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PubMed1993

Familial recurrence risks and inheritance of multiple sclerosis.

The cause of multiple sclerosis is unknown. There is considerable circumstantial evidence that multiple sclerosis is a complex trait, probably autoimmune in nature, and is determined by both genetic and environmental factors. It is recognized that relatives of multiple sclerosis patients are at greater risk for developing the disease than the general population, although this risk is still relatively low in absolute terms. Monozygotic co-twins of multiple sclerosis patients appear to have the highest risk of any group of relatives, although the absolute risk is well under 100%, as would be predicted if multiple sclerosis is purely a genetic disorder.

Autoantigens↗
PubMed1993

Hormonal factors in susceptibility to multiple sclerosis.

Evidence implies that hormonal factors are involved in susceptibility to multiple sclerosis. Diseases associated with a class II allele occur more frequently in women than in men. Multiple sclerosis is more frequent in women, particularly in the early- and late-onset groups. Pregnancy has a favorable effect on the course of multiple sclerosis on both a short- and a long-term basis. Experimental allergic encephalomyelitis, an animal model with similarities to multiple sclerosis, is also influenced by hormonal factors in both occurrence and severity. The multiple levels of interaction between immune, endocrine, neurologic, and genetic systems probably explain the action of sex steroids in multiple sclerosis susceptibility.

Alleles↗
PubMed1977

[Tuberous sclerosis--early diagnosis and its significance in juvenile epilepsy].

Twenty-three cases of tuberous sclerosis, found in the ten years' material of the authors among 2900 epileptics between o-16 years of age, are presented. 11 patients were treated before the age of 3 years, all showing infantile spasms. The earliest, in most cases congenital extraneural signs were depigmented areas on the skin. They were absent only in one case. They allowed, together with the Westsyndrome to establish the diagnosis if tuberous sclerosis before the appearance of other characteristic symptoms. Sebaceous adenoma, generally accepted as pathognostic for tuberous sclerosis, presented itself in all 12 early cases later then the leukoderma and the epileptic fits. Tuberous sclerosis is one of the important causes of epilepsy in childhood, primarily in early childhood. In this period of life the West-syndrome is the most frequent type of epileptic manifestations of tuberous sclerosis

Adenoma↗
PubMed1996

Spinal cord lesions in patients with multiple sclerosis: comparison of MR pulse sequences.

PURPOSE: To compare T2-weighted conventional spin-echo (CSE), fast spin-echo (FSE), shorttau inversion recovery (STIR) FSE, and fluid-attenuated inversion recovery (FLAIR) FSE sequences in the assessment of cervical multiple sclerosis plaques. METHODS: Twenty patients with clinically confirmed multiple sclerosis and signs of cervical cord involvement were examined on a 1.5-T MR system. Sagittal images of T2-weighted and proton density-weighted CSE sequences, T2-weighted FSE sequences with two different sets of sequence parameters, STIR-FSE sequences, and FLAIR-FSE sequences were compared by two independent observers. In addition, contrast-to-noise measurements were obtained. RESULTS: Spinal multiple sclerosis plaques were seen best on STIR-FSE images, which yielded the highest lesion contrast. Among the T2-weighted sequences, the FSE technique provided better image quality than did the CSE technique, but lesion visibility was improved only with a repetition time/echo time of 2500/90; parameters of 3000/150 provided poor lesion contrast but the best myelographic effect and overall image quality. CSE images were degraded by prominent image noise; FLAIR-FSE images showed poor lesion contrast and strong cerebrospinal fluid pulsation artifacts. CONCLUSIONS: The STIR-FSE sequence is the best choice for assessment of spinal multiple sclerosis plaques. For T2-weighted FSE sequences, shorter echo times are advantageous for spinal cord imaging, long echo times are superior for extramedullary and extradural disease. FLAIR-FSE sequences do not contribute much to spinal imaging for multiple sclerosis detection.

Adult↗
PubMed1977

[Familial cases of disseminated sclerosis].

The report contains a description of 3 families with disseminated sclerosis (2 siblings in each family). The detected changes in the immunological reactivity of these patients are correlated with the data of the previously studied 112 patients with disseminated sclerosis and speaks in favour of a neuroallergical reaction, the important role of which in the pathogenesis of disseminated sclerosis is at present generally acknowledged. Having in view the heredity of developing allergic reactions the authors suggest that there is a certain relation between the state of the immunocompetent systems and the predispositional factors in disseminated sclerosis. This serves as a basis for the assumption that disseminated sclerosis can be attributed to diseases with a hereditary predisposition where for the manifestation of the disease there should be an effect of exogenous (viral?) factors.

Adult↗
PubMed1998

The correlation of urodynamic findings with cranial magnetic resonance imaging findings in multiple sclerosis.

PURPOSE: To our knowledge there are no studies of the correlation between urinary complaints or urodynamic findings in multiple sclerosis and magnetic resonance imaging (MRI) findings. We investigated the correlation of urodynamic results in multiple sclerosis patients with voiding complaints to the cranial MRI findings. We also sought to correlate urodynamic results in these patients with International Prostate Symptom Scores (IPSS). MATERIALS AND METHODS: We retrospectively reviewed urodynamic results and cranial MRI findings in 90 multiple sclerosis patients (64 women, 26 men, mean age 44.5 years) with voiding complaints. The most recent urodynamic study and cranial MRI for each patient were reviewed. The interval between the 2 studies and MRI was no more than 6 months. Detrusor contractions were categorized as areflexic, hyporeflexic, hyperreflexic or hyperreflexic with impaired contractility. The presence of impaired compliance or detrusor-external sphincter dyssynergia was recorded. The cranial MRI findings were categorized on the basis of the presence of atrophy or enhancing lesions, total number of lesions and size of largest lesion. The urodynamic and MRI findings were correlated. Of the patients 40 who had urodynamic studies done within the last 6 months completed the IPSS, and severity of cranial MRI findings in these patients was correlated with the IPSS results. In addition, the presence of irritative findings of detrusor hyperreflexia or detrusor hyperreflexia with impaired contractility was correlated with the irritative score (sum of questions 1, 2, 4, 7), and the presence of detrusor-external sphincter dyssynergia was correlated with the obstructive score (sum of questions 3, 5, 6). RESULTS: There was no correlation between urodynamic category, presence of impaired compliance or presence of detrusor-external sphincter dyssynergia and any of the MRI findings of atrophy or enhancing lesions, total number of lesions or size of the largest lesions. In the patients who completed the IPSS there was no correlation between total number of lesions and IPSS score. There was no correlation between the presence of detrusor-external sphincter dyssynergia and obstructive score on the IPSS or between the presence of detrusor hyperreflexia and irritative score. CONCLUSIONS: Although patients with multiple sclerosis often are followed closely with urodynamic studies and cranial MRI, there appears to be no correlation between these 2 studies. Symptom scores also do not appear to correlate with urodynamic findings. Therefore, urodynamic studies appear to be warranted and irreplaceable in the evaluation of voiding dysfunction in multiple sclerosis patients.

Adolescent↗
PubMed1998

Arytenoid cartilage sclerosis: normal variations and clinical significance.

PURPOSE: Our purpose was to determine the variation in location, distribution, and sex predilection of arytenoid cartilage sclerosis in a population of patients without laryngeal cancer as an aid to understanding the significance of this entity when seen in patients with laryngeal cancer. METHODS: One hundred CT examinations of patients of different ages and with no history of laryngeal cancer or radiation therapy were evaluated for the presence of arytenoid cartilage sclerosis. The arytenoid cartilage was subdivided into three regions: superior process, body, and vocal process. Each region was assessed on each side separately on bone window scans. RESULTS: Arytenoid cartilage sclerosis was seen in 16% (n = 16) of the patients. Sclerosis was most common in the body (n = 12) and least common in the true vocal process (n = 2); the left side was the preferred location for all three regions. In 50% of the patients, at least two regions were affected. Eighty-one percent of sclerotic arytenoid cartilage was seen in women. CONCLUSION: Knowledge of the frequency and distribution of arytenoid cartilage sclerosis as a normal variant can aid in determining the risk of arytenoid cartilage involvement in patients with laryngeal cancer.

Adolescent↗
PubMed1998

[Temporal mesial sclerosis syndrome in epilepsy].

Mesial temporal sclerosis is a frequent cause of epilepsy. Patients with mesial temporal sclerosis usually have an early brain insult, a febrile convulsion in most cases, and a seizure free interval of variable duration. This is followed by complex partial seizures with stereotypic semiology. Histological analysis of the hippocampal formation demonstrates a well defined pattern of cell loss and axonal proliferation. This pattern indicates selective cell vulnerability to the excitotoxic process that causes mesial temporal sclerosis, and synaptic and axonal reorganization, which are involved in the pathogenesis of this disorder. Epilepsy associated with mesial temporal sclerosis is not a static process, neurons in this region of the temporal lobe are physiologically and biochemically active, participating in the pathophysiology of the disease by facilitating the recurrence of seizures. There are no pathognomonic findings in mesial temporal sclerosis, but its confident diagnosis can be achieved by convergence of different lines of evidence, including clinical, morphological, and functional findings. Complex partial seizures are often resistant to antiepileptic medication, while surgical resection of the epileptic focus provides seizure freedom in a large number of patients.

Amygdala↗
PubMed1998

Differential diagnosis of multiple sclerosis: contribution of magnetic resonance techniques.

It is widely accepted that magnetic resonance imaging (MRI) findings are not totally specific for the diagnosis of multiple sclerosis. White matter lesions that mimic those of multiple sclerosis may be detected in both normal volunteers and patients harbouring different diseases. Virtually all the characteristic features of multiple sclerosis are sometimes encountered in other conditions affecting predominantly the white matter. Different conditions such as vasculitis, subcortical atherosclerotic leukoencephalopathy, Lyme disease, or acute disseminated encephalomyelitis can be virtually indistinguishable from multiple sclerosis on conventional MR images. Also the FLAIR technique adds little to the differential diagnosis. The calculation of magnetisation transfer ratio (MT ratio) may be useful to better characterise some entities, such as vasculitis, from multiple sclerosis.

Brain↗
PubMed1998

Clinical, neurophysiological, and magnetic resonance imaging correlations in multiple sclerosis.

Magnetic resonance imaging (MRI) has a pivotal role in diagnosis of multiple sclerosis and is being increasingly used as a paraclinical measure to assess treatment efficacy in clinical trials. However, the correlations between clinical and MRI findings in patients with multiple sclerosis are weak and, therefore, newer MR techniques are being developed to increase both MRI sensitivity for detecting disease activity and its pathological specificity for better assessing disease evolution. Evoked potentials (EPs) can be used to confirm the diagnosis of multiple sclerosis and their abnormalities are correlated with symptoms and signs referable to involvement of the corresponding nervous pathways. However, their use is limited when assessing disease progression and monitoring clinical trials in multiple sclerosis. Both magnetic resonance imaging (MRI) and evoked potentials (EPs) provide information which cannot be obtained by clinical evaluation, especially for assessing disease activity. Nevertheless, both these paraclinical techniques cannot substitute for clinical measures of disability when assessing disease progression and monitoring phase III clinical trials in multiple sclerosis.

Blood-Brain Barrier↗
PubMed1998

Quantitative assessment of magnetic resonance imaging lesion load in multiple sclerosis.

Changes of lesion load on yearly conventional spin echo (CSE) T2-weighted scans of the brain from patients with multiple sclerosis, measured using computer assisted techniques, are used to monitor long term disease evolution, either natural or modified by treatment. Although lesion load measurements have several advantages over clinical measures of outcome (they provide a more objective and sensitive measure of disease evolution, which has a linear distribution and a more strict relation with the underlying pathology), the poor correlation between changes of lesion load and changes of disability is of concern when using such an approach for monitoring multiple sclerosis trials. In this review, the main sources of variation in T2 lesion load from brain MRI of patients with multiple sclerosis will be considered, along with possible strategies to, at least partially, overcome them. Also, some of the newer fully automated techniques to segment multiple sclerosis lesions, which have been validated against manual outlining, and a recently developed coregistration technique are presented. It is hoped that a more reliable and standardised approach to lesion load measurements in multiple sclerosis will lead to better correlation with clinical disease course, to a higher confidence in the results of trials, and to reduced numbers of scans needed to conduct the trials, thus improving cost efficiency and reducing discomfort of the patients.

Brain↗
PubMed2001

Developmental expression of the tuberous sclerosis proteins tuberin and hamartin.

Tuberous sclerosis complex is an autosomal dominant multisystem disorder, characterized by the development of hamartomas in multiple organs, primarily the skin, heart, kidney, and brain. The tuberous sclerosis genes, TSC1 and TSC2, encode hamartin and tuberin, respectively. Employing specific antibodies for hamartin and tuberin, we analyzed the expression of these two proteins by Western blot analyses in normal developing human and rat tissues. Both proteins are expressed ubiquitously in human fetal tissues and placenta, but are expressed at relatively low levels in human adult tissues, except brain. Similarly, high expression of these two proteins is observed in rat embryonic tissues, with a progressive decline after birth. To better characterize the developmental expression of tuberin and hamartin, we conducted a detailed study in rat tissues from embryonic day 13 to adult by Western blot analysis and immunohistochemistry. Immunohistochemical staining of rat tissues for tuberin and hamartin revealed tissue-specific expression patterns throughout development. Both tuberin and hamartin are expressed in epithelia, muscle (smooth, cardiac and skeletal muscle) and the nervous system (neurons, glia, choroid plexus and arachnoid). Except for the central nervous system, immunostaining intensity declines with age, confirming the protein blot analysis. These results indicate that tuberin and hamartin may play a critical role in development, and thus provide a framework for understanding the developmental and hamartomatous manifestations of tuberous sclerosis. These findings also suggest that tuberin and hamartin have additional functions in the adult brain, consistent with the marked neurological problems that afflict many patients with tuberous sclerosis.

Age Factors↗
PubMed2003

Tuberous sclerosis genes regulate cellular 14-3-3 protein levels.

The genes TSC1, encoding hamartin, and TSC2, encoding tuberin are responsible for tuberous sclerosis. This autosomal dominant tumor suppressor gene syndrome affects about 1 in 6000 individuals. A variety of tumors characteristically occur in different organs of tuberous sclerosis patients and are believed to result from defects in cell cycle/cell size control. We performed a proteomics approach of two-dimensional gel electrophoresis with subsequent mass spectrometrical identification of protein spots after ectopic overexpression of human TSC1 or TSC2. We found the cellular levels of four isoforms of the 14-3-3 protein family, 14-3-3 gamma, 14-3-3, 14-3-3 sigma, and 14-3-3 zeta, to be regulated by the two tuberous sclerosis gene products. In the same experiments the protein levels of keratin 7, capZ alpha-1 subunit, ezrin, and nedasin were not affected by ectopic TSC1 or TSC2. Western blot analyses confirmed the deregulation of 14-3-3 proteins upon ectopic overexpression of TSC1 and TSC2. A TSC1 mutant not encoding the transmembrane domain and the tuberin-binding domain but harbouring most of the coiled-coil region and the ERM protein interaction domain of hamartin did not affect 14-3-3 protein levels. The here presented findings suggest that deregulation of 14-3-3 protein amounts might contribute to the development of tumors in tuberous sclerosis patients. These data provide important new insights into the molecular development of this disease especially since both, the TSC genes and the 14-3-3 proteins, are known to be involved in mammalian cell cycle control.

14-3-3 Proteins↗
PubMed2003

Tuberous sclerosis complex: genetics to pathogenesis.

Desiree-Magloire Bourneville first reported tuberous sclerosis complex as "tuberous sclerosis of the cerebral convolutions" in 1880. This disorder is characterized by multiple hamartomas in several organs, particularly the brain. Commonly recognized clinical features include hypomelanotic skin macules, facial angiofibromas, periungual fibromas, delayed development, and seizures. Abnormalities on brain imaging include subependymal nodules, cortical tubers, and radial white matter lines. The kidney, heart, and retina are among other commonly affected organs. Although the majority of cases (65%) are sporadic, genetic linkage studies of familial cases led to the discovery of two separate genes linked to tuberous sclerosis complex: TSC1, located at chromosome 9q34, encoding a protein called hamartin; and TSC2, located at chromosome 16p13.3, encoding a protein called tuberin. Tuberin has a region of homology to rap1GAP, a guanosine triphosphatase-activating protein. This observation is consistent with the idea of tuberin functioning in a cellular signaling pathway. Hamartin contains a single potential transmembrane domain; orthologues in yeast, drosophila, and rat have been cloned. Hamartin also binds to ezrin and other ezrin-radixin-moesin proteins, which link the cell membrane to the cytoskeleton. Tuberin and hamartin interact directly with each other, and the complex may function together to regulate specific cellular processes. This study reviews current ideas regarding the function of tuberin and hamartin, and the pathogenesis of tuberous sclerosis complex.

Animals↗
PubMed2003

TSC1 and TSC2: genes that are mutated in the human genetic disorder tuberous sclerosis.

The tuberous sclerosis complex genes TSC1 and TSC2 were first identified by positional cloning strategies in the heritable human disorder tuberous sclerosis. They encode previously unknown proteins, termed hamartin and tuberin respectively, that form a functional complex. The phenotypic manifestations of tuberous sclerosis are extremely diverse and suggest normal roles for TSC1 and TSC2 in regulating the growth, proliferation, migration and differentiation of many cell types. Investigations of TSC1 and TSC2 in a number of model organisms and cell-culture systems have provided new insights into the mechanisms through which these roles are effected. Most promisingly, the hamartin-tuberin complex has been shown to function as a negtive regulator of the insulin receptor/phosphoinositide 3-kinase/S6 kinase pathway. Drugs that act to inhibit this pathway may have therapeutic potential for tuberous sclerosis and the related disorder lymphangioleiomyomatosis.

Animals↗
PubMed2004

Tuberin and hamartin expression is reduced in the majority of subependymal giant cell astrocytomas in tuberous sclerosis complex consistent with a two-hit model of pathogenesis.

Subependymal giant cell astrocytomas are distinctive brain tumors that are seen only in tuberous sclerosis complex. Although histologically benign, they cause both moribidity and occasional mortality owing to progressive growth in some patients. Tuberous sclerosis complex is an autosomal dominant genetic disorder with a high sporadic case rate that is due to mutations in either of two genes, TSC1 and TSC2, encoding hamartin and tuberin, respectively. The pathogenesis of subependymal giant cell astrocytomas in tuberous sclerosis complex is uncertain. In this study, we examined the expression of tuberin and hamartin in subependymal giant cell astrocytomas from nine patients with tuberous sclerosis complex by immunohistochemistry with confocal microscopy. Loss of hamartin expression was seen in all subependymal giant cell astrocytomas, including five from patients with germline TSC2 mutations and two from patients with germline TSC1 mutations. The subependymal giant cell astrocytomas of six of nine patients had no expression of tuberin as well, whereas three patients retained some tuberin expression. Tuberin expression was seen in one patient with a TSC2 germline mutation and two patients whose mutational status was not determined. Overall, these data indicate a loss of both tuberin and hamartin expression in the subependymal giant cell astrocytomas of patients with both TSC1 and TSC2 mutations and are consistent with a two-hit disease pathogenesis model for the development of subependymal giant cell astrocytomas.

Antibodies, Monoclonal↗
PubMed2001

Baló's concentric sclerosis: surviving normal myelin in a patient with a relapsing-remitting dinical course.

Baló's concentric sclerosis is a demyelinating disorder in which bands of demyelination alternate with concentric bands of myelin preservation. The pathogenesis of the lesion is unknown. Previous reports using modern histopathologic techniques have shown the bands of myelin preservation to be comprised of remyelinated or partially demyelinated myelin. Here we report a case of Baló's concentric sclerosis in a 24-year-old East Indian patient with a previous history of relapsing-remitting multiple sclerosis (MS). Pathologically, the bands of myelin preservation showed myelin sheaths of normal thickness, with focal areas of demyelination. The findings, taken together with those of previously reported cases, suggest that Baló's concentric sclerosis is a variant of MS, and the concentric lesion may be an intermediary form in evolution of a chronic active MS plaque. The pathogenesis of this concentric lesion may be explained by periodic suppression of demyelination in the rapidly expanding border, allowing remyelination or only transient incomplete demyelination to occur.

Adult↗
PubMed1995

Incidence of cancer among patients with systemic sclerosis.

BACKGROUND: To determine cancer risk among patients with systemic sclerosis and localized scleroderma, a population-based retrospective cohort study was performed. Patients in Sweden with a discharge diagnosis of systemic sclerosis or localized scleroderma were obtained from the computerized database of hospital discharge diagnoses for the years 1965-1983. Nine hundred seventeen patients with systemic sclerosis and 102 with localized scleroderma were identified. METHODS: Using record linkage analysis with data from the Swedish National Cancer Registry, standardized incidence ratios (SIR)s (the ratio of observed to expected incidence) were calculated for specific cancer sites. RESULTS: The SIR for developing cancer in the cohort with systemic sclerosis was 1.5 (95% CI, 1.2-1.9). For specific cancer sites, risks were elevated for lung cancer (SIR, 4.9; 95% CI, 2.8-8.1), nonmelanoma skin cancers (SIR, 4.2; 95% CI, 1.4-9.8), and primary liver cancer (SIR, 3.3; 95% CI, 1.1-7.6). There was a suggestive increase in hematopoietic cancers (SIR, 2.3; 95% CI, 0.9-4.8). In contrast, cancer risks in the similarly ascertained cohort with localized scleroderma were no different from those of the general population. CONCLUSIONS: This study confirms earlier reports of an association between systemic sclerosis and an increased risk of cancer. Specific tumor sites correspond to the sites commonly affected by fibrosis such as the lung and skin.

Adult↗