A French observational study of botulinum toxin use in the management of children with cerebral palsy: BOTULOSCOPE.

BACKGROUND: Dystonia and spasticity are common symptoms in children with Cerebral Palsy (CP), whose management is a challenge to overcome in order to enable the harmonized development of motor function during growth. AIM: To describe botulinum toxin A (BTX-A) use and efficacy as a treatment of focal spasticity in CP children in France. METHODS: This prospective observational study included 282 CP children mostly administered according to French standards with BTX-A in lower limbs. Realistic therapeutic objectives were set with parents and children together before treatment initiation and assessed using the Visual Analogue Scale (VAS). Child management was recorded and the efficacy of injections was assessed during a 12-month follow-up period by physicians (Modified Ashworth Scale, joint range of motion, Physician Rating Scale, Gillette Functional Assessment Questionnaire and Gross Motor Function Measure-66) and by patients/parents (Visual Analogue Scale). RESULTS: BTX-A treatment was administered in different muscle localizations at once and at doses higher than those recommended by the French Health Authorities. Children were treated in parallel by physiotherapy, casts and ortheses. Injections reduced spasticity and improved joint range of motion, gait pattern and movement capacity. Pain was reduced after injections. BTX-A administration was safe: no botulism-like case was reported. The log of injected children who were not included in the study suggested that a large population could benefit from BTX-A management. CONCLUSIONS: We showed here the major input of BTX-A injections in the management of spasticity in CP children. The results are in favor of the use of BTX-A as conservative safe and efficient treatment of spasticity in children, which enables functional improvement as well as pain relief.

[Botulinum toxin in the management of spastic hip adductors in non-ambulatory cerebral palsy children]. / Toxine botulinique dans la spasticité des adducteurs de hanche chez les enfants IMC et IMOC non marchants.

PURPOSE OF THE STUDY: Spasticity of the hip adductors is a challenging problem for children with severe motor impairment due to cerebral palsy. It inhibits motor development and is also a risk factor for hip dislocation. Botulinum toxin has been found to be an effective means of treating spastic pes equinus in walking cerebral palsy patients and could have other indications. We conducted a prospective study to determine the functional and orthopedic contribution of botulinum toxin in the treatment of spastic hip adductors in non-ambulatory cerebral palsy children. MATERIAL AND METHODS: The study included 11 quadriplegic children with cerebral palsy (mean age 5 years 9 months). Seven of the children had unilateral migration of the hip at study onset (> 40% radiographically). The children were given a single injection of botulinum toxin (Dysport: 20 units/kg/hip) in the adductor muscles (21 treated hips). The children were seen again at months 1, 3, 6 and 12 after treatment (with the exception of one patient not seen after the 6(th) month at the request of the parents). Spasticity was measured with the modified Ashworth scale. The motor level was determined with 8 position and motor items and with the GMFCS classification. Hip x-rays were obtained at study onset and once or twice during the follow-up. RESULTS: There were no adverse effects of the treatment. Spasticity decreased by one point or more on the Ashworth scale in 20 hips at month 1 and remained low at month 3 in 14, and at month 6 in 12 of the 21 hips treated. The effect of the anti-spasticity treatment faded out from the 6(th) to the 12(th) month. Three children who experienced pain in the lower limbs were definitively relieved after treatment. Nine children achieved functional improvement (progress in at least one of the motor items). Three children were able to walk with a walker and two of them improved from level IV to level III on the GMFCS. The best functional responses appeared to occur in the younger children and in those who had good results at months 3 and 6. Among the 7 children whose hip was displaced by more than 40%, 5 had an unfavorable radiological progression and underwent surgery. DISCUSSION: This study demonstrates that the botulinum toxin can be effective against spasticity of the hip adductors and that its effect is still significant 6 months after the injection in more than half the hips treated. It has an analgesic effect. This treatment has a functional impact even in children with severe motor impairment. The benefit has been modest but three children were able to progress to walking with a walker. The best functional results were observed in the younger children and in those whose spasticity had declined at month 3 and 6. It could thus be favored either by innate potential for motor development or by the treatment itself. The botulinum toxin did not improve the orthopedic prognosis of the children: 5 of the 7 with a risk of luxation worsened. Nevertheless, our study suggests that the botulinum toxin is a well-tolerated anti-spasticity treatment that is effective for the hip adductors providing an important contribution to the management of non-ambulatory cerebral palsy children.

Paw preference and brain dopamine asymmetries.

The hemispheric content of dopamine and its metabolites in the frontal cortex, caudatus putamen and nucleus accumbens septi was evaluated in relation to behavioral lateralization assessed by paw preference. Three groups of C3H/He mice were selected on the basis of their performance in the paw preference test (left-handed, ambidextrous and right-handed) and levels of dopamine and its metabolites were measured in the two hemispheres of each group. Mice showed significant differences in hemispheric content of dopamine and 3-4 dihydroxyphenylacetic acid in the nucleus accumbens septi depending on the behavioral lateralization as expressed by paw preference. The hemispheric dominance (right hemisphere/right hemisphere + left hemisphere content of dopamine and metabolites x 100) was also calculated for each mouse. Significant differences in hemispheric dominance for dopamine, 3-4 dihydroxyphenylacetic acid and 3-methoxytyramine in the nucleus accumbens were found between right-handed and left-handed mice. This dominance was ipsilateral to the preferred paw: % right hemisphere/total content of dopamine and its metabolites were lowest in left-handed, highest in right-handed and intermediate in ambidextrous mice. Finally, individual % right hemisphere/total content for dopamine, 3-4 dihydroxyphenylacetic acid and 3-methoxytyramine in the nucleus accumbens positively correlated with individual paw preference scores. The analysis of the other brain areas did not reveal any significant effect. These results suggest a strong relationship between mesoaccumbens dopamine asymmetries and both the direction and the intensity of behavioral lateralization as expressed by paw preference in mice.

Brain monoaminergic, neuroendocrine, and immune responses to an immune challenge in relation to brain and behavioral lateralization.

Host responses to immune challenges involve central neurotransmission, the hypothalamo-pituitary adrenal axis, and the immune system. In the present work, we investigated the possibility of an asymmetry in the modification of brain monoamine metabolism induced by a systemic injection of lipopolysaccharide (LPS) in adult female mice. We also studied the possible influence of behavioral lateralization, as assessed by a paw preference test, on the reactivity of the nervous, neuroendocrine, and immune systems to a LPS challenge. The results showed that LPS administration induced an enhanced brain activity as demonstrated by an increase in noradrenergic, serotoninergic, and dopaminergic metabolism. Increased serotonin metabolism, observed in the hypothalamus and hippocampus, only occurred on the left side. Furthermore, the increase in serotonin turnover in the medial hypothalamus, the elevation of plasma adrenocorticotropin levels, and the decrease in T lymphocyte proliferation were observed in right-handed and ambidextrous mice but not in left-handed animals. Taken together, the results demonstrate that an immune challenge could induce neurochemical, neuroendocrine, and immune responses similar to those of stress, suggesting that LPS may be a stress inducer. Interestingly, these responses that may be asymmetrically expressed appear to depend on behavioral lateralization.

Influence of early life events on immune reactivity in adult mice.

The effects of postnatal manipulations on different immune parameters were investigated in adult female mice. Postnatal stress consisted of a 15-min daily exposure to clean bedding (temperature maintained at 35 degrees C) for the first 2 weeks of life in the absence of the mother but in the presence of littermates. Controls were unhandled until weaning. At 60 days of age, female mice stressed during postnatal development showed enhanced immune reactivity as assessed by NK-cell activity and T-cell mitogenesis in comparison with unhandled mice. By contrast, B-lymphocyte proliferation induced by lipopolysaccharide (LPS) was not affected by alterations of postnatal environment. Furthermore, the association between immune reactivity and behavioral lateralization observed in adult mice was not altered by postnatal stress.

Modulation of immune reactivity by unilateral striatal and mesolimbic dopaminergic lesions.

Asymmetrical modulation of immune reactivity by central dopaminergic pathways was suggested by previous reports which described an association between alterations of immune response and peculiar patterns of dopamine asymmetries in pathological and physiological situations. In the present experiments, we studied the respective roles of the nigrostriatal and mesolimbic dopaminergic networks in the asymmetrical modulation of immune responses. Lymphocyte proliferation as well as natural killer (NK) cell activity were analysed in mice, 2 weeks after unilateral lesions of dopaminergic projections by in situ injection of 6-hydroxydopamine in the striatum or the nucleus accumbens. After lesions of the striatum, proliferation of splenic lymphocytes was impaired only in the right-lesioned group. Left-lesions appeared to not modify T lymphocyte reactivity. After lesions of the nucleus accumbens, no modification of T lymphocyte mitogenesis was observed but splenic NK cell activity was depressed in left-lesioned mice as compared with controls or right-lesioned animals. Proliferation of B lymphocytes was not affected by striatal or mesolimbic dopaminergic lesions. It was concluded that both striatal and mesolimbic dopaminergic pathways are asymmetrically involved in neuro-immunomodulation. These dopaminergic regions appear to function independently as the effective side as well as the immune parameters that were altered differ according to the structure lesioned.

Distribution of brain monoamines in left- and right-handed mice injected with bacillus Calmette-Guerin.

Concentrations of brain monoamines from various cerebral structures were determined in right and left sides of the brain from female mice selected for paw preference and injected or not with BCG 8 weeks before. BCG-induced changes in brain monoamine distribution in prefrontal cortex, medial hypothalamus and brain stem were only observed in right-handers. In the posterior hypothalamus, even though there was no BCG effect, norepinephrine asymmetry observed in right-handed controls was suppressed after BCG-injection. Moreover, BCG-induced brain monoamine changes in right-handers mainly involved the right hemisphere except the NE decrease in brain stem which was left-sided. This work demonstrates that the injection of BCG leads to long lasting asymmetrical changes in brain monoamine distribution that furthermore depend on behavioral lateralization of mice.

Late central demyelination after Fischer's syndrome: MRI studies.

The case of a patient who presented with clinical, electrophysiological, and MRI evidence of central demyelination is described. The patient had been admitted to hospital for Fischer's syndrome a few years previously. The association of these two events suggests that central and peripheral myelinopathy may be related in Fischer's syndrome.

Analysis of the prion protein gene in thalamic dementia.

Thalamic degenerations or dementias are poorly understood conditions. The familial forms are (1) selective thalamic degenerations and (2) thalamic degenerations associated with multiple system atrophy. Selective thalamic degenerations share clinical and pathologic features with fatal familial insomnia, an autosomal dominant disease linked to a mutation at codon 178 of the prion protein (PrP) gene that causes the substitution of asparagine for aspartic acid (178Asn mutation). We amplified the carboxyl terminal coding region of the PrP gene from subjects with selective thalamic dementia or thalamic dementia associated with multiple system atrophy. Three of the four kindreds with selective thalamic dementia and none of the three kindreds with thalamic dementia associated with multiple system atrophy had the PrP 178Asn mutation. Thus, analysis of the PrP gene may be useful in diagnosing the subtypes of thalamic dementia. Moreover, since selective thalamic dementia with the PrP 178Asn mutation and fatal familial insomnia share clinical and histopathologic features, we propose that they are the same disease.

Hemispheric asymmetry in the effects of substantia nigra lesioning on lymphocyte reactivity in mice.

Asymmetry in brain modulation of the immune system has previously been demonstrated at the neocortex level. In these experiments, the possibility of subcortical immunomodulation was investigated. In mice the substantia nigra was lesioned using the neurotoxin 6-hydroxydopamine. Four and six weeks after left or right lesions of the substantia nigra, spleen lymphocyte mitogenesis was slightly depressed or enhanced respectively as compared to sham operated controls. Differences appeared when comparing left and right lesioned groups. However, natural killer cell activity was unaffected by unilateral lesions of the substantia nigra. These results show that asymmetrical brain modulation may occur at the sub-cortical level and suggest that central dopamine is involved in neuroimmunomodulation.

[Myopathy in adults caused by acid maltase deficiency. A trial of treatment with high protein diet]. / Myopathie de l'adulte par déficit en maltase acide. Essai de traitement par régime hyperprotidique.

A 21-year old women with rhizomelic muscular deficit and signs of hypercapnia developed acute respiratory failure. Laboratory tests revealed high creatine kinase activity, and electromyograms showed myogenic patterns with a few myotonic discharges. Biopsy of the quadriceps muscle elicited major vacuolar myopathy with glycogen overload. Acid maltase activity was undetectable in muscular tissue. After 7 months on high-protein diet (1540 calories, 37% proteins) there was no clinical or biochemical improvement. The other published cases of acid maltase deficiency treated with high-protein diet are discussed.

Early effects of unilateral lesions of substantia nigra on immune reactivity.

It has recently been demonstrated that central dopaminergic pathways are asymmetrically involved in the modulation of the immune response. Mitogen-induced proliferation of T lymphocytes was shown to be enhanced 4-6 weeks after right lesion of the substantia nigra (SN) in mice, when compared to left lesioned and control animals. In order to study the involvement of post lesion neuronal reorganization in these results, the same immunological parameters were determined as early as 2 weeks after right or left lesion of the SN. We showed that the lymphoproliferation induced by alpha CD3 and concanavalin A was decreased in both lesioned groups, but phytohemagglutinin-induced mitogenesis was more impaired in the right than in the left lesioned animals. Hence, the time course effects of the right lesions of SN shifted from depression to enhancement of the T lymphocyte responsiveness. This shift appeared to occur around the two weeks period following the lesion. These immunomodulatory effects of unilateral SN lesioning, which depended on time and side of lesion, were similar to those observed after hemidecortication. Based on these findings, it is reasonable to suggest that asymmetry in brain immunomodulation involves functionally related dopaminergic and cortical networks.

[Autosomal dominant centronuclear myopathy]. / Myopathie centronucléaire autosomique dominante.

In a family 6 members in 3 generations were affected by centronuclear myopathy (CNM) of autosomal dominant inheritance. The apparent onset was in the early forties and the disease progressed slowly. Limb weakness was predominant. Strabismus was present in 5 cases and calves hypertrophy in 3. Serum creatinine kinase was always within the normal range. In one case myotonic bursts were found at electromyography. In 2 cases brain stem auditory evoked potential studies demonstrated abnormal prolongation of interpeak latencies I-III and favoured subclinical nervous system involvement. Muscular biopsies showed typical features of centronuclear myopathy with 50 to 80% central nuclei. In two cases immunocytochemical labelling of dystrophin showed staining in the sarcoplasm in favour of an arrest in the morphogenesis of developing myofiber. Others families with autosomal dominant CNM in the literature and also some sporadic adult cases had similar clinical features.

[Subacute familial thalamic atrophy. Memory disorders and complete insomnia]. / Atrophie thalamique subaiguë familiale. Troubles mnésiques et insomnie totale.

Thalamic atrophy is rarely primitive. Selective atrophy of the dorso-medial and anterior thalamic nuclei has been reported in a few families. The clinical course is subacute. Symptoms and signs include sleep disorders and intellectual deficit. We report a new family with this uncommon disease and discuss its etiology.

[Wilson's disease: demonstration of lesions of the cortex and white matter by MRI]. / Maladie de Wilson: démonstration de lésions corticales et de la substance blanche par IRM.

Lesions of cortex and white matter are present in Wilson's disease in approximately 10 p. cent of cases. Before Magnetic Resonance Imaging (MRI) only post-mortem examination evidenced them. We report the case of a 15 year-old girl in whom Wilson's disease was diagnosed after partial motor epileptic seizures. She later presented with progressive extrapyramidal and pyramidal signs, severe cognitive weakening and disorder of behaviour. MRI clearly showed cortical and subcortical lesions by an enhanced signal (T2 values). It showed as well the classical picture of lesion in the lenticular nuclei. With T1 values it showed an extensive cortical atrophy and a widening of the ventricules.