ABSTRACT
The objective was to evaluate the applicability and reliability of an unbiased stereological computerised tomography (CT) method for estimating total human body (HB), skeletal muscle (SM) and adipose tissue (AT) volumes in groups of neuromuscular patients. In 10 neuromuscular patients HB, SM and AT volumes were estimated using systematic sampling on equidistant CT sections throughout the total body axis using a counting grid with systematically ordered intersection points. Each intersection point hitting HB, SM or AT represented a known volume dependent on intersection point distance and sum of section thickness and gap. Random and systematic intra- and interobserver errors for volume estimates were below 0.035. These errors were negligible to the coefficient of variation of the group mean, being 0.190 for HB, 0.323 for SM and 0.471 for AT. Even in the presence of intrafascicular and intramuscular fat in neuromuscular patients, unbiased and reliable quantification of HB, SM and AT is possible.
Subject(s)
Adipose Tissue/pathology , Muscle, Skeletal/pathology , Neuromuscular Diseases/pathology , Tomography Scanners, X-Ray Computed , Adult , Female , Human Body , Humans , Male , Middle Aged , Reproducibility of Results , Sensitivity and SpecificitySubject(s)
Carotid Artery, Internal , Cerebral Hemorrhage/prevention & control , Endarterectomy, Carotid/adverse effects , Monitoring, Intraoperative , Ultrasonography, Doppler, Transcranial , Blood Flow Velocity , Carotid Artery, Internal/diagnostic imaging , Carotid Stenosis/surgery , Cerebral Hemorrhage/etiology , Humans , Middle Cerebral Artery/diagnostic imaging , Middle Cerebral Artery/physiology , Pulsatile Flow , Regional Blood FlowABSTRACT
BACKGROUND: In animals and healthy volunteers beta2-adrenergic agonists increase muscle strength and mass, in particular when combined with strength training. In patients with facioscapulohumeral muscular dystrophy (FSHD) albuterol may exert anabolic effects. The authors evaluated the effect of strength training and albuterol on muscle strength and volume in FSHD. METHODS: Sixty-five patients were randomized to strength training of elbow flexors and ankle dorsiflexors or non-training. After 26 weeks albuterol (sustained-release, 8 mg BID) was added in a randomized, double-blind, placebo-controlled design. Primary outcome was maximum voluntary isometric strength (MVIC) at 52 weeks. Secondary outcomes comprised dynamic strength and muscle volume. RESULTS: Training and albuterol were well tolerated. Training of elbow flexors did not result in a significant effect on MVIC, but dynamic strength improved significantly. Elbow flexor MVIC strength increased significantly in albuterol vs placebo treated patients. Ankle dorsiflexor strength decreased in all groups. Eleven out of twelve non-trained muscles in the albuterol group showed a positive effect on MVIC compared to the placebo group (p < 0.05 in seven muscle groups). Muscle volume decreased in the placebo-treated, and increased in the albuterol-treated patients. No synergistic or antagonistic effects were observed between training and albuterol. CONCLUSIONS: In FSHD strength training and albuterol appear safe interventions with limited positive effect on muscle strength and volume. Consequences of prolonged use are presently unclear, which precludes routine prescription.
Subject(s)
Adrenergic beta-Agonists/therapeutic use , Albuterol/therapeutic use , Muscular Dystrophy, Facioscapulohumeral/therapy , Weight Lifting , Adrenergic beta-Agonists/administration & dosage , Adult , Albuterol/administration & dosage , Ankle Joint , Combined Modality Therapy , Delayed-Action Preparations , Double-Blind Method , Elbow Joint , Female , Humans , Male , Middle Aged , Muscular Dystrophy, Facioscapulohumeral/drug therapy , Physical Endurance , Respiratory Function Tests , Treatment OutcomeABSTRACT
Nemaline myopathy is a congenital neuromuscular disorder characterized by muscle weakness and the presence of nemaline rods. Five genes have now been associated with nemaline myopathy: alpha-tropomyosin-3 (TPM3), alpha-actin (ACTA1), nebulin (NEB), beta-tropomysin (TPM2) and troponin T (TNNT1). In addition, mutations in the ryanodine receptor gene (RYR1) have been associated with core-rod myopathy. Here we report linkage in two unrelated families, with a variant of nemaline myopathy, with associated core-like lesions. The clinical phenotype consists of muscle weakness in addition to a peculiar kind of muscle slowness. A genome-wide scan revealed a locus for nemaline myopathy with core-like lesions on chromosome 15q21-q23 for both families. Combining the two families gave a two-point LOD score of 10.65 for D15S993. The alpha-tropomyosin-1 gene (TPM1) located within this region is the strongest candidate gene. However, no mutations were found in the protein-coding region of TPM1, although small deletions or mutations in an intron cannot be excluded. The critical region contains few other candidate genes coding for muscle proteins and several genes of unknown function, and has not yet been sequenced completely. The novel phenotype of nemaline myopathy in the two presented families corresponds to an also novel, as yet uncharacterized, genotype.
Subject(s)
Chromosomes, Human, Pair 15/genetics , Myopathies, Nemaline/genetics , Adolescent , Adult , Female , Genetic Linkage , Genotype , Haplotypes , Humans , Lod Score , Male , Microsatellite Repeats , Muscle, Skeletal/pathology , Myopathies, Nemaline/pathology , Pedigree , Phenotype , Tropomyosin/geneticsABSTRACT
Described are patients initially diagnosed with progressive spinal muscular atrophy (PSMA), in whom further evaluation established another diagnosis. The authors prospectively investigated incident and prevalent cases of PSMA. Seventeen of 89 patients, after initial registration, were later excluded because reassessment revealed a diagnosis other than PSMA. In 11 of the 17 patients with a revised diagnosis, a potential treatment was available: multifocal motor neuropathy (7), chronic inflammatory demyelinating polyneuropathy (2), inflammatory myopathy (1), and MG (1). Other misdiagnoses included myopathy, syringomyelia, ALS, idiopathic chronic axonal polyneuropathy, and idiopathic brachial plexus neuropathy. One patient with a possible herniated lumbar disk recovered spontaneously.
Subject(s)
Diagnostic Errors , Muscular Atrophy, Spinal/diagnosis , Adult , Aged , Aged, 80 and over , Diagnosis, Differential , Female , Follow-Up Studies , Humans , Male , Middle Aged , Motor Neuron Disease/diagnosis , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Prospective StudiesABSTRACT
We present a five-generation family with a novel phenotype of autosomal dominant nemaline myopathy not linked to the three genes known to be causative for nemaline myopathy (alpha-tropomyosin-3, nebulin, and alpha-actin). Although there was muscle weakness in the neck flexors and proximal muscles of the limbs, as found in other families, facial, ankle dorsiflexor and respiratory muscles were normal. The most remarkable clinical feature was a peculiar kind of slowness in movement not reported previously in nemaline myopathy.
Subject(s)
Myopathies, Nemaline/genetics , Myopathies, Nemaline/pathology , Adult , Aged , Biopsy , Family Health , Female , Humans , Male , Microscopy, Electron , Movement Disorders/genetics , Movement Disorders/pathology , Muscle Weakness/genetics , Muscle Weakness/pathology , Myofibrils/pathology , Myofibrils/ultrastructure , Neural Conduction , Pedigree , Phenotype , Tomography, X-Ray ComputedABSTRACT
This study determines the interrater and intrarater reliability of the Traumatic Coma Data Bank (TCDB) computed tomography (CT) scan classification for severe head injury. This classification grades the severity of the injury as follows: I = normal, II = diffuse injury, III = diffuse injury with swelling, IV = diffuse injury with shift, V = mass lesion surgically evacuated, or VI = mass lesion not operated. Patients with severe closed head injury were included. Outcome was assessed using the Glasgow Outcome Score (GOS) at 3 and 6 months. Four observers, two of them classifying the scans twice, independently evaluated CT scans. Of the initial CT scans of 63 patients (36 males, 27 females; age, 34+/-24 years), 6.3% were class I, 26.9% class II, 28.6% class III, 6.3% class IV, 22.2% were class V, and 9.6% class VI. The overall interrater and intrarater reliability was 0.80 and 0.85, respectively. Separate analyses resulted in higher inter- and intrarater reliabilities for the mass lesion categories (V and VI), 0.94 and 0.91, respectively, than the diffuse categories (I-IV) 0.71 and 0.67. Merging category III with IV, and V with VI resulted in inter- and intrarater reliabilities of 0.93 and 0.78, respectively. Glasgow outcome scores after 6 months were as follows: 19 dead (30%), one vegetative (2%), five severely disabled (8%), 17 moderately disabled (27%), and 21 good recovery (33%). Association measures (Sommers' D) between CT and GOS scores were statistically significant for all observers. This study shows a high intra- and interobserver agreement in the assessment of CT scan abnormalities and confirms the predictive power on outcome when the TCDB classification is used.
Subject(s)
Databases as Topic/classification , Head Injuries, Closed/classification , Head Injuries, Closed/diagnostic imaging , Tomography, X-Ray Computed/classification , Adolescent , Adult , Aged , Aged, 80 and over , Analysis of Variance , Child , Child, Preschool , Databases as Topic/statistics & numerical data , Female , Glasgow Outcome Scale , Humans , Male , Middle Aged , Observer Variation , Predictive Value of Tests , ROC Curve , Reproducibility of Results , Tomography, X-Ray Computed/statistics & numerical data , Trauma Severity IndicesABSTRACT
BACKGROUND: Spinal muscular atrophy (SMA) results from mutations of the survival motor neuron (SMN) gene on chromosome 5. The SMN gene exists in two highly homologous copies, telomeric (SMN1) and centromeric (SMN2). SMA is caused by mutations in SMN1 but not SMN2. The clinical phenotype of SMA appears to be related to the expression of SMN2. Patients suffering from the milder forms of SMA carry more copies of the SMN2 gene compared with patients with more severe SMA. It is suggested that the SMN2 gene is translated into an at least partially functional protein that protects against loss of motor neurons. OBJECTIVE: To investigate whether genetic mechanisms implicated in motor neuron death in SMA have a role in ALS. METHODS: The presence of deletions of exons 7 and 8 of SMN1 and SMN2 was determined in 110 patients with sporadic ALS and compared with 100 unaffected controls. RESULTS: The presence of a homozygous SMN2 deletion was overrepresented in patients with ALS compared with controls (16% versus 4%; OR, 4.4; 95% CI, 1.4 to 13.5). Patients with a homozygous SMN2 deletion had a shorter median time of survival (p < 0.009). Furthermore, multivariate regression analysis showed that the presence of an SMN2 deletion was independently associated with survival time (p < 0.02). No homozygous deletions in SMN1 were found. Carrier status of SMA appeared to be equally present in patients and controls (1 in 20). CONCLUSION: These results indicate that, similar to SMA, the SMN2 gene can act as a prognostic factor and may therefore be a phenotypic modifier in sporadic ALS. Increasing the expression of the SMN2 gene may provide a strategy for treatment of motor neuron disease.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/physiopathology , Gene Deletion , Nerve Tissue Proteins/genetics , Age of Onset , Cyclic AMP Response Element-Binding Protein , Female , Humans , Male , Middle Aged , Prognosis , RNA-Binding Proteins , SMN Complex Proteins , Survival of Motor Neuron 1 Protein , Survival of Motor Neuron 2 Protein , Time FactorsABSTRACT
Recently, decreased striatal dopamine D2-receptor binding was demonstrated in vivo in amyotrophic lateral sclerosis (ALS). To further elucidate the pathogenetic mechanism underlying this D2-receptor deficit, a multi-level comparison was made between 30 sporadic ALS subjects and 24 patients with multiple system atrophy (MSA), a disorder clinically characterized by bradykinesia, neuroradiologically by severe D2-receptor loss, and neuropathologically by degenerating striatal cells. The extent of D2-deficit in ALS and MSA were within the same range, but extrapyramidal signs and symptoms were virtually absent in our ALS patients. Striatal cell loss in general or competitive D2-receptor occupancy could be considered unlikely in ALS. The striatum receives massive glutamatergic input and the pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. As other mechanisms (cell loss, receptor occupancy) could be ruled out, and as animal studies suggest that (excess of) glutamate decreases striatal D2-receptor synthesis, the striatal D2-receptor deficit in ALS is most likely to be caused by a receptor down-regulation.
Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Multiple System Atrophy/metabolism , Neostriatum/metabolism , Nerve Degeneration/metabolism , Receptors, Dopamine D2/metabolism , Amyotrophic Lateral Sclerosis/pathology , Amyotrophic Lateral Sclerosis/physiopathology , Benzamides/pharmacology , Binding Sites/drug effects , Binding Sites/physiology , Dopamine Antagonists/pharmacology , Down-Regulation/physiology , Female , Humans , Hypokinesia/etiology , Hypokinesia/metabolism , Hypokinesia/physiopathology , Iodine Radioisotopes , Male , Middle Aged , Multiple System Atrophy/pathology , Multiple System Atrophy/physiopathology , Muscle Weakness/etiology , Muscle Weakness/metabolism , Muscle Weakness/physiopathology , Neostriatum/pathology , Neostriatum/physiopathology , Nerve Degeneration/pathology , Nerve Degeneration/physiopathology , Pyrrolidines/pharmacology , Radioligand Assay , Receptors, Dopamine D2/drug effectsABSTRACT
The pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. The striatum receives massive glutamatergic input. Animal studies suggest that glutamate decreases striatal D2-receptor synthesis. In drug-naive, sporadic ALS patients we demonstrated decreased striatal D2-receptor binding in vivo that could be partially reversed by the glutamatergic transmission blocker riluzole. Our findings support the glutamatergic excitotoxicity hypothesis in sporadic ALS.
Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Corpus Striatum/metabolism , Receptors, Dopamine D2/metabolism , Riluzole/pharmacology , Aged , Humans , Middle Aged , Pilot Projects , Receptors, Dopamine D2/drug effectsABSTRACT
To determine whether MRI can reveal more vascular lesions in patients clinically suspected of having vascular parkinsonism, we compared 15 such patients with 15 patients who had idiopathic Parkinson's disease and 10 hypertensive controls. Patients with suspected vascular parkinsonism had significantly more subcortical lesions than those with Parkinson's disease or hypertension. The cutoff point that best distinguished patients with suspected vascular parkinsonism from patients with Parkinson's disease was a 0.6% level of lesioned brain tissue volume. There were two types of vascular parkinsonism: one had an acute onset and lesions located in the subcortical gray nuclei (striatum, globus pallidus, thalamus); the other had an insidious onset and lesions diffusely distributed in the watershed areas.
Subject(s)
Cerebrovascular Disorders/complications , Cerebrovascular Disorders/diagnosis , Magnetic Resonance Imaging , Parkinson Disease/complications , Parkinson Disease/diagnosis , Aged , Aged, 80 and over , Brain/pathology , Female , Humans , Hypertension/diagnosis , Male , Middle AgedABSTRACT
PURPOSE: To describe an MR imaging quantification method for estimation of total volumes of both white and gray matter subcortical lesions and ventricular cerebrospinal fluid (CSF) in the living human brain, and to determine the method's reliability. METHODS: In 12 subjects, total subcortical lesion and ventricular CSF volumes were estimated using systematic sampling. Systematic sampling was performed on equidistant MR sections using a counting grid with systematically ordered intersection points. The grid was randomly positioned on each consecutive MR section. Each grid intersection point hitting the structure of interest represents a fixed known volume dependent on grid intersection point distance and the sum of the section thickness and section gap. RESULTS: Total volume estimation of subcortical lesion and ventricular CSF takes 15 and 5 minutes per subject, respectively. Coefficients of error of the individual volume estimates ranged from .01 to .13 and are negligible to the coefficients of the group mean (range, .70 to .89). For subcortical lesion volume, the random intraobserver error yielded .04 and for ventricular CSF .02; the random interobserver error amounted to .11 and .04, respectively; and the systematic interobserver error was .15 and .04, respectively. CONCLUSION: The method described here for subcortical lesion and ventricular CSF volume estimation is accurate, reliable, valid, and fast.
Subject(s)
Brain/pathology , Cerebrospinal Fluid/physiology , Cerebrovascular Disorders/diagnosis , Magnetic Resonance Imaging/methods , Parkinson Disease, Secondary/diagnosis , Cerebral Ventricles/pathology , Cerebrovascular Disorders/physiopathology , Humans , Image Enhancement , Observer Variation , Parkinson Disease, Secondary/physiopathology , Reproducibility of ResultsABSTRACT
Focal dystonia of the right hand and speech impairment as a result of a circumscribed left-sided anterior thalamic lesion is reported in a 9-year-old girl with borderline normal psychomotor development. Both focal dystonia and speech impairment improved during anticholinergic treatment and worsened after drug withdrawal.