undergone SDR via multi-level lumbosacral laminoplasties should raise some concern.

Adolescent↗

Assessment of autonomic nervous system with analysis of heart rate variability in children with spastic cerebral palsy.

The purpose of this study was to investigate the function of the autonomic nervous system in children with spastic cerebral palsy (CP) through an analysis of heart rate variability (HRV) occurring with orthostatic stress. Twelve children with spastic CP and twelve normal children participated in this study. The echocardiogram (ECG) signals were recorded for 3 minutes in both the supine and 70 degrees C head-up tilt positions, and then the HRV signals underwent power spectrum analysis at each position. Two components were measured; a low- frequency (LF) component (0.05 - 0.15 Hz) primarily reflecting sympathetic activity during orthostatic stress and a high-frequency (HF) component (0.15 - 0.4 Hz) reflecting parasympathetic activity. In the supine position, there was no significant difference between any of the HRV components of the two groups. In the head-up tilt position, absolute and normalized LF were significantly increased and absolute HF was significantly decreased in the normal children (p < 0.05), but not in the children with spastic CP. The results of this study suggest that cardiac autonomic functions, such as vagal withdrawal and sympathetic activation which occur during head-up tilt position, are not sufficient to overcome the orthostatic stress arising in spastic CP children.

Autonomic Nervous System↗

Bacloffen (Lioresal) in the long-term management of spasticity.

This report summarizes experience with baclofen (Lioresal) in the management of spasticity and muscle spasms in 113 patients treated for up to six years. Baclofen was found to be of little help in nine patients with spasticity of cerebral origin, but was effective in reducing spasticity of spinal origin in 72 out of 90 patients (80%). It also reduced the number and severity of spasms in 76 out of 87 patients (87%). Side effects necessitating reduction of dosage were experienced by 20% of patients. Baclofen appears to be a safe and effective agent in the management of spasticity, with the advantage that adequate dosage can usually be achieved without sedation. Beneficial effects have persisted throughout the follow-up period.

Adolescent↗

The effect of dantrium on spasticity of hemiplegic patients.

The effect of a new peripherally acting muscle relaxant drug Dantrium, on spasticity tested on 11 hemiplegic patients. The effect was evaluated both with regular clinical examination and with electromyographic technique. The latter concerned a quantitative analysis of the patients' voluntary control of fine neuromuscular activity both with and without the drug. The results indicated that spasticity was initially markedly reduced in the majority of the patients without, however, meaningfully increasing the daily-living functions of the patients. After a few months, the medication could be discontinued without any immediate increase in the spasticity. No severe side-effects were noted. In some cases, the medication had to be discontinued due to marked tiredness. Electromyographically, it was found that the ability of the patients to control fine neuromuscular activity with the paretic muscles was increased significantly with Dantrium, indicating that the reduction of the spasticity increased the ability for fine control of the muscles.

Adolescent↗

[Findings on magnetic resonance in spastic cerebral palsy].

OBJECTIVES: To study the types of lesion found on magnetic resonance (MR) in cerebral palsy (CP) and their correlation with a the type of CP, gestational age at birth and aetiology. PATIENTS AND METHODS: We made a retrospective review of all patients over one year in age, diagnosed as having spastic CP, who were seen in a paediatric neurology clinic between 1987 and 1998. The MR were evaluated blindly using data from the clinical history. RESULTS: Seventy two patients fulfilled criteria for inclusion in the study. The following results were obtained (all associations were statistically significant with p<0.01):1. Patterns of lesion: MR findings were classified into one of the following patterns: parasagittal lesion (7), diffuse multicystic encephalomalacia (4), periventricular leukomalacia (PVL) (26), bilateral dilatation of the basal ventricles without alteration of the signal from the periventricular white matter (5), bilateral lesions in the basal ganglia (5), focal multicystic encephalomalacia (limited to one vascular area) (4), unilateral lesions of hypersignal in the white matter (4), unilateral dilation of a lateral ventricle with or without homolateral cortical atrophy (3), malformations/disorders of migration (7), normal (7). 2. Correlation of the findings with the gestational age and type of CP: a) Spastic tetraplegia: 64% of the premature babies showed PVL. In newborn babies at term the lesions were more varied. b) Spastic diplegia: 80% of the premature babies had PVL and 83% of newborn babies at term had normal MR. c) Spastic hemiplegia: 81% had unilateral lesions. 3. Correlation with the aetiology: 62% of the cases of parasagittal lesions, diffuse multicystic encephalomalacia and bilateral lesions of the basal ganglia were due to hypoxic-ischemic encephalopathy. CONCLUSION: The MR findings in CP show good correlation with gestational age, type of CP and aetiology.

Basal Ganglia↗

[Ultrastructural study on the peripheral nerve and skeletal muscle of patients with spastic cerebral palsy].

OBJECTIVE: To explore pathological features of the peripheral nerve and skeletal muscle of patients with spastic cerebral palsy. METHODS: The peripheral nerve and skeletal muscle of 25 patients with spastic cerebral palsy were observed by gross examination during operation, and under microscope and electron microscope. RESULTS: Gross examination showed that peripheral nerve and skeletal muscle was normal during operation. Microscope showed that some skeletal muscle fibers degenerated, and the connective tissue proliferated. electronmicroscopically the damage of demyelination was extensive on the peripheral nerve; the pathological changes of Schwann's cell were sooner and more severe than axons; the pathological changes of myelinated nerve fiber were more obvious than the nonmyelinated nerve fiber; the lymphocyte were found around the microvasculature within the perineurium; the mitochondrion of skeletal muscle fiber increased in number, the sarcoplasmic reticulum and transverse tubule decreased and developed badly, the degenerative muscle fiber showed cell edema or the pathological changes of myofibril. All the peripheral nerve and skeletal muscle fiber affected had no repair and regeneration. CONCLUSIONS: The demyelination of the peripheral nerve of patients with spastic cerebral palsy is primary, and the skeletal muscle of patients with spastic cerebral palsy is secondary pathological change. The activity of nerve and muscle regeneration is bad.

Adolescent↗

[Treatment of spasticity with intrathecal baclofen].

INTRODUCTION: Severe spasticity, according to Lance's definition, is a manifestation of superior motoneurone injury syndrome which is characterized by increased stretching tonic reflexes, osteotendinous hyperreflexia, and release of propioceptive reflexes. Baclofen (a beta-4 chlorophenyl derived from gamma-amino-butyric acid) was firstly administered by intradural route in humans by Penn and Kroin in 1985 for the treatment of severe spasticity of muscular and central origin. MATERIAL AND METHODS: We report the results obtained in eleven patients with severe spastic picture, six of medullar origin and five of central origin who were treated with intradural administration of baclofen using an implanted programmable continuous perfusion system (Synchromed 8611H). The age of patients ranged from 12 up to 58 years. Six were males and five females. The duration of the treatment ranged from a maximal period of 36 months to a minimal period of 12 months. The initial dose of baclofen varied from 50 micrograms/day to 144 micrograms/day. RESULTS: The better results were obtained in patients with spasticity of medullar origin. The most marked beneficial effects were the reduction of spasms elicited, or not, by external stimuli. In all cases the doses of baclofen had to be progressively increased, leading to a mean final dose of 235.6 micrograms/day, with a maximal dose of 480 micrograms/day and a minimal dose of 144 micrograms/day. CONCLUSIONS: Baclofen administered by intradural route is more effective than administered by orally and the required doses were lower. Intradural administration was effective even though the oral route was unsuccessful.

Adolescent↗

[Experimental and clinical studies on selective sacral rhizotomy in treatment of spastic bladder after spinal cord injury].

OBJECTIVE: To observe the effect of selective sacral rhizotomy in treating spastic bladder after spinal cord injury and to explore the mechanism and the best surgical method of different sacral rhizotomies. METHODS: The spastic bladder models were established in 12 male dogs and were divided into 4 groups according to the different rhizotomies of the sacral nerve as the following: rhizotomy of the anterior root of S2 (group A), rhizotomy of the anterior root of S2 and half of the anterior root of S3 (group B), rhizotomy of the anterior roots of S2 and S3 (group C), and total rhizotomy of the nerve roots of S2-4 (group D). By urodynamic examination and electrophysiological observation, the changes of all functional data were recorded and compared between pre-rhizotomy and post-rhizotomy to testify the best surgical method. In clinical trial, according to the results of the above experiments, rhizotomy of the anterior root of S2 or one of the half-anterior root of S3 were conducted on 32 patients with spastic bladder after spinal cord injury. The mean bladder capacity, the mean urine evacuation and the mean urethra pressure were (120 +/- 30), (100 +/- 30)ml and (120 +/- 20) cm H2O, respectively before rhizotomy. RESULTS: After rhizotomy, the bladder capacity in 4 groups amounted to (150 +/- 50), (180 +/- 50), (230 +/- 50), and (400 +/- 50) ml, respectively; and the urine evacuation volume were (130 +/- 30), (180 +/- 50), (100 +/- 50) and (50 +/- 30)ml, respectively. In the treated 32 patients, the mean bladder capacity were raised to 410 ml, and the mean urine evacuation volume were also increased to 350 ml. Incontinence of urine disappeared in all patients. After 22-month follow-up on 13 patients, no recurrence was observed. CONCLUSION: The effect of selective sacral rhizotomy in treating spastic cord injury is significant and worthy of further studies.

Adult↗

Efficiency of laser therapy applied in labial traumatism of patients with spastic cerebral palsy.

The aim of this study was to report the effectiveness of laser therapy applied to traumatic labial injury of patients with spastic cerebral palsy. We report two cases of patients with internal mucosa and lower lip traumatism caused by oral reflex automatism with spastic tonic bite and lower lip interposition. One patient presented extensive lower lip ulceration, loss of tissue, crusty and hemorrhagic areas, with increasing pain and spasticity. The other patient presented local congestion signs, extremely enlarged tissue growth and increased labial volume. Laser therapy was applied to all injured areas, with a low-potency diode InGaAlP laser [685 nm Quasar (Dentoflex), 190 J/ cm2, with a 24-h interval between the first and second administration, and a 7-day interval between the two subsequent ones. At first re-evaluation, 24 h later, there was a striking reduction in inflammation, a decrease in vascular congestion, and a reduction of the ulcerated area with spasticity and pain reduction. At the 14-day re-evaluation, significant clinical differences in the advanced healing process were seen. Low-intensity laser showed to be effective in traumatic soft tissue treatment in cerebral palsy patients by accelerating the healing process, reducing secondary contamination, promoting analgesia; thus, it can be an important tool in the treatment of these patients.

Cerebral Palsy↗

[The results of single-stage multilevel muscle-tendon surgery in the lower extremities of patients with spastic cerebral palsy].

OBJECTIVES: We evaluated the results of single-stage multilevel muscle-tendon surgery performed for the treatment of contractures in the lower extremities of patients with spastic cerebral palsy. METHODS: The study included 23 patients (11 girls, 12 boys; mean age 6 years 3 months; range 4 to 17 years) with spastic cerebral palsy, who underwent single-stage multilevel muscle-tendon surgery for the treatment of contractures in the lower extremities secondary to spasticity. Quadriplegia, diplegia, and hemiplegia were present in five, 14, and four patients, respectively. Preoperatively, 13 patients could walk, while 10 patients lacked ambulation even with support. Evaluations were based on pre- and postoperative (mean 4 years 9 months; range 1 to 8 years) physical examination findings and on the Gross Motor Function Classification System (GMFCS) scores. The patients' mean age at the last follow-up was 11.5 years (range 9 to 19 years). RESULTS: The range of motion of all the operated joints improved postoperatively, resulting in significant improvements in posture, sitting, gait, and hygiene of the patients. Of ten patients who could not walk, five could ambulate with the use of a walker or crutches postoperatively. The mean pre- and postoperative GMFCS scores were 3.045 and 1.864, respectively (p<0.001). All the patients showed an improvement of at least one GMFCS level. CONCLUSION: Surgery for spastic cerebral palsy can be most beneficial only when all contractures of the hip, knee, and ankle have been corrected. Symmetrical and multilevel operations should be performed when necessary, for single-stage and symmetrical multilevel muscle-tendon surgical applications have definite advantages over staged interventions.

Adolescent↗

Resting asynchronous left ventricular contraction abnormality analyzed by a phase method in spastic angina pectoris.

UNLABELLED: Quantitative phase analysis of equilibrium ventriculography was performed to study the character of left ventricular (LV) wall motion abnormalities in patients with spastic angina pectoris, who may have clinically and electrocardiographically silent ischemia combined with myocardial stunning, during rest and hyperventilation stress testing. METHODS: Phase analysis of the left ventricle at rest was performed by equilibrium radionuclide ventriculography in 13 control subjects and 36 patients with spastic angina pectoris. First-pass methodology along with hyperventilation stress testing was performed to assess spasm occurrences. Phase analysis of equilibrium multigated blood-pool scintigrams was performed to evaluate LV asynchrony at rest. RESULTS: The mean s.d. of LV phase distribution in the patients with variant and vasospastic angina was greater than that in the healthy control subjects (11.28 +/- 1.79 and 10.02 +/- 1.57 degrees versus 6.16 +/- 1.07 degrees). In addition, the mean s.d. of LV phase distribution in the variant angina group was greater than that in the vasospastic angina group. Furthermore, a linear correlation was found between the s.d. of LV phase distribution at rest and the percent decrease in ejection fraction during hyperventilation stress. CONCLUSION: Asynchronous LV contraction without significant hypokinesis was detected at rest in spastic angina pectoris. The severity of this asynchronous contraction corresponded well with decreases in ejection fraction during hyperventilation stress testing. Thus, analysis of the s.d. of LV phase distribution at rest is expected to provide useful information regarding LV asynchrony in spastic angina pectoris.

Adult↗

[Complicated form of spastic paraplegia with congenital cataract: a case report].

We report a 33-year-old man who manifested spastic paraplegia with congenital cataract, dementia, deformity of the foot (pes cavus, high arch and hammer toes), ataxia, and peripheral neuropathy. Magnetic resonance imaging showed mild deformity of the trunk of the corpus callosum and atrophy of superior cerebellar vermis. Metabolic diseases were ruled out by the clinical course and special examinations. Other patients, including 2 of ours, with spastic paraplegia and thin corpus callosum have been reported, but the present case is different because of congenital cataract and the form of the corpus callosum. We consider that there may be a variety of complicated forms of spastic paraplegia. To assess the etiology of complicated forms of spastic paraplegia, further case accumulation is very important.

Adult↗

Placebo controlled utility and feasibility study of the H-reflex and flexor reflex in spastic children treated with intrathecal baclofen.

OBJECTIVE: To evaluate feasibility and utility of the soleus H-reflex and tibialis anterior flexor reflex (FR) in identifying spinal cord neuronal response to intrathecal baclofen (ITB) in children with severe spastic cerebral palsy. METHODS: During a randomized, double-blind, placebo-controlled dose-escalation test treatment, maximum H amplitude/maximum M amplitude (H/M ratio) and FR parameters were bilaterally recorded at baseline and 2-3 h after intrathecal bolus administration of placebo and increasing doses of baclofen until both an improvement in the individual treatment goal(s) and a one-point reduction on the Ashworth scale were observed. RESULTS: Electrophysiological data of 14 children were studied. The H-reflex was feasible in 13 children, the FR threshold area in 9 and the FR, elicited with supramaximal stimulation, in only one child. After ITB, the H/M ratio significantly decreased (left: 0.67+/-0.47 to 0.15+/-0.18, P=0.005; right: 0.55+/-0.32 to 0.14+/-0.19, P=0.002) without placebo effect. FR threshold area after ITB, only decreased significantly in children not taking oral baclofen (left: 146+/-53 to 41+/-54 mV ms, P=0.000; right: 156+/-80 to 66+/-48 mV ms, P=0.002). CONCLUSIONS: This is the first randomized, double-blind, placebo-controlled dose-escalation study in spastic children demonstrating the soleus H-reflex to be a feasible and objective measure to quantify the decreasing motoneuron excitability in response to ITB bolus administration. Only in children not taking oral baclofen, FR threshold area can also be used as an objective outcome measure, yet feasibility is limited. SIGNIFICANCE: We suggest introducing the H-reflex as the electrophysiological gold standard for the evaluation of the effect of ITB in spastic children.

Adolescent↗

A founder variant in TBCB is associated with global developmental delay, autism spectrum, and spastic paraparesis.

PURPOSE: Hereditary spastic paraparesis (HSP) is a genetically diverse group of Mendelian disorders characterized by length-dependent axonal degeneration. Microtubule dysfunction is a known mechanism in HSP that impairs axonal dynamics. TBCB encodes tubulin-folding cofactor B (TBCB), which, along with TBCE, regulates &#x3b1;&#x3b2;-heterodimer dynamics and neuronal axonal growth. Here, we describe a new form of complicated HSP caused by a founder variant in TBCB. METHODS: Exome sequencing revealed a homozygous c.589T>A p.(Tyr197Asn) variant in TBCB in a cohort of 10 individuals assembled through genematching tools. Protein function was assessed using Saccharomyces cerevisiae ortholog ALF1, and a CRISPR-Cas9-generated homologous mutant in Drosophila melanogaster. TBCB expression and localization were examined in fibroblasts using western blot and immunofluorescence. RESULTS: Participants displayed late-childhood-onset spastic paraparesis, global developmental delay, and autism spectrum. TBCB protein levels were reduced in affected fibroblasts. The ALF1 mutant in yeast increased benomyl sensitivity, resembling a loss-of-function phenotype. In Drosophila melanogaster, the homologous mutant led to reduced survival and impaired climbing ability. CONCLUSION: We describe a novel neurodevelopmental disorder with spastic paraparesis and a high carrier rate in the Ashkenazi Jewish population. Our results indicate that TBCB has a vital role in the development of central nervous system and potentially in axonal function in humans.

Humans↗

HTLV-I associated myelopathy/tropical spastic paraparesis in a 7-year-old boy associated with infective dermatitis.

HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy characterized by a slowly progressive spastic paraparesis and sphincter disturbances beginning in adulthood. Only eight well-documented cases occurring in childhood and adolescence have been described. Infective dermatitis associated to the HTLV-I (IDH) is a chronic eczema of childhood occurring in vertically infected carriers. Here we describe a 7-year-old boy with HAM/TSP and IDH. The neurological manifestations were spastic gait, hyperreflexia of lower limbs, clonus and bilateral Babinski's sign. High levels of HTLV-I antibodies in the serum and in the cerebrospinal fluid were observed. The association of these two diseases and the early onset of HAM/TSP are probably related to a strong humoral anti-HTLV-I response.

Antibodies, Viral↗

Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke.

BACKGROUND: Spasticity is a disabling complication of stroke, and it is uncertain whether intramuscular injections of botulinum toxin type A reduce disability in persons with spasticity of the wrist and fingers after a stroke. METHODS: We performed a randomized, double-blind, placebo-controlled, multicenter trial to assess the efficacy and safety of one-time injections of botulinum toxin A (200 to 240 units) in 126 subjects with increased flexor tone in the wrist and fingers after a stroke. The primary outcome measure was self-reported disability in four areas: personal hygiene, dressing, pain, and limb position (on a four-point scale ranging from no disability to severe disability) at six weeks; at base line, each subject selected one of these areas in which there was moderate-to-severe disability as the principal target of treatment. RESULTS: Subjects who received botulinum toxin A had greater improvement in flexor tone in the wrist and fingers at all follow-up visits through 12 weeks than did subjects who received placebo (P<0.001 for all comparisons). Subjects treated with botulinum toxin A had greater improvement in the principal target of treatment at weeks 4, 6, 8, and 12 (P<0.001, P<0.001, P=0.03, and P=0.02, respectively); at week 6, 40 of the 64 subjects in the botulinum-toxin group (62 percent), as compared with 17 of the 62 in the placebo group (27 percent), reported improvement of at least one point on the Disability Assessment Scale in the principal target of treatment (P<0.001). There were no major adverse events associated with injection of botulinum toxin A. CONCLUSIONS: Intramuscular injections of botulinum toxin A reduce spasticity of the wrist and finger muscles and associated disability in patients who have had a stroke.

Adult↗