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PubMed2001

Aminopyridines for symptomatic treatment in multiple sclerosis.

BACKGROUND: Because of their ability to increase nerve conduction in demyelinated nerve fibers, potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) have been proposed as a symptomatic therapy for people with multiple sclerosis (MS). OBJECTIVES: To determine the efficacy and safety of aminopyridines in improving neurological deficits in people with MS. SEARCH STRATEGY: Computerised general (MEDLINE, EMBASE) and specialised databases (Cochrane MS Group's trials register, CCTR). Hand search of bibliographic references from retrieved studies and recent MS symposia reports. Contact with principal investigators of known studies. SELECTION CRITERIA: Trials were included if they fulfilled all following criteria: randomised controlled trials (RCTs); adults with MS, out of exacerbation; AP or DAP treatment versus placebo; clinical endpoints. DATA COLLECTION AND ANALYSIS: We identified 26 potentially pertinent studies. Three reviewers independently extracted data and assessed trial quality from the 16 studies available as full papers. MAIN RESULTS: Five studies (six publications) and 144 participants were considered in this review. Two more abstracts are awaiting assessment. All five studies were single-centre, double-blind, crossover trials. Four studies assessed the efficacy of AP versus placebo, one compared DAP with active placebo. The duration of treatment ranged from hours to three months. The median quality score of the studies was 3 (range 2-5). The heterogeneity of outcome assessment and the absence of information on individual study periods, allowed quantitative pooling of results for few categorical variables. Of the 144 treated patients, there were six major side effects: one acute encephalopathy, three episodes of confusion, and two seizures. Manual muscle testing was assessed in three studies (54 patients), with 29 patients (54%) improving in at least one muscular district during study treatment versus four patients (7%) during placebo (odds ratio [OR] 14.5, 95% confidence interval [CI] 4.7-43.7). Ambulation was assessed in three studies (54 patients): 9 patients (17%) improved during study treatment versus none during placebo (p<0.001). An improvement in EDSS score was found in 13 of the 144 participants during study treatment (9%) versus none during placebo (p<0.001). No improvement in neuropsychological tests was found in the two trials that evaluated cognitive function. Finally, 47 of 136 people with MS (35%) felt improved when receiving the study drug, against 7(5%) on placebo (OR 9.7, 95% CI 4.3-22.0). REVIEWER'S CONCLUSIONS: Based on currently available information, no unbiased statement can be made about the safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs involving more than 300 participants. We conclude that publication bias remains a pervasive problem in this area, and that until the results of these unpublished studies are available to the scientific community, no confident estimate of effectiveness of aminopyridines in the management of MS symptoms is possible.

4-Aminopyridine↗
PubMed2002

A calmodulin binding site in the tuberous sclerosis 2 gene product is essential for regulation of transcription events and is altered by mutations linked to tuberous sclerosis and lymphangioleiomyomatosis.

Mutations in the tuberous sclerosis 2 (TSC2) gene product have been genetically linked to the pathology of both tuberous sclerosis (TSC) and the gender-specific lung disease, lymphangioleiomyomatosis (LAM). Both diseases are classified as disorders of cellular migration, proliferation, and differentiation. Earlier studies from our laboratory (1) linked TSC2 with steroid/nuclear receptor signaling. Studies presented here provide evidence for calmodulin (CaM) signaling in the propagation of this TSC2 activity. Far Western screening of a lambda phage human brain cDNA library to identify interacting proteins for the TSC2 gene product (tuberin) yielded multiple clones encoding human CaM. Direct binding with 32P-labeled tuberin demonstrated Ca2+-dependent binding to CaM-Sepharose which was lost upon deletion of the C-terminal 72 residues. The sequence (1740)WIARLRHIKRLRQRIC(1755) was identified as one capable of forming a basic amphipathic helix indicative of CaM binding domains in known calmodulin binding proteins. Studies with a synthetic peptide of this sequence demonstrated very tight Ca2+-dependent binding to CaM as judged by tryptophan fluorescence perturbation studies and phosphodiesterase activation by CaM. Deletion mutagenesis studies further suggested that this CaM binding domain is required for tuberin modulation of steroid receptor function and that mutations in this region may be involved in the pathology of TSC and LAM.

Amino Acid Sequence↗
PubMed2000

Recurrent myelinoclastic diffuse sclerosis: a case report of a child with Schilder's variant of multiple sclerosis.

Myelinoclastic diffuse sclerosis (MDS, Schilder's disease) is a rare CNS demyelinating disorder affecting mainly children and usually presenting as an intracranial mass lesion. We report the first case of recurrent intracranial MDS where the third episode of demyelination involved the cervical spinal cord. This may represent a subset of the disease, which should be considered as Schilder's variant (childhood form) of multiple sclerosis.

Child↗
PubMed1993

Static and dynamic models of interdisease competition: past and projected mortality from amyotrophic lateral sclerosis and multiple sclerosis.

Longitudinal Gompertzian analysis is an effective method for determining both the pure probability of death for a given condition and the size of inherently susceptible subpopulations [1]. Gompertzian analysis has been used in this study to provide the parameters necessary to construct a stationary population lifetable (static model) of mortality for amyotrophic lateral sclerosis (ALS) and for multiple sclerosis (MS). The static model demonstrates the relative effect of changing general mortality upon the mortality from each specific disease in a situation where interdisease competition is continuously changing. In order to represent mortality in a real population more closely (where age structure is not the result of mortality rates alone) a dynamic model was constructed for both conditions using the age distributions of the population of England and Wales. The quality of the model was verified by comparison of estimated mortality with historical data from the last three decades. The dynamic model has then been used to estimate mortality from each condition over the next three decades on the basis of population projections made by the Central Statistical Office [2], assuming no major change in the factors which lead to either condition. This analysis demonstrates both the theoretical applicability and practical capabilities of Gompertz-derived mortality models for analysing changing mortality patterns.

Adult↗
PubMed1987

Disease family trees: the possible roles of iodine in goitre, cretinism, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases and cancers of the thyroid, nervous system and skin.

Geographical distribution patterns of incidence and mortality for a wide variety of diseases display strong positive and negative correlations when analyzed statistically. It is argued that these relationships do not occur by chance, but reflect the causal role of surpluses and/or deficiencies of various bulk and trace elements. This concept is explored for one such "disease family tree", that of iodine. Deficiencies of this essential trace element appear to be associated with many diseases, or birth defects, including goitre, cretinism, multiple sclerosis, amyotrophic lateral sclerosis and cancer of the thyroid and nervous system. Although the evidence is weaker, iodine deficiency may also be implicated in Alzheimer's and Parkinson's diseases. In contrast, too much iodine may be linked to elevated mortality from cancer of the skin and melanoma. Rat studies indicate that iodine deficiencies can cause reduced brain weight, limited myelin formation, retarded neuronal maturation, a lowering of the production of various enzymes and slowing of the rates of protein and R.N.A. synthesis. Similar processes appear to occur in many of the diseases identified above.

Alzheimer Disease↗
PubMed1977

Jejunal immunopathology in amyotrophic lateral sclerosis and multiple sclerosis. Identification of viral antigens by immunofluorescence.

Jejunal mucosa from 7 patients with amyotrophic lateral sclerosis (A.L.S.), 20 newly reported patients with multiple sclerosis (M.S.), and 35 control patients without either disease was studied by immunofluorescence. An immune reaction was present in all A.L.S. specimens and consisted of altered ratios of immunoglobulin-labelled cells in the lamina propria, complement-labelled cells in the same location, and, in some, immunoglobulin and complement deposits in the epithelial basement membrane. Poliovirus antigen was detected in 4 cases, and in 1 of the these cases measles antigen was also present. A fifth specimen showed large amounts of herpesvirus antigen. In 2 cases studied at necropsy, both viral infection and immunological change was confined to the proximal jejunum. Measles antigen was identified in every case of M.S., and in biopsy specimens from 16 of the 20 M.S. patients immunological reactions similar to those seen in A.L.S. were present. With 2 exceptions, the controls did not show these changes in the jejunal mucosa. The exceptions were a patient with Friedreich's ataxia, who had an increase of IgG-labelled cells and some complement-bearing cells in the lamina propria, and a patient diagnosed as having non-tropical sprue, in whom large quantities of herpes antigen were seen.

Amyotrophic Lateral Sclerosis↗
PubMed1982

Isolation of virus from the spinal fluid of three patients with multiple sclerosis and one with amyotrophic lateral sclerosis.

A transmissible agent with the properties of a thermolabile filterable virus was isolated from the cerebrospinal fluid (CSF) of 4 Houston patients with chronic central nervous system (CNS) disease. 3 had multiple sclerosis and I had amyotrophic lateral sclerosis. No isolations were made from 27 patients whose CSF was taken for diagnosis of illness unrelated to degenerative CNS disease. Neutralising antibodies to the 4 isolates were present in the serum of each of the 4 patients with virus (14 positive results among 15 tests) but in hardly any of the sera from 8 patients without virus (3 antibody-positive results among 32 tests). The agent is antigenically related to the virus isolated in Japan from cases of subacute myelo-optico-neuropathy.

Adult↗
PubMedDate not supplied

Neurologic disorders: amyotrophic lateral sclerosis, myasthenia gravis, multiple sclerosis, and poliomyelitis.

The patient who has multiple cranial neuropathies may pose a diagnostic dilemma. The neurologic disorders of amyotrophic lateral sclerosis, multiple sclerosis, myasthenia gravis, and poliomyelitis often cause bulbar dysfunctions such as diplopia, facial weakness, slurred or hypernasal speech, dysphagia, and hoarseness. In general, treatment is supportive and is directed toward restoring or aiding lost function (i.e., tracheostomy, esophagostomy, and cricopharyngeal myotomy). The relative infrequency of these disorders can lead to delays in diagnosis and rehabilitative therapy.

Adult↗
PubMed2004

The two faces of L-DOPA: benefits and adverse side effects in the treatment of Encephalitis lethargica, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.

Parkinson's disease, encephalitis lethargica, multiple sclerosis and amyotrophic lateral sclerosis patients all display two distinct types of symptoms. Some of these are due directly to a deficiency of dopamine and are quickly reduced by laevodihydroxyphenylalanine (L-DOPA). The second set, however, are the result of neurological damage caused by metabolites of dopamine, which include dopachrome and other chrome indoles that are both hallucinogenic and neurotoxic. If this hypothesis is correct, three corollaries follow. Patients of all four disorders should display excessive oxidative stress, natural methyl acceptors should delay development and elevated antioxidant supplementation, given with L-DOPA, ought to prolong the "honeymoon" period in which the benefits of the drug out weigh its subsequent disadvantages. A literature review suggests that all three corollaries are probably correct.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Reduction of expression of tuberin, the tuberous-sclerosis-complex-gene-2 product in tuberous sclerosis complex associated connective tissue nevi and sporadic squamous and basal cell carcinomas.

BACKGROUND: Patients affected with tuberous sclerosis complex (TSC) are prone to the development of multiple benign tumors of the skin and other organs. Tuberin, the protein product of the tuberous-sclerosis-complex-2 tumor suppressor gene (TSC2) has been shown to inhibit cell proliferation. In TSC associated kidney tumors and sporadic brain tumors the loss/reduction of tuberin has been shown. METHODS: Specimens of nine squamous cell carcinomas (SCC) and five basal cell carcinomas (BCC) from patients without TSC and six biopsies of connective tissue nevi (CTN) of patients with TSC were obtained. Specimens were analyzed by immunoblotting for the expression of tuberin. RESULTS: Absent or reduced levels of tuberin were detected in the dermal parts of three of six shagreen patches, two of five BCC, and four of nine SCC. CONCLUSIONS: In tumors/hamartomas of patients with TSC the complete loss of TSC2 and tuberin is a mechanism which could be shown for CTN, thereby excluding the possibility of haploinsufficiency of TSC2. In a substantial number of cutaneous BCC and SCC the loss or downregulation of tuberin seems to be epigenetic, as alterations of TSC2 are not known in these tumors. The absence or reduction of tuberin might contribute to their proliferation.

Basal Cell Carcinoma↗
PubMed2000

The natural history of multiple sclerosis: a geographically based study: 8: familial multiple sclerosis.

We have examined the demographics and long-term outcome of 1044 patients with sporadic and familial multiple sclerosis in a population-based cohort from London, Ontario. The mean follow-up was 25 years in duration, and by this time most patients had reached the unambiguous endpoint scores of the Kurtzke disability status scale (DSS), DSS 6, 8 or 10. An affected family member was identified in 19.8% of the total population, and this subgroup was further divided arbitrarily into the following three groups by the type and number of relatives affected: (i) first degree only; (ii) first degree plus others; (iii) second or third degree. The outcome in these groups was compared with that for those patients who, at a mean 25 year follow-up, had no relatives known to be affected. Familial cases closely resembled those remaining sporadic in both demographics and outcome, although onset in the most heavily loaded families was earlier and male/female ratio was greater. The times to DSS 6, 8 and 10 did not differ significantly when sporadic, familial and familial subgroups were compared. These results provide no clinical support for viewing familial multiple sclerosis as distinct from the sporadic form. The observed recurrence rate for siblings in a strictly defined epidemiological sample was 3.5%, much as projected. These results validate the recurrence risks which have previously been derived from age-corrected data for these first-degree relatives.

Adult↗
PubMed2005

EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses.

Relapses, exacerbations or attacks of multiple sclerosis are the dominating feature of relapsing-remitting multiple sclerosis (MS), but are also observed in patients with secondary progressive MS. High-dose methylprednisolone is the routine therapy for relapses at present, but other treatments are also in current use. The objective of the task force was to review the literature on treatment of MS relapses to provide evidence-based treatment recommendations. Review was carried out on the literature with classification of evidence according to the EFNS guidelines for scientific task forces. Short-term, high-dose methylprednisolone treatment should be considered for the treatment of relapses of MS (level A recommendation). The optimal glucocorticoid treatment regimen, in terms of clinical efficacy and adverse events, remains to be established. A more intense, interdisciplinary rehabilitation programme should be considered as this probably further improves recovery after treatment with methylprednisolone (level B recommendation). Plasma exchange is probably efficacious in a subgroup of patients with severe relapses not responding to methylprednisolone therapy, and should be considered in this patient subgroup (level B recommendation). There is a need for further randomized, controlled trials in order to establish the optimal treatment regimen for relapses of MS.

Evidence-Based Medicine↗
PubMed1979

Effect of birthplace on the development of amyotrophic lateral sclerosis and multiple sclerosis. A study among Finnish war evacuees.

After World War II the southeastern part of Finland was ceded to the Soviet Union and its entire population evacuated to other areas of the country. The prevalences of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) were studied among the evacuees and compared to the corresponding data among the nonevacuated population. The prevalence of ALS among the war evacuees was two times higher than among the nonevacuated population (18.0 and 8.8 per 100,000, respectively). The prevalence of MS among the evacuees was only half of that found among the nonevacuated population, 38.3 and 73.0 per 100,000, respectively. The findings for ALS indicate that birthplace may have an effect on the later development of the disease and that there may have existed some environmental factor(s) which have made the evacuees more liable to contract the disease later in their lives. The low figure of MS for evacuees supports our previous results of an uneven geographic distribution of MS in Finland with the high-risk areas in the western and southwestern parts of the country. No accumulation of MS was found among the evacuees living in the high-risk areas.

Amyotrophic Lateral Sclerosis↗
PubMed1985

Characterization of DNA and RNA in circulating immunocomplexes in multiple sclerosis, amyotrophic lateral sclerosis and normal controls.

The total levels of DNA and RNA in serum immunocomplexes from multiple sclerosis (MS) patients and healthy control persons were compared. Furthermore, the levels of single-stranded DNA (ss DNA) and double-stranded DNA (ds DNA) in serum immunocomplexes from MS patients, amyotrophic lateral sclerosis (ALS) patients and controls were studied. The mean values of DNA and RNA were found to be elevated (P less than 0.01) in MS compared to the control means. Furthermore, the RNA/DNA ratio and the ratio ss DNA/ds DNA were decreased in MS. In contrast the ss:ds DNA ratio in ALS was increased. In ALS, however, the sum of ss DNA and ds DNA was lower (P less than 0.05) than the control mean value.

Adult↗
PubMed2006

COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord.

BACKGROUND: While multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are primarily inflammatory and degenerative disorders respectively, there is increasing evidence for shared cellular mechanisms that may affect disease progression, particularly glial responses. Cyclooxygenase 2 (COX-2) inhibition prolongs survival and cannabinoids ameliorate progression of clinical disease in animal models of ALS and MS respectively, but the mechanism is uncertain. Therefore, three key molecules known to be expressed in activated microglial cells/macrophages, COX-2, CB2 and P2X7, which plays a role in inflammatory cascades, were studied in MS and ALS post-mortem human spinal cord. METHODS: Frozen human post mortem spinal cord specimens, controls (n = 12), ALS (n = 9) and MS (n = 19), were available for study by immunocytochemistry and Western blotting, using specific antibodies to COX-2, CB2 and P2X7, and markers of microglial cells/macrophages (CD 68, ferritin). In addition, autoradiography for peripheral benzodiazepine binding sites was performed on some spinal cord sections using [3H] (R)-PK11195, a marker of activated microglial cells/macrophages. Results of immunostaining and Western blotting were quantified by computerized image and optical density analysis respectively. RESULTS: In control spinal cord, few small microglial cells/macrophages-like COX-2-immunoreactive cells, mostly bipolar with short processes, were scattered throughout the tissue, whilst MS and ALS specimens had significantly greater density of such cells with longer processes in affected regions, by image analysis. Inflammatory cell marker CD68-immunoreactivity, [3H] (R)-PK11195 autoradiography, and double-staining against ferritin confirmed increased production of COX-2 by activated microglial cells/macrophages. An expected 70-kDa band was seen by Western blotting which was significantly increased in MS spinal cord. There was good correlation between the COX-2 immunostaining and optical density of the COX-2 70-kDa band in the MS group (r = 0.89, P = 0.0011, n = 10). MS and ALS specimens also had significantly greater density of P2X7 and CB2-immunoreactive microglial cells/macrophages in affected regions. CONCLUSION: It is hypothesized that the known increase of lesion-associated extracellular ATP contributes via P2X7 activation to release IL-1 beta which in turn induces COX-2 and downstream pathogenic mediators. Selective CNS-penetrant COX-2 and P2X7 inhibitors and CB2 specific agonists deserve evaluation in the progression of MS and ALS.

Aged↗
PubMed2003

Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium.

The objective of this study was to determine the clinical characteristics of multiple sclerosis (MS) in African American (AA) patients in the New York State Multiple Sclerosis Consortium (NYSMSC) patient registry. The NYSMSC is a group of 18 MS centers throughout New York State organized to prospectively assess clinical characteristics of MS patients. AAs comprise 6% (329) of the total NYSMSC registrants (5602). Demographics, disease course, therapy, and socioeconomic status were compared in AA registrants versus nonAfrican Americans (NAA). There was an increased female preponderance and a significantly younger age at diagnosis in the AA group. AA patients were more likely to have greater disability with increased disease duration. No differences were seen in types of MS and use of disease modifying therapies. Our findings suggest a racial influence in MS. Further genetic studies that consider race differences are warranted to elucidate mechanisms of disease susceptibility.

Adult↗
PubMed1998

The peripheral insulin-like growth factor system in amyotrophic lateral sclerosis and in multiple sclerosis.

A lack of trophic support may lead to degeneration of adult nerve cells. Several growth factors, including insulin-like growth factor I (IGF-I), control the survival of spinal motor neurons during development as well as after experimental injury. These neurons are selectively affected in patients with amyotrophic lateral sclerosis (ALS). Thus, we analyzed whether reduced levels of circulating IGF-I may be present in this disease. Significant increases were found in three of four of the main circulating IGF-binding proteins in ALS patients, whereas serum IGF-I and insulin levels were significantly reduced. On the contrary, multiple sclerosis patients did not show any significant change in the IGF-I trophic system even though oligodendrocytes are known targets of the trophic action of IGF-I. These results suggest an involvement of the peripheral IGF-I trophic system in ALS.

Adult↗
PubMed2005

[Structure of peripheral blood platelets surface in patients with amyotrophic lateral sclerosis and multiple sclerosis].

Using scanning electronic microscopy of peripheral blood platelets in 32 patients with amyotrophic lateral sclerosis (ALS) and 6 patients with multiple sclerosis (MS), platelets activation, emerging in pseudopodiums formation, aggregation and lysis, was found. Platelets activation was more pronounced in ALS than in MS. It was most markedly seen for quantitative evaluation of the above traits. The features of platelet activation found in the study support the evidence for considering ALS as a systemic disorder being characterized by a broad spectrum of alterations of biological processes.

Amyotrophic Lateral Sclerosis↗