Capsaicin jelly against migraine pain.

OBJECTIVE: Recent studies support the role of extracranial perivascular afferents in a substantial percentage of migraineurs. Perivascular afferent fibres of the superficial temporal artery contain peptides, like calcitonin gene-related peptide (CGRP) and substance P (SP). CGRP and SP are considered relevant in the genesis of migraine pain. Capsaicin is an agonist of the transient receptor potential vanilloid type 1. It causes membrane depolarisation of sensory neurons, which release CGRP, SP and other pain peptides; excitation is followed by a refractory state, causing inactivation. Topical capsaicin has been found to be efficacious in several types of neuropathic pain. We attempted to verify whether topical periarterial capsaicin could ameliorate pain in absence of and during a migraine attack. METHODS: On 23 migraineurs showing pain at pressure on scalp arteries, we administered topical capsaicin 0.1% or vaseline jelly on painful arteries in absence of migraine attack. In those having pain reduction > 50%, we made the same comparison during a migraine attack. RESULTS: Topical capsaicin caused > 50% reduction of arterial pain in absence of attack in 17/23 patients, as opposed to two with vaseline. During attacks of mild- to moderate-intensity, > 50% improvement was obtained in 11/17 with capsaicin and in one with vaseline. CONCLUSIONS: Although referring to a small number of patients, our data show that topical capsaicin may relieve arterial pain in absence of and during a migraine attack in a substantial number of patients experiencing scalp arterial tenderness. More active capsacinoids might be tried in the future and could provide a new method for treating migraine attacks.

A family with segregation of an unbalanced translocation (7;13) (q36;q32) in three patients with severe mental retardation, microcephaly and dysmorphic features, detected by subtelomere FISH: genetic counselling and prenatal diagnosis.

We report a Sardinian family in which three members showed a mental-retardation-microcephaly-multiple malformations syndrome resulting from an unbalanced translocation (7;13)(q36;q32) which led to subtelomeric trisomy 7q36qter and partial monosomy 13q32qter. The unbalanced translocation was transmitted by alternate segregation from a female and a male carriers of the balanced translocation. The three patients had severe mental retardation, microcephaly and multiple minor facial and fingers anomalies. Neuroimages showed brain atrophy, associated in two patients with partial agenesis of the corpus callosum. FISH with chromosome 13 and 7 specific painting probes and subtelomere specific probes was instrumental for defining and characterizing the chromosomal translocation. Extensive genetic counseling and prenatal diagnosis has been offered to all the members of the family.

Pergolide improvement in neuroleptic-resistant Tourette cases: various mechanisms causing tics.

The objective was to report the possibility that in Tourette's disorder (TD) the same pathways may not be involved in all patients. Tics in three children affected with TD showed no improvement after treatment with several neuroleptic drugs (D2 blockers) at appropriate doses. However, they did improve greatly and persistently with pergolide treatment. One of the 3 patients showed a less usual tic feature, the most relevant of which resembled violent myoclonias of both upper limbs. This suggests that in these patients the improvement due to pergolide is not linked to an effect on D2-receptors-carrying GABAergic neurons, as usually assumed, because the patients did not respond to neuroleptics acting in this way. In these 3 cases, unlike in other TD patents, a prevalent action of pergolide by pre-synaptic inhibition of dopamine release on D1-receptors-carrying GABAergic neurons is suggested. Therefore, direct and indirect pathways could be differentially involved in different cases of TD.

Long-term risperidone for pervasive developmental disorder: efficacy, tolerability, and discontinuation.

To investigate the safety (e.g., weight gain, liver function, extrapyramidal side effects, and seizures) and efficacy of the long-term use of risperidone in children and adolescents and to ascertain the effects of drug withdrawal in a semi-naturalistic prospective, subjects with autism or pervasive developmental disorders not otherwise specified (PDDNOS) were treated with risperidone for 6 months after which parents were given the option of continuing for a further 6 months (final assessment at 12 months). Behavioral rating included Childhood Autism Rating Scale (CARS), Child Psychiatric Rating Scale (CPRS), Clinical Global Impression (CGI), and Child-Global Assessment Scale (C-GAS). Risperidone significantly ameliorated behavioral symptoms of PDD in 10 out of 11 subjects, with the effects on core symptoms being of smaller amplitude and of slower onset. No loss of effectiveness was observed in patients who continued risperidone for 12 months, while a relapse of associated behavioral symptoms occurred in the others. Weight gain was common, although the rate of increase lessened over a period of time; after drug withdrawal, considerable weight loss was observed in the patient who had previously shown the most significant increase. After 6 months of therapy, two patients developed facial dystonia: this disappeared after reducing dosage in one case, after drug discontinuation in the other. Amenorrhea was also observed, but no changes in liver function, blood tests or EEG were reported. The data indicate that risperidone is an effective and relatively safe drug for long term treatment of behavioral disruption in autistic children and adolescents.

Attention-deficit/hyperactivity disorder: a neuropsychiatric disorder with childhood onset.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by attentional problems such as hyperkinesia, restlessness and disturbances in timing. Environmental psychosocial factors interact with a genetic predisposition in causing measurable biological impairment. It is a common, persistent disorder of childhood that may change in manifestation with development from preschool through adult life. Untreated, it predisposes children to psychiatric and social pathology later in life. Unlike other psychiatric disorders of childhood, it can be successfully treated.

Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene.

Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), is a clinically and genetically heterogeneous condition. Mutations of the myelin protein zero (MPZ) gene have been associated with CMT1B, Dejerine-Sottas disease, and congenital hypomyelination, which are inherited demyelinating neuropathies characterized by different clinical severity. HMSN type II (HMSN II) or CMT2, the axonal form of CMT, is genetically heterogeneous. Linkage to 1p35-p36 (CMT2A), 3q (CMT2B), and 7p (CMT2D) chromosomes has been reported in the disease; however, most HMSN II families do not link to any of the reported loci. In a large HMSN II Sardinian family, we found a missense mutation in the chromosome 1q MPZ gene. This Ser44Phe mutation was located in exon 2 and was present in the heterozygous state in all affected individuals. This is the first example of an HMSN II family showing an MPZ point mutation. The MPZ gene Ser44Phe mutation found in the HMSN II family presented in this study suggests that genetic analysis of HMSN II families should also include the MPZ gene, previously not considered to be involved in the axonal form of HMSN.

A novel point mutation in the peripheral myelin protein 22 (PMP22) gene associated with Charcot-Marie-Tooth disease type 1A.

We studied the peripheral myelin protein gene PMP-22 in a large Sardinian family with Charcot-Marie-Tooth disease type 1A (CMT1A), in which the duplication commonly found in CMT1A was absent, but with evidence of linkage on chromosome 17. Sequencing of DNA and cDNA showed a missense point mutation G368-->T in exon 5 of PMP22, predicted to determine a valine for glycine substitution at codon 107, which could be plotted in the center of the PMP22 protein putative transmembrane domain III. Using sequence-specific oligonucleotide probes (SSOP), we found the point mutation in all affected CMT1A subjects but not in healthy family members or in 314 chromosomes of controls, thus indicating that the G368-->T point mutation is not a polymorphism. In the hypothetical model of PMP22, the amino acid at position 107 plots deeply into alpha-helical transmembrane domain III, a domain where point mutations have never previously been found. Although the same mutation was present in all CMT1A subjects examined, clinical findings showed a different stereotyped pattern in relation to the generation examined, for a progressive increase in severity and an earlier onset from the first to the third generation examined. Molecular analysis suggests that CMT1A disease in this family is due to the G368-->T point mutation, although other mechanisms may account for the clinical variability in the members of different generations.

Dystrophin gene abnormalities in two patients with idiopathic dilated cardiomyopathy.

Two new cases of dilated cardiomyopathy (DC) caused by dystrophinopathy are reported. One patient, a 24 year old man, had a family history of X linked DC, while the other, a 52 year old man, had sporadic disease. Each had abnormal dystrophin immunostaining in muscle or cardiac biopsy specimens, but neither had muscle weakness. Serum creatine kinase activity was raised only in the patient with familial disease. Analysis of dystrophin gene mutations showed a deletion of exons 48-49 in the patient with familial DC and of exons 49-51 in the other. Dystrophin transcription in cardiac tissue from the patient with sporadic disease showed abundant expression, predominantly of the muscle isoform. This study, together with previous reports, suggests that some patients with DC have a dystrophinopathy that can be diagnosed using a combination of biochemical and genetic analyses.

A mutation in the dystrophin gene selectively affecting dystrophin expression in the heart.

We have previously shown in a large X-linked pedigree that a deletion removing the dystrophin muscle promoter, the first muscle exon and part of intron 1 caused a severe dilated cardiomyopathy with no associated muscle weakness. Dystrophin expression was present in the muscle of affected males and transcription studies indicated that this dystrophin originated from the brain and Purkinje cell isoforms, upregulated in this skeletal muscle. We have now studied dystrophin transcription and expression in the heart of one member of this family. In contrast to the skeletal muscle, dystrophin transcription and expression were absent in the heart, with the exception of the distal Dp71 dystrophin isoform, normally present in the heart. The 43- and 50-kD dystrophin-associated proteins were severely reduced in the heart, despite the presence of Dp71, but not in skeletal muscle. The absence of dystrophin and the down-regulation of the dystrophin-associated proteins in the heart accounted for the severe cardiomyopathy in this family. The mutation present in these males selectively affects dystrophin expression in the heart; this could be secondary to the removal of cardiac-specific regulatory sequences. This family may represent the first example of a mutation specifically affecting the cardiac expression of a gene, present physiologically in both the skeletal and cardiac muscles.

Efficacy and tolerability of vigabatrin in children with refractory partial seizures: a single-blind dose-increasing study.

The efficacy and tolerability of vigabatrin (VGB) in children with refractory partial epilepsy were assessed in a single-blind, add-on, fixed-sequence, placebo-controlled trial. After 1-month observation, the patients entered a 7-month treatment period that involved administration of placebo for 1 month followed by VGB at the initial dosage of 40 mg/kg/day, to be increased to 60 and 80 mg/kg/day at 2-month intervals if seizures persisted. Of the 46 children enrolled in the study, 7 dropped out prematurely due to lack of efficacy of the drug (n = 6) or increased seizure frequency (n = 1). In 11 patients who either became seizure-free (n = 3) or improved markedly (n = 8), treatment was completed at a dose < 80 mg/kg/day. The average number of seizures per month in the 39 patients who completed the study decreased from 97 during placebo to 21, 12, and 9 after 2, 4, and 6 months of VGB treatments respectively (p < 0.0001 at each time). Response to VGB remained statistically significant when dropouts were included in the evaluation. The number of patients who had > 50% reduction in seizure frequency after 2, 4, and 6 months was 28, 33, and 35, respectively. Eight patients became seizure-free during the last 2 months of VGB treatment (3 at 40, 3 at 60, and 2 at 80 mg/kg/day, as compared with none during placebo treatment). Serum levels of associated antiepileptic drugs (AEDs) showed no significant changes, except for serum phenytoin (PHT) concentration, which significantly (p < 0.01) decreased after VGB treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Familial cardiomyopathy, mental retardation and myopathy associated with desmin-type intermediate filaments.

The clinical and morphological findings of a familial case affected by mental retardation, severe biventricular hypertrophic cardiomyopathy and vacuolar myopathy are reported. The phenotype of this patient is similar to that described by other authors, in which a lysosomal glycogen storage disease with normal acid maltase levels was suspected. However, in our case the vacuoles were stained by several antibodies directed against various sarcolemmal proteins, such as dystrophin and spectrin, and therefore, were not of lysosomal origin. Some of these vacuoles were clearly derived from the splitting of the fibres and invagination of the extracellular space; autophagic vacuoles were not observed. The accumulation of desmin-type, intermediate filaments was demonstrated on immunocytochemistry both in the skeletal and cardiac muscles. A brother of the propositus was also affected by mental retardation, severe cardiomyopathy and died suddenly at the age of 24 yr. A cardiomyopathy and mental subnormality were also present in other male cousins of the proband, while sudden death occurred in several females relatives, whose intelligence was normal. None of these latter individuals was available for further investigation. This report expands the spectrum of desmin associated myopathy and cardiomyopathy to include a familial condition with associated mental retardation.