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PubMed2003

Cognitive presentation of multiple sclerosis: evidence for a cortical variant.

BACKGROUND: Although neuropsychiatric complications are well recognised, the presentation of multiple sclerosis with cognitive or neuropsychiatric symptoms has generally been considered a rare occurrence and to reflect subcortical pathology. OBJECTIVES: To document the clinical, neuropsychological, and radiological features of six cases of cognitive presentation of multiple sclerosis, to review the relevant literature, and to propose a possible cortical basis for this clinical presentation. SUBJECTS: Six patients (five women; age range 38 to 60 years) presented to the memory and cognitive disorders clinic in Cambridge with an initially undiagnosed cognitive/neuropsychiatric syndrome. All underwent neuropsychological evaluation, brain imaging, and ancillary investigations to establish a diagnosis of multiple sclerosis. RESULTS: The six cases all had a progressive dementia syndrome with prominent amnesia, often accompanied by classic cortical features including dysphasia, dysgraphia, or dyslexia. Mood disturbance was ubiquitous and in three patients there was a long history of preceding severe depression. All six developed characteristic physical signs on follow up, with marked disabilities. A review of 17 previously reported cases highlighted the prominence of memory impairment and depression in the early stages. CONCLUSIONS: On clinical, pathological, and radiological grounds, the neuropsychiatric presentation of multiple sclerosis may represent a clinicopathological entity of "cortical multiple sclerosis." Failure to recognise this will delay diagnosis and may expose patients to potentially dangerous and invasive investigation. Because the neuropsychiatric features of cortical multiple sclerosis are a major cause of handicap, their early recognition may be particularly important in view of emerging treatments.

Adult↗

PubMed2003

The role of the PTPRC (CD45) mutation in the development of multiple sclerosis in the North West region of the United Kingdom.

BACKGROUND: A point mutation in protein tyrosine phosphatase receptor, type c polypeptide (PTPRC) has been associated with familial multiple sclerosis. This CG mutation at position 77 of exon 4 results in altered expression of CD45 isoforms on immune cells. OBJECTIVE: To study the incidence of PTPRC mutations in subjects with multiple sclerosis in the North West region of the United Kingdom. METHODS: Affected and unaffected subjects from five pedigrees with familial multiple sclerosis, 330 non-familial cases of multiple sclerosis, and 197 controls were studied. Genomic DNA was amplified using CD45IE34 and CD45IE44 primers, digested with Mspl, and run on an agarose gel. Polymerase chain reaction products were sequenced to exclude any other mutations. RESULTS: No PTPRC exon 4 genomic mutations were seen in any of the five families. In the non-familial cases the incidence of mutation was 4.1% in 197 controls and 5.1% in 330 multiple sclerosis patients. No significant association was found in this study with this mutation and disease susceptibility, sex, or an extended disability scale score of < 5.5. CONCLUSIONS: This candidate does not appear to influence the development of familial multiple sclerosis in this population. The negative result could arise from a type II error owing to the number of families and non-familial cases screened. Alternatively it might suggest that the contribution of the PTPRC mutation depends upon the genetic background.

Adult↗

PubMed1995

MR imaging field strength: prospective evaluation of the diagnostic accuracy of MR for diagnosis of multiple sclerosis at 0.5 and 1.5 T.

PURPOSE: To compare the diagnostic efficacy of middle-field-strength and high-field-strength magnetic resonance (MR) imaging in diagnosis of multiple sclerosis. MATERIALS AND METHODS: One hundred thirty-two patients with suspected multiple sclerosis underwent MR imaging at 0.5 and 1.5 T. Imaging parameters were identical except for band width optimization at middle field strength. Images were interpreted by radiologists expert in MR imaging who were blinded to diagnosis and field strength. The diagnosis of multiple sclerosis was made by experienced neurologists, and indeterminate cases and patients without clinical evidence of multiple sclerosis were followed up for 6 months to 1 year. RESULTS: There was no difference in accuracy, sensitivity, or specificity between scanners in the diagnosis of multiple sclerosis or white matter disease. Equal numbers of lesions were detected at both field strengths in all parts of the brain. Image quality was always good or adequate at middle field strength. CONCLUSION: Higher field strength does not confer higher accuracy in the diagnosis of multiple sclerosis with current-generation MR imagers.

Double-Blind Method↗

PubMed1997

Cerebral hemiatrophy: classification on the basis of MR imaging findings of mesial temporal sclerosis and childhood febrile seizures.

PURPOSE: To classify cerebral hemiatrophy on the basis of childhood febrile seizures and magnetic resonance (MR) imaging findings of mesial temporal sclerosis. MATERIALS AND METHODS: Medical records and brain MR images obtained in 23 patients aged 1-64 years with cerebral hemiatrophy were retrospectively reviewed. Age, neurologic deficit, and history of childhood febrile seizures were recorded and correlated with MR findings of mesial temporal sclerosis, focal cortical or white matter signal intensity abnormalities, ipsilateral thalamic or contralateral cerebellar atrophy, and compensatory calvarial changes. RESULTS: Eleven patients had MR mesial temporal sclerosis findings. Of these, nine had a history of childhood febrile seizures. Of the other 12 patients, only one had a history of childhood febrile seizures. All patients without mesial temporal sclerosis had focal parenchymal lesions in the distribution of the middle cerebral artery. CONCLUSION: Two patterns of central nervous system involvement in cerebral hemiatrophy are suggested: (a) MR mesial temporal sclerosis findings and a history of childhood febrile seizures and (b) no MR mesial temporal sclerosis findings and rarely a history of childhood febrile seizures. This correlates with previous descriptions of cerebral hemiatrophy (a) with multifocal neuronal loss after seizures and (b) with a more focal cerebral hemisphere abnormality usually due to vascular insult.

Adolescent↗

PubMed1999

Prevalence of multiple sclerosis in Gypsies and Bulgarians.

There are occasional reports about the low prevalence of multiple sclerosis among Gypsies. To verify these reports of low prevalence of multiple sclerosis among Gypsies compared to the white population in Bulgaria, an epidemiological study was conducted in two small regions of Bulgaria. All patients with clinically or laboratory-supported, definite multiple sclerosis according to Poser's criteria were personally interviewed and examined. The study was begun on January 1, 1997 and March 31, 1998 was selected as prevalence day. For the white population, the prevalence ratio of multiple sclerosis per 100,000 population was 44.9 in the first region and 44.4 in the second. The prevalence of multiple sclerosis in Gypsies was found to be 19.1/100,000 in the first region and 18.4 in the second. It is concluded that multiple sclerosis is less common in Gypsies than in whites living in the same areas.

Adolescent↗

PubMed2005

Mitral annular calcification, aortic valve sclerosis, and incident stroke in adults free of clinical cardiovascular disease: the Strong Heart Study.

BACKGROUND AND PURPOSE: Mitral annular calcification (MAC) and aortic valve (AV) sclerosis have each been linked to cardiovascular disease. Whether MAC and AV sclerosis are risk factors for stroke independent of other echocardiographic or laboratory predictors has not been established. We evaluated the relationship between MAC, AV sclerosis, and first stroke events in a population-based cohort. METHODS: Our study cohort consisted of 2723 American Indians participating in the Strong Heart Study who were free of prevalent cardiovascular disease. Participants underwent standardized clinical, echocardiographic, and laboratory evaluation, and incident stroke was ascertained using validated methods. RESULTS: During a median follow-up of 7 years, 86 strokes occurred. Age- and sex-adjusted incidence rates of stroke were significantly increased for MAC (rate ratio [RR], 3.12; 95% CI, 1.77 to 5.25) but not for AV sclerosis (RR, 1.15; 95% CI, 0.45 to 2.49). MAC was also associated with a reduced time to first stroke events after adjustment for clinical variables and the inflammatory markers C-reactive protein and fibrinogen (hazard ratio [HR], 2.42; 95% CI, 1.39 to 4.21) or the echocardiographic covariates left ventricular hypertrophy and left atrial enlargement (HR, 1.89; 95% CI, 1.04 to 3.41). Individuals with and without AV sclerosis showed no significant difference in stroke-free survival in unadjusted analyses (P=0.698). Crossing of the survival curves precluded multivariable analysis using Cox models. CONCLUSIONS: In this cohort of American Indians without clinical cardiovascular disease, the presence of MAC, but not AV sclerosis, proved to be a strong risk factor for incident stroke after extensive adjustment for other predictors. Individuals exhibiting MAC may benefit from aggressive risk factor modification, but this will require further investigation.

Aged↗

PubMed2004

Managing epilepsy in tuberous sclerosis complex.

Epilepsy is very common in tuberous sclerosis complex and occurs in 80 to 90% of affected individuals during their lifetime. Onset usually occurs during childhood, and up to one third of children with tuberous sclerosis complex will develop infantile spasms. Although not completely understood, the incidence of epilepsy is thought to relate to the neuropathologic features of the disorder, including cortical tubers and other dysgenetic features. Individuals with tuberous sclerosis complex frequently have epileptiform features to their electroencephalograms. Treatment of epilepsy in tuberous sclerosis complex is similar to epilepsy resulting from other causes and includes anticonvulsant medications, the vagus nerve stimulator, and the ketogenic diet. Vigabatrin has been shown to be particularly effective in treating infantile spasms in the setting of tuberous sclerosis complex. Epilepsy surgery has a very important role in the management of children and adults with pharmacoresistant epilepsy in tuberous sclerosis complex.

Anticonvulsants↗

PubMed2005

Tau, phospho-tau, and S-100B in the cerebrospinal fluid of children with multiple sclerosis.

Axonal injury and glial activation are an early neuropathologic event in adults with multiple sclerosis. To investigate whether markers of axonal injury and glial activation are already elevated in the cerebrospinal fluid of children with multiple sclerosis, we studied the cerebrospinal fluid of 25 children with multiple sclerosis and 67 controls for the presence of tau, phospho-tau, and S-100B proteins using specific enzyme-linked immunoabsorbent assays. In general, tau, phospho-tau, and S-100B protein levels did not differ significantly between groups. However, in a subgroup of nine children with multiple sclerosis, all of whom had prominent clinical symptoms at the time of lumbar puncture and radiologic disease activity, tau protein levels were significantly elevated when compared with other controls. These data indicate that axonal injury is not restricted to adult multiple sclerosis but can already occur in children with multiple sclerosis.

Adolescent↗

PubMed1997

Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex.

The relationship between the number of cortical tubers observed by magnetic resonance imaging (MRI) and the severity of cerebral dysfunction of tuberous sclerosis patients has been examined in a meta-analysis of the published literature. The literature review has identified five independent studies for examining the association. These studies consistently reveal that the cortical tuber count detected on MRI scans is increased among those with more severe cerebral disease. Severity of the cerebral dysfunction is measured by the seizure status and its control and by the developmental status and the level of mental retardation. Meta-analysis demonstrates that within a study population, the MRI-detected cortical tuber count is six times more likely to be above the median count for tuberous sclerosis patients with severe cerebral dysfunction (poor seizure control or moderate-severe retardation or both) than more mildly affected tuberous sclerosis patients. Similarly, across studies, moderately to severely affected patients are five times more likely to have greater than seven MRI-detected cortical tubers than those more mildly affected. These associations are both statistically significant and strong. The cortical tuber count is a biomarker that reasonably predicts the severity of cerebral dysfunction of tuberous sclerosis. Cortical tubers of tuberous sclerosis form in the early gestational period. The embryologic disruption determining the clinical severity of the cortical dysfunction of tuberous sclerosis is set in the early gestational period.

Cerebral Cortex↗

PubMed1977

In vitro-labeled DNA for detecting viral genomes in multiple sclerosis: I. Papovaviruses.

Papovaviruses appear to be neurotropic and one, JC virus, is implicated as the cause of one type of demyelinating disease, progressive multifocal leukoencephalopathy. To investigate whether human papovaviruses play a role in multiple sclerosis, radioactively labeled DNA from BK virus, human papilloma virus, and simian virus 40 was used as a probe in order to detect related unlabeled DNA sequences in DNA isolated from multiple sclerosis brain and/or spinal cord. Labeled viral probes were denatured and DNA allowed to reassociate in the presence of excess unlabeled DNA from multiple sclerosis tissue or from controls. The reassociation rate of the probe is proportional to the concentration of viral DNA present, and an increase in the reassociation rate of the probe over that of control reactions would indicate the presence of unlabeled viral DNA in multiple sclerosis cellular DNA. However, addition of DNA derived from multiple sclerosis patients did not increase rates of reassociation of viral probes. Known human papovaviruses probably have no role in the pathogenesis of multiple sclerosis.

BK Virus↗

PubMed1978

Decreased lymphocyte transformation to vaccinia virus in multiple sclerosis.

Lymphocyte transformation to vaccinia virus was measured in multiple sclerosis (MS) patients and normal controls. There was a significant reduction of lymphocyte transformation to vaccinia virus in multiple sclerosis patients compared with the control group. In addition, a positive correlation existed between the degree of disability of the multiple sclerosis patients and the extent of lymphocyte transformation in the presence of vaccinia virus. There was no correlation between cell-mediated immunity to vaccinia virus and either serum or cerebrospinal fluid (CSF) antibody levels to vaccinia in multiple sclerosis patients or controls, all of whom had been previously vaccinated. In conjunction with other studies, all of whom had been previously vaccinated. In conjunction with other studies that have demonstrated elevated antibody titers to vaccinia virus in the CSF of multiple sclerosis patients, these results support the possibility that vaccinia virus may play a role in the pathogenesis of multiple sclerosis.

Adolescent↗

PubMed1984

Measles antibodies, anti-proteinase and plasminogen distribution in serum and plasma from patients affected with multiple sclerosis and patients affected with non-neurological diseases.

Total protein content, alpha 1-antitrypsin, alpha 2-macroglobulin and plasminogen levels and measles antibody titers were determined in serum and plasma from patients affected with multiple sclerosis and patients affected with non-neurological diseases. The results were compared with those from a control group of healthy donors. Both multiple sclerosis patients and patients affected with non-neurological diseases differed from controls for the following parameters: total protein, plasminogen and measles antibody activity. However, when studied longitudinally the different parameters were not altered to the same degree in multiple sclerosis and non-neurological diseases, a fact which is translated in the difference of significance levels. Individual plasminogen values were very often higher in non-neurological diseases than in multiple sclerosis, whereas for increased measles antibody titers it was the reverse. Also, there were no notable changes in alpha 1-antitrypsin and alpha 2-macroglobulin values in multiple sclerosis, whereas in some non-neurological disease patients particularly high alpha 1-antitrypsin and alpha 2-macroglobulin values were observed. In the multiple sclerosis patients, no correlations existed between the duration of the disease and disturbed biochemical parameters, or between the disturbed parameters themselves.

Adult↗

PubMed2005

Treatment of children and adolescents with multiple sclerosis.

The onset of multiple sclerosis is being increasingly recognized in children and adolescents. There are now approved immunomodulatory therapies for adults with multiple sclerosis. Treatment early in the disease course appears to have a greater impact on disease outcome, an issue of particular importance for children who face decades of multiple sclerosis disease activity. This review summarizes the multiple sclerosis therapies currently available, efficacy data available from studies of these medications in adults and limited information on the use of these medications in children. Future directions in multiple sclerosis therapeutics and specific issues relating to pediatric multiple sclerosis are discussed.

Adolescent↗

PubMed1999

Incidental detection of hippocampal sclerosis on MR images: is it significant?

BACKGROUND AND PURPOSE: The prevalence of hippocampal sclerosis in the general nonepileptic patient population is not well described. While reports of its association with partial complex seizures are abundant, its absence in nonafflicted patients is generally presumed but not well documented. To test the hypothesis that hippocampal sclerosis is specific for epilepsy, we reviewed the MR imaging studies of 207 patients referred for hearing loss to determine whether high-resolution MR imaging could detect unsuspected hippocampal sclerosis in nonepileptic patients. METHODS: Our institution screens patients with hearing loss by using high-resolution coronal and axial temporal bone MR imaging that includes the hippocampus within the imaging volume. We retrospectively reviewed 207 studies randomly selected from this database. RESULTS: The hippocampus was normal in 205 patients; in the remaining two patients we identified one or more primary determinants for hippocampal sclerosis. Subsequent retrospective chart review revealed that both patients had had previously diagnosed seizure disorders. CONCLUSION: The imaging determinants of hippocampal sclerosis are not prevalent in nonepileptic patients. Incidental identification of hippocampal sclerosis on MR images is uncommon and significant, and should prompt further clinical investigation to exclude a seizure disorder.

Adolescent↗

PubMed2000

Isolated demyelinating syndromes: comparison of different MR imaging criteria to predict conversion to clinically definite multiple sclerosis.

BACKGROUND AND PURPOSE: Various authors have developed criteria to classify MR imaging findings that suggest the possibility of multiple sclerosis. The purpose of this study was to evaluate and compare the capacity of three sets of MR imaging criteria for predicting the conversion of isolated demyelinating syndromes to clinically definite multiple sclerosis. METHODS: Seventy patients with clinically isolated neurologic symptoms suggestive of multiple sclerosis were prospectively studied with MR imaging. The MR imaging findings were evaluated by two independent neuroradiologists who were blinded to clinical follow-up data. Based on the clinical outcome at follow-up (presence of a second attack that established clinically definite multiple sclerosis), the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the criteria proposed by Paty et al, Fazekas et al, and Barkhof et al were calculated. RESULTS: Clinically definite multiple sclerosis developed in 22 (31%) patients after a mean follow-up time of 28.3 months. The criteria proposed by Paty et al and those proposed by Fazekas et al showed identical results: sensitivity, 86%; specificity, 54%; accuracy, 64%; positive predictive value, 46%; and negative predictive value, 89%. The criteria proposed by Barkhof et al showed the following: sensitivity, 73%; specificity, 73%; accuracy, 73%; positive predictive value, 55%; and negative predictive value, 85%. CONCLUSION: The four dichotomized MR imaging parameters proposed by Barkhof et al are more specific and accurate than the criteria proposed by Paty et al or Fazekas et al for predicting conversion to clinically definite multiple sclerosis.

Adult↗

PubMed2001

Familial amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Kii Peninsula of Japan: clinical and neuropathological study and tau analysis.

We report the first case of neuropathologically verified parkinsonism-dementia complex of the Kii peninsula, together with the patient's brother, who had amyotrophic lateral sclerosis. The propositus woman developed parkinsonism and dementia at 63 years of age and died at 70 without displaying clinical features of amyotrophic lateral sclerosis. The brain exhibited marked atrophy of the frontal and temporal lobes. Microscopically, there were many neurofibrillary tangles in the central nervous system, most markedly in the mesial temporal lobe and deep nuclei, as well as changes of amyotrophic lateral sclerosis but no senile plaques or Lewy bodies. Neurofibrillary tangles exhibited twisted tubule structures on electon microscopic examination, and an analysis of insoluble tau protein extracted from the fresh brain revealed a 60-, 64-, 68-kD triplet. The tau gene exhibited no mutations. Her brother developed progressive bulbar palsy-type amyotrophic lateral sclerosis at 45 years of age and died at 49 without presenting with dementia or parkinsonism. Neuropathological examination revealed not only pathologic features of amyotrophic lateral sclerosis but also a moderate number of neurofibrillary tangles in the temporal cortex and deep nuclei. The siblings were neuropathologically similar despite their different clinical manifestations. These findings suggest that amyotrophic lateral sclerosis and parkinsonism-dementia complex of this family may be phenotypic variants of a tauopathy caused by genetic abnormalities.

Aged↗

PubMed2001

Interleukin-1beta converting enzyme/Caspase-1 (ICE/Caspase-1) and soluble APO-1/Fas/CD 95 receptor in amyotrophic lateral sclerosis patients.

OBJECTIVES: The aim of the study was to investigate the role of ICE/ Caspase-1 and soluble APO-1/Fas/CD 95 receptor in amyotrophic lateral sclerosis patients. MATERIAL AND METHODS: The apoptosis parameters were measured by enzyme-linked immunosorbent assay (ELISA) in serum and cerebrospinal fluid from 25 amyotrophic lateral sclerosis and 15 control patients. RESULTS: There has been shown a significant increase of ICE/Caspase-1 level in serum, and significant decrease of this parameter in cerebrospinal fluid from amyotrophic lateral sclerosis patients. Soluble APO-1/Fas/CD 95 level in amyotrophic lateral sclerosis patients did not differ from the control group. There was no significant correlation between clinical status, duration of amyotrophic lateral sclerosis, and levels of ICE/Caspase-1 and soluble APO-1/Fas/CD 95. CONCLUSION: Our study suggests that ICE/Caspase-1 may play a role in neurodegeneration in ALS. Due to ethical difficulties we cannot include patients suffering from progressive neurological diseases, who are a more appropriate control group for the amyotrophic lateral sclerosis patients. Therefore we are limited in drawing conclusions from the research.

Adult↗

PubMed2001

[New approaches in research of therapy of multiple sclerosis].

BACKGROUND: Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. With a prevalence of 0.1-0.15% in Germany multiple sclerosis is the most common cause of severe disability in young adults. PATHOGENESIS: Epidemiological and family studies demonstrate the role of environmental and genetic factors in the pathogenesis of multiple sclerosis. Based on those observations and findings in experimental animal models, it is believed that multiple sclerosis is caused by an autoimmune process. However, target antigens and mechanisms leading to tissue destruction are largely unknown. THERAPY: Since the efficacy of current immunomodulatory and immunosuppressive therapies (beta-interferons, glatiramer acetate, mitoxantrone) is limited, it is necessary to develop new strategies for the treatment of multiple sclerosis. To reach this goal, a much better understanding of disease pathogenesis is necessary which takes into account the clinical, paraclincial and histopathological heterogeneity of the disease. CONCLUSION: Only further intensive research activity on basic mechanisms of disease pathogenesis and a consequent development of resulting therapeutic strategies--from animal models to phase III studies--will result in significant improvement of the long-term course of multiple sclerosis.

Adjuvants, Immunologic↗