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Resolution of partial cataplexy in multiple sclerosis by treatment with weak electromagnetic fields.

Cataplexy, an ancillary symptom of narcolepsy, involves the sudden loss of muscle tone without altered consciousness usually brought on by sudden excitement or emotional influence and extreme exertions (Guilleminault et al., 1974; Parks et al., 1974; Guilleminault, 1976; Aldrich, 1992; 1993; Scrima, 1981; Baker, 1985). Attacks of generalized cataplexy produce complete atonic, areflexic partial or complete paralysis of striated muscles commonly involving the leg muscles resulting in collapse of the knees and falling while milder forms often termed partial cataplexy may manifest by sagging of the face, eyelid, or jaw, dysarthria, blurred vision, drooping of the head, weakness of an arm or leg, buckling at the knees, or simply a momentary sensation of weakness that is imperceptible to observers (Guilleminault, 1976; Aldrich, 1993). The duration of cataplexy is usually a few seconds, although severe episodes can last several minutes and rarely several hours or days in the case of "status cataplecticus" (Parkes et al., 1974; Guilleminault, 1976; Billiard & Cadilhac, 1985; Aldrich, 1992; 1993). This report concerns a 51 year old man with chronic progressive multiple sclerosis who exhibited daily episodes of partial cataplexy which resolved within 3 weeks after he received treatment with picotesla electromagnetic fields.

Brain↗

Long-term use of antecubital veins for plasma exchange. The Canadian Cooperative Multiple Sclerosis Study Group.

True or sham plasma exchange was done weekly for 20 weeks in patients in two of the randomization groups in a prospective, blind clinical trial of experimental treatments for multiple sclerosis. Because patients could be randomized to receive sham plasma exchange and placebo medications, it was decided when the trial was designed that the use of fistulae, arteriovenous shunts, venous cutdowns, or other aggressive forms of venous access would not be permitted for any patient. Accordingly, patients judged to have inadequate superficial antecubital veins were ineligible for the trial. To date, only 13 (4.4%) of 294 patients considered for entry into the trial have been rejected on these grounds. In only 4 of the 93 patients undergoing exchange was it necessary to discontinue plasma exchange because of inadequate venous access. In 79.3 percent of the 1207 exchanges done in these patients, there were no problems of any kind with venous access. In 5.4 percent of these 1207 exchanges, it was necessary to terminate the procedure prematurely because of difficulties with patients' veins. Thus, the great majority of patients free of serious systemic illness (other than chronic progressive multiple sclerosis) can undergo weekly plasma exchange for up to 20 weeks using superficial antecubital veins without the need to resort to more invasive methods of venous access.

Bloodletting↗

Detection of sequences homologous to human retroviral DNA in multiple sclerosis by gene amplification.

Twenty-one patients with multiple sclerosis, chronic progressive type, were examined for DNA sequences homologous to a human retrovirus. Genomic DNA from peripheral blood mononuclear cells was analyzed for the presence of homologous sequences to the human T-cell leukemia/lymphoma virus type I (HTLV-I) long terminal repeat, 3' gag, pol, and env domains by the enzymatic in vitro gene amplification technique, polymerase chain reaction. Positive identification of homologous pol sequences was made in the amplified DNA from six of these patients (29%). Three of these six patients (14%) also tested positive for the env region, but not for the other regions tested. In contrast, none of the samples from 35 normal individuals studied was positive when amplified and tested with the same primers and probes. Comparison of patterns obtained from controls and from patients with adult T-cell leukemia or tropical spastic paraparesis suggests that the DNA sequences identified are exogenous to the human genome and may correspond to a human retroviral species. The data support the detection of a human retroviral agent in some patients with multiple sclerosis.

Antibodies, Viral↗

Long-lasting effects of cyclophosphamide on lymphocytes in peripheral blood and spinal fluid.

Moderate doses of cyclophosphamide can cause effects on lymphocytes that may last for some time after discontinuation of the treatment. Since cyclophosphamide is also often used at high doses, we studied the short- and long-term effects of such a high dose (8 grams in 20 days) in 50 patients with chronic progressive multiple sclerosis with the use of monoclonal antibodies. The treatment caused a depletion of lymphocytes, especially CD4+ cells resulting in a significant decrease of the CD4/CD8 ratio. These changes can still be found up to 13.5 years after treatment. Although there was some recovery in the first few years after treatment this was only partial. Therefore, some of the effects of high dose cyclophosphamide on cellular immunity may be permanent. These changes should be taken into account when studying immune parameters or considering new treatments in these patients.

Adult↗

Computed tomography and magnetic resonance imaging in adult-onset leukodystrophy.

Five clinically affected and nine at-risk members of a kindred with an autosomal dominant adult-onset leukodystrophy simulating chronic progressive multiple sclerosis were studied with computed tomography (CT) and magnetic resonance imaging (MRI). Computed tomographic scans showed white matter lucencies occurring earliest and most prominently in the frontoparietal region. The lesions were nondiscrete, diffuse, and bilaterally symmetric. These changes were more clearly visualized as areas of increased signal intensity with T2-weighted MRI. Magnetic resonance imaging also showed increased signal intensity in the brain stem, cerebellar white matter, or both of four patients. Both MRI and CT differentiated this entity from multiple sclerosis, but MRI was superior to CT in detailing the extent of white matter involvement.

Adult↗

Partial plasma protein replacement in therapeutic plasma exchange.

We wished to determine whether subtotal replacement of protein in plasma removed at plasma exchange would be adequate to prevent hypovolemia and hypoproteinemia. Seven well nourished outpatients with chronic progressive multiple sclerosis underwent 60 plasma exchanges in which two liters of plasma were replaced with 750 ml saline followed by 1250 ml of a 5% albumin solution (62.5% albumin replacement). Total serum protein, protein electrophoresis, and immunoglobulin levels were measured before and after each exchange. Clinically, the exchanges were well tolerated. Total serum protein dropped by a mean of only 18% during the study and mean preexchange serum albumin levels were unchanged, even though immunoglobulins decreased by 57-72%. We conclude that in well nourished patients, partial albumin replacement of this magnitude is an adequate substitute for plasma removed in a plasma exchange.

Adult↗

Adult-onset metachromatic leucodystrophy presenting without psychiatric symptoms.

A 24-year-old man presented with a spastic and ataxic condition resembling chronic-progressive multiple sclerosis. Radiological examination revealed symmetrical diffuse paraventricular demyelination. Electrophysiological findings suggested additional involvement of the brain stem and the peripheral nervous system. The diagnosis of adult-onset metachromatic leucodystrophy was confirmed by biochemical and ultrastructural examination. In contrast to almost all adult cases reported so far, psychiatric symptoms were not present.

Adult↗

Lamin B1 duplications cause autosomal dominant leukodystrophy.

Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system, with a phenotype similar to chronic progressive multiple sclerosis. In this study, we identify a genomic duplication that causes ADLD. Affected individuals carry an extra copy of the gene for the nuclear laminar protein lamin B1, resulting in increased gene dosage in brain tissue from individuals with ADLD. Increased expression of lamin B1 in Drosophila melanogaster resulted in a degenerative phenotype. In addition, an abnormal nuclear morphology was apparent when cultured cells overexpressed this protein. This is the first human disease attributable to mutations in the gene encoding lamin B1. Antibodies to lamin B are found in individuals with autoimmune diseases, and it is also an antigen recognized by a monoclonal antibody raised against plaques from brains of individuals with multiple sclerosis. This raises the possibility that lamin B may be a link to the autoimmune attack that occurs in multiple sclerosis.

Animals↗

The kinetics of interferon induction by poly ICLC in humans.

A preliminary trial of the interferon (IFN) inducer polyriboinosinic acid-polyribocytidylic acid in poly-L-lysine and carboxymethylcellulose (poly ICLC) was conducted in patients with chronic progressive multiple sclerosis (MS). Because IFN induction in men is greater than in women, the kinetics of IFN induction were studied. As no significant differences were found in the serum half-life of IFN, sex-linked differences in IFN clearance or degradation are not likely to be responsible for the differences noted. Because fever was the major limiting side effect in MS patient, the relationship of fever to IFN levels was assessed. Changes in temperature were not related to changes in IFN levels, suggesting that fever might be blocked without reducing IFN levels.

Carboxymethylcellulose Sodium↗

VP1 DNA sequences of JC and BK viruses detected in urine of systemic lupus erythematosus patients reveal no differences from strains expressed in normal individuals.

The ubiquitous human polyomaviruses BK (BKV) and JC (JCV) persist with no adverse effects in immunocompetent individuals. Virus-induced pathogenesis has been linked to virus reactivation during impaired immune conditions. Previous studies have shown a significant difference between the VP1 DNA sequences of JCV obtained from control urine samples and those in progressive multifocal leukoencephalopathy brain samples. This difference could not be detected when comparing normal control urinary JCV DNA with DNA sequences from chronic progressive multiple sclerosis patients. Since BKV and JCV are readily activated in systemic lupus erythematosus (SLE) patients, the presence of specific strains, related to VP1 DNA sequences, was investigated in these patients. VP1 DNA sequences in 100 urine samples from 21 SLE patients and 75 urine samples from 75 healthy pregnant women were analysed and compared to previously reported sequences. The results show that the VP1 sequence profiles of JCV and BKV excreted by SLE patients do not differ significantly from those excreted by immunocompetent individuals. The European JCV subtypes 1A or 1B were represented among all JCV-positive urine specimens, while BKV VP1 sequences showed complete, or almost complete, identity with the MM or JL strains. Different urine samples from the same patient collected over a 1 year period were predominantly stable. BKV VP1 DNA in urine specimens from healthy pregnant women was only detected during the third trimester of their pregnancy. These results argue against SLE-specific JCV and BKV strains and suggest reactivation of the viruses rather than recurrent re-infections of patients with SLE.

Amino Acid Sequence↗

[A Japanese family with probably autosomal dominant adult-onset leukodystrophy].

We report here a family with leukodystrophy clinical features of which are characterized as adult onset, probably autosomal dominant inheritance, hyperreflexia, cerebellar ataxia, autonomic dysfunction and no peripheral nerve involvement. T2-weighted brain MRI revealed diffuse high signal areas in the cerebral white matter. The disorder in our subjects can be distinguished from most leukodystrophies in terms of genetic inheritance, clinical manifestations and laboratory data. Our family is quite similar to the kindred which Eldridge et al. described in 1984 as "hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis". Our family is the third report of this type of leukodystrophy and the first among non-Irish/Scottish family.

Age of Onset↗

Effects of neuropsychological treatment in patients with multiple sclerosis.

The chronic and progressive nature of multiple sclerosis (MS) often excludes patients from neuropsychological treatment. At the Multiple Sclerosis Rehabilitation Hospital, Haslev, 40 patients with mild to moderate cognitive and behavioral impairment associated with MS were randomized to either specific cognitive treatment (20 pts) by direct training, compensatory strategies and neuropsychotherapy, or to non-specific, deliberately diffuse mental stimulation (20 pts). Treatment was for a mean of 46 days. The effects of treatment were evaluated by neuropsychological tests before treatment, immediately after treatment (short-term effects) and 6 months later (long-term effects). After short-term treatment, effects on cognitive measures were not convincing, but on the Beck Depression Inventory (BDI) the specific cognitive treatment group reported significantly less depression. After 6 months only this group showed an effect, since the visuo-spatial memory was improved. However, the depression ratings (BDI) were almost maintained from the short-term level. Interestingly, the non-specific treatment group rated themselves as significantly more depressed. Conclusively, it is worth while to offer specific neuropsychological treatment to MS patients with cognitive and behavioral dysfunction.

Adult↗

Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities.

HLA class II gene polymorphism was investigated in 100 patients with clinically definite multiple sclerosis (MS) by restriction fragment length polymorphism analysis of Taq I-digested DNA using DRB, DQA, and DQB cDNA probes. Twenty-six patients had primarily chronic progressive MS and 74 had relapsing/remitting MS. The latter group included patients with a secondary progressive evolution of symptoms. Both clinical forms of MS were found to be associated with the DRw15,DQw6 haplotype. In addition, primarily chronic progressive MS was positively associated with the DQB1 restriction fragment pattern seen in DR4,DQw8, DR7,DQw9, and DRw8, DQw4 haplotypes, as well as negatively associated with the Taq I DQB1 allelic pattern corresponding to the serological specificity DQw7. Relapsing/remitting MS was positively associated with the DQB1 allelic pattern observed in the DRw17,DQw2 haplotype. These three DQB1 alleles are in strong negative linkage disequilibria with DRw15. The two susceptibility markers of each clinical form of MS act additively in determining the genetic susceptibility, as the relative risks for individuals carrying both markers roughly equal the sum of respective risks. Different alleles of the DQB1 locus defined by restriction fragment length polymorphisms contribute to susceptibility and resistance to primarily chronic progressive MS as well as to susceptibility to relapsing/remitting MS. The observed immunogenetic heterogeneity between the different clinical forms of MS favors the hypothesis that primarily chronic progressive MS and relapsing/remitting MS are two distinct disease entities.

Alleles↗

The pathology of primary progressive multiple sclerosis.

The pathological hallmark of chronic multiple sclerosis includes focal demyelination, gliosis, inflammation and axonal injury. There is limited information on whether these pathological features differ across the clinical phenotypes of the disease (relapsing-remitting, secondary progressive, and primary progressive). This review will focus on the pathological aspects of PPMS and pathogenic implications. A better understanding of the differences in PPMS pathology and pathogenesis will lead to more effective treatment strategies.

Animals↗

A novel mitochondrial DNA point mutation in the tRNA(Ile) gene: studies in a patient presenting with chronic progressive external ophthalmoplegia and multiple sclerosis.

We report a new mutation, a G to A transition at nucleotide position 4298 within the mitochondrial tRNA(Ile) gene in a patient with chronic progressive external ophthalmoplegia and multiple sclerosis. The mutation, which alters an evolutionary conserved nucleotide within the anticodon stem, was heteroplasmic in skeletal muscle but was not present in the patient's blood. Single fibre PCR analysis revealed significantly higher levels of the G4298A mutation in cytochrome c oxidase (COX) negative fibres than in COX-positive fibres. This mutation represents the seventh pathogenic nucleotide substitution to be found in this gene and as such confirms the tRNA(Ile) gene as a susceptible "hot spot" for mitochondrial DNA point mutations. Of particular interest is that this patient has the clinical features of both multiple sclerosis and a mitochondrial DNA disorder.

Animals↗

Current status of multiple sclerosis therapy in Germany: a national survey.

We conducted a semi-standardized enquiry concerning diagnostic, immunotherapeutic and supportive care strategies for multiple sclerosis (MS). A questionnaire was sent to all German neurological departments in December 1996, with 63% (n = 244) responding before May 1997. As might be expected, MS therapy in Germany is not very standardized. Most clinics use intravenous steroids for treating relapses, although with different dosing regimens. Nevertheless, oral steroids are also used. Interferon-beta and azathioprine are both used for the treatment of relapsing-remitting MS at the same frequency. Only 33% of German neurological departments said that they used an immunomodulating agent for chronic-progressive cases, indicating it in about 50% of cases. Azathioprine is the drug of first choice, followed by methotrexate. Regarding supportive care measures, the technique of intermittent self-catheterization is widely under-represented. Despite the lack of conclusive evidence from prospective studies for the value of azathioprine, it is still one of the most commonly used drugs for the treatment of relapsing-remitting and chronic-progressive MS. There was no evidence of a consensus on treatment standards for chronic-progressive disease courses.

Adjuvants, Immunologic↗

Normal T cell subsets and lymphocyte activity in multiple sclerosis.

Nine patients with either chronic progressive or relapsing/remitting multiple sclerosis were treated with several courses of lymphopheresis. The lymphocytes obtained by this procedure showed a significantly lower percentage of OKT3+ cells than normal controls at the beginning of therapy. This percentage increased to normal levels after five lymphopheresis treatments and then decreased during the last stages of treatment. Patients had normal levels of OKT4+ and OKT8+ cells compared to controls and these percentages showed no statistically significant changes during the course of treatment. The proliferative response of patient's lymphocytes after stimulation with concanavalin A, PHA and alloantigen was not significantly different from normal controls and these responses were unchanged during the lymphopheresis treatment. Natural killer cell activity was also normal in our patients. The results reported in this study do not suggest a basic T cell abnormality in our patients with multiple sclerosis. Furthermore, the lymphopheresis treatments did not induce any significant change in T cell numbers or functional activity in vitro.

Adult↗

The pathogenesis of primary progressive multiple sclerosis: antibody-mediated attack and no repair?

Primary progressive multiple sclerosis (MS) differs from the more common form of MS which has an initial relapsing-remitting course in a number of ways, including pathological features, clinical course, differential diagnosis and response to treatment. The lesions in primary progressive MS tend to be more diffuse, less inflammatory and less likely to remyelinate than those occurring in relapsing-remitting MS and secondary progressive MS; there are also fewer focal lesions in the brain in primary progressive MS. Recent evidence suggests that antibodies to central nervous system (CNS) antigens have an important role in disease progression. Such antibodies could cause demyelination, inhibit remyelination and cause axonal destruction. Ongoing immune attack by autoantibody and lack of CNS repair could be responsible for the gradually increasing disability in primary progressive MS. Further research on the B-cell and autoantibody response in primary progressive MS might lead to advances in diagnosis and treatment. Inhibition of autoantibody production by inducing B-cell apoptosis with rituximab is a potential new therapy for primary progressive MS.

Autoantibodies↗