Chronic Progressive Course Research Articles

The Biological Significance of Yawning Elicited by Application of Electromagnetic Fields in Multiple Sclerosis

To the Editor: Brief extracerebral applications of AC pulsed electromagnetic fields (EMFs) in the picotesla range intensity have been reported beneficial in the symptomatic treatment of patients with multiple sclerosis (MS) with either a relapsing-remitting or a chronic progressive course (Sandyk, 1992, 1994 a, b, 1995 a; Sandyk & Derpapas, 1993 a, b; Sandyk & Iacono, 1993, 1994 a, b; Sandyk & Dann, 1994, 1995. This treatment modality is effective also in the symptomatic management of acute exacerbation of symptoms and has also been shown to stabilize the course of the disease (Sandyk & Derpapas, 1993b; Sandyk & Dann, 1995; Sandyk, in press). The mechanisms by which administration of these EMFs improves symptoms of MS remain elusive. Application of DC EMFs of higher intensities has been shown to alter synaptic conductivity by modifying the release of neurotransmitters through an effect involving changes in transmembrane calcium flux (Bawin & Adey, 1976; Jaffe et al, 1980; Blackman, 1988; Rusovan & Kanje, 1992. In addition, exposure to EMFs has been shown to alter the circadian release of pineal melatonin (Welker et al, 1983; Semm, 1992) which, in turn, influences synaptic neurotransmission and immune mechanisms

Progressive Cognitive Improvement in Multiple Sclerosis from Treatment with Electromagnetic Fields

It has long been recognized that cognitive impairment occurs in patients with multiple sclerosis (MS) particularly among patients with a chronic progressive course. MS is considered a type of “subcortical dementia” in which cognitive and behavioral abnormalities resemble those observed in patients with a frontal lobe syndrome. The Bicycle Drawing Test is employed for the neuropsychological assessment of cognitive impairment specifically that of mechanical reasoning and visuographic functioning. It also provides clues concerning the patient's organizational skills which are subserved by the frontal lobes. Extracerebral pulsed applications of picotesla flux intensity electromagnetic fields (EMFs) have been shown to improve cognitive functions in patients with MS. I present three patients with long standing symptoms of MS who, on the initial baseline, pretreatment Bicycle Drawing Test, exhibited cognitive impairment manifested by omissions of essential details and deficient organizational skills. All patients demonstrated progressive improvement in their performance during treatment with EMFs lasting from 6–18 months. The improvement in cognitive functions, which occurred during the initial phases of the treatment, was striking for the changes in organizational skills reflecting frontal lobe functions. These findings demonstrate that progressive recovery of cognitive functions in MS patients are observed over time through continued administration of picotesla flux intensity EMFs. It is believed that the beneficial cognitive effects of these EMFs are related to increased synaptic neurotransmission and that the progressive cognitive improvement noted in these patients is associated with slow recovery of synaptic functions in monoaminergic neurons of the frontal lobe or its projections from subcortical areas.

Treatment with Electromagnetic Fields Reverses the Long-Term Clinical Course of a Patient with Chronic Progressive Multiple Sclerosis

It is estimated that 10–20% of patients with multiple sclerosis (MS) have a chronic progressive (CP) course characterized by an insidious onset of neurological deficits followed by steady progression of disability in the absence of symptomatic remission. To date no therapeutic modality has proven effective in reversing the clinical course of CP MS although there are indications that prolonged treatment with picotesla electromagnetic fields (EMFs) alters the clinical course of patients with CP MS. A 40 year-old woman presented in December of 1992 with CP MS with symptoms of spastic paraplegia, loss of trunk control, marked weakness of the upper limbs with loss of fine and gross motor hand functions, severe fatigue, cognitive deficits, mental depression, and autonomic dysfunction with neurogenic bladder and bowel incontinence. Her symptoms began at the age of 18 with weakness of the right leg and fatigue with long distance walking and over the ensuing years she experienced steady deterioration of functions. In 1985 she became wheelchair dependent and it was anticipated that within 1–2 years she would become functionally quadriplegic. In December of 1992 she began experimental treatment with EMFs. While receiving regularly weekly transcortical treatments with AC pulsed EMFs in the picotesla range intensity she experienced during the first year improvement in mental functions, return of strength in the upper extremities, and recovery of trunk control. During the second year she experienced the return of more hip functions and recovery of motor functions began in her legs. For the first time in years she can now initiate dorsiflexion of her ankles and actively extend her knees voluntarily. Over the past year she started to show signs of redevelopment of reciprocal gait. Presently, with enough function restored in her legs, she is learning to walk with a walker and is able to stand unassisted and maintain her balance for a few minutes. She also regained about 80% of functions in the upper limbs and hands. Most remarkably, there was no further progression of the disease during the 4 years course of magnetic therapy. This patient's clinical recovery cannot be explained on the basis of a spontaneous remission. It is suggested that pulsed applications of picotesla EMFs affect the neurobiological and immunological mechanisms underlying the pathogenesis of CP MS.

Elevated serum levels of interleukin-12 in chronic progressive multiple sclerosis

The serum levels of the heterodimeric cytokine IL-12 were measured by solid-phase ELISA in a group of healthy subjects, multiple sclerosis (MS) patients with secondary chronic progressive course of the disease and patients suffering from other neurological diseases (OND) Serum levels of IL-12 higher than 5 pg/ml (limit of sensitivity of the assay) were only found in 2/30 (6.7%) of the healthy subjects and none of the 8 subjects with OND. In contrast, IL-12 was found in the majority of CPMS patients’ sera (10/15, 66.7%) with values ranging between 5.5 and 18.6 pg/ml. These results are suggestive for an up-regulated production of IL-12 in CPMS.

Treatment of Autoimmune Disease by Oral Tolerance to Autoantigens

Multiple sclerosis (MS) is a chronic demyelinating disease of the human central nervous system (CNS) which can be characterized clinically by a remitting–relapsing or a chronic progressive course. There is a striking similarity between the clinical and histopathological features of MS and the experimentally induced disease, experimental autoimmune encephalomyelitis (EAE). Induced by the injection of myelin basic protein (MBP) and adjuvants, EAE is characterized by clinical neurologic signs of paralysis and histopathologic changes consisting of perivascular mononuclear infiltration and demyelination. We have reported that the oral administration of MBP exerts a profoundly suppressive effect on EAE induced in the Lewis rat. This MBP-induced oral tolerance is characterized by an inhibition of EAE clinical neurologic signs, reduced CNS histopathologic changes, a profound decrease in the T-lymphocyte proliferative response specific for the fed antigen, and a decrease in serum antibody specific for MBP. In a chronic relapsing model of EAE in the B10.PL mouse, we have shown that the oral administration of MBP either prior to MBP challenge or on the first day of clinical signs results in a decreased number and severity of EAE relapses. The oral tolerance approach has also proven effective in the suppression of other organ-specific autoimmune diseases including collagen-induced arthritis, adjuvant arthritis, uveoretinitis, experimental myasthenia gravis, diabetes, and thyroiditis as well as graft rejection. Two primary mechanisms have been proposed to explain oral tolerance in EAE-active suppression following feeding of lower doses of antigen and clonal anergy or deletion following administration of higher doses.In vivoapproaches in rats and transgenic mice have been used to further explore the mechanisms underlying oral tolerance. Administration of recombinant interleukin (IL)-2 was shown to reverse the tolerance induced by feeding low doses of MBP, but not the tolerance induced by feeding high doses of MBP, indicating that deletion had occurred in the high-dose group. Moreover, the oral administration of MBP to MBP-specific T-cell receptor (TCR) transgenic mice resulted in a profound decrease of the transgenic T cells in the blood, lymph node cells (LNC), mesenteric LNC, and spleen compartments. The proliferative response to MBP was also profoundly reduced in these organs, indicating that the cells had been deleted from these sites. The results achieved in animal models have led to clinical trials of oral tolerization in three human autoimmune diseases—MS, uveoretinitis, and rheumatoid arthritis—with promising results.

Remission of scleromyxoedema following treatment with extracorporeal photopheresis

Scleromyxoedema, a disseminated papular and sclerotic variant of lichen myxoedematosus, is a rare disease with a chronic progressive course, and little tendency towards spontaneous remission. The treatment of scleromyxoedema has been largely ineffective. Aggressive chemotherapeutic agents have been used, often leading to therapy-related morbidity and mortality. We report a 41-year-old woman with scleromyxoedema, associated with a monoclonal gammopathy of IgG-kappa type, whose condition almost completely cleared with 12 monthly sessions of extracorporeal photopheresis. The patient had previously not responded to isotretinoin, and chlorambucil with prednisolone.

Side effect profile of interferon beta-1b in MS: results of an open label trial.

To determine which patients are prone to side effects from interferon beta-1b and which side effects are most troublesome, we studied 72 patients with clinically definite MS who were started on interferon beta-1b after its release and found that the side effects significantly associated with treatment included skin reactions, flu-like symptoms, fatigue, leukopenia, new or worsened depression, and new or worsened headache. Of these, only fatigue and depression were significantly associated with discontinuance of therapy. Moreover, the course of disease before initiation of treatment also had a significant impact on the likelihood of discontinuing medication. Thus, despite an apparently similar therapeutic benefit (as judged by the similarly reduced attack rate in each group), patients with a secondary chronic progressive course were more likely to discontinue treatment (63%) than patients with either a relapsing/progressive course (18%) or a remitting/relapsing course (7%). Indeed, in the final regression equation, the only factors significantly related (r = 0.875) to the discontinuance of therapy were fatigue (p < 0.0001), a fatigue-depression interaction (p < 0.0001), and a chronic progressive course of disease (p<0.0001). Thus, if future clinical trials are to provide useful information on the value of interferon beta-1b in progressive MS, the side effects of fatigue and depression will need to be ameliorated to limit the drop-out rate from such trials.

Pregnancy Is Associated With a Lower Risk of Onset and a Better Prognosis in Multiple Sclerosis

The effects of pregnancy were studied in a multiple sclerosis incidence cohort. In order to eliminate interaction bias between the disease and pregnancy, analysis of the risk of relapse during pregnancy and the puerperium was limited to the onset bout, using fecundity figures for Sweden. The risk of onset bout was significantly reduced during pregnancy while the risk of onset bout in the post-partum period did not differ significantly from the risk during non-pregnancy periods. We also found a decreased risk of multiple sclerosis onset in parous compared with nulliparous women. The association between nulliparity and multiple sclerosis tended to increase with age. Furthermore, the effect of pregnancy on the long-term prognosis in established multiple sclerosis was analysed by comparing the risk of change from a relapsing-remitting to a chronic progressive course and the risk of reaching level 6 of the Disability Status Scale in women with pregnancy after multiple sclerosis onset with that in non-pregnant control patients, matched for neurological deficit, disease duration and age. There was a significantly decreased risk of a progressive course in women who were pregnant after multiple sclerosis onset.

Urinary myelin basic protein—like material as a correlate of the progression of multiple sclerosis

In the multicenter, randomized, placebo-controlled trial of alternate-day injections of recombinant interferon beta-1b in relapsing-remitting multiple sclerosis (MS), urine specimens were collected periodically from all patients (n = 64) in two of the clinical test sites over the 2 years of the study. Urine specimens were also collected over two consecutive 24-hour periods from 43 patients from a third center. Urine samples were assayed for their content of myelin basic protein-like material (MBPLM), the level of which was correlated with clinical changes, cranial magnetic resonance imaging results, and the development of progressive disease. Concordant changes in creatinine values affected some of the relationships of MBPLM. The level of urinary MBPLM correlated with a chronic progressive course and with the number of lesions and the total lesion area on cranial magnetic resonance images. A rise in the level of urinary MBPLM appeared to antedate the clinical transition from a relapsing-remitting to a chronic progressive course. By chance, the randomized entry of patients led to significant differences in urinary MBPLM levels among the three treatment groups, thus precluding correlation studies of treatment effects. However, the patient group from which 24-hour specimens were collected showed that the patients with relapsing-remitting MS changing to a chronic progressive course, and more specifically, those patients with chronic progressive MS receiving placebo, had the highest values of urinary MBPLM. These findings indicate that urinary MBPLM may offer an objective test and possibly serve as a surrogate marker for detecting or predicting the failure of remission or the transition to a progressive phase of MS.

A magnetization transfer imaging study of normal-appearing white matter in multiple sclerosis.

We attempted to define the role of subtle changes in the normal-appearing white matter (NAWM) in the development of disability in multiple sclerosis (MS). Twenty-seven clinically definite MS patients with either relapsing-remitting or chronic-progressive courses and 10 sex- and age-matched controls entered the study. For each patient and control, we studied two NAWM areas in the frontal lobe with magnetization transfer imaging (MTI). For patients, we also calculated the MT ratios (MTRs) for three contiguous areas of NAWM progressively further from "isolated" lesions visible on conventional MRI. Frontal NAWM in MS patients had lower mean MTRs than the frontal white matter of the controls (p = 0.02). MTRs in the NAWM adjacent to isolated lesions increased with distance from them to the cortical gray matter (p = 0.04). This pattern was typical for patients with chronic-progressive MS whose MTRs in the first two regions of NAWM adjacent to lesions were lower than those of the same regions of patients with relapsing-remitting MS. This study confirms that there are alterations in the NAWM of MS patients and suggests that such changes might be relevant to the disability in MS.

Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis

The effects of pregnancy were studied in a multiple sclerosis incidence cohort. In order to eliminate interaction bias between the disease and pregnancy, analysis of the risk of relapse during pregnancy and the puerperium was limited to the onset bout, using fecundity figures for Sweden. The risk of onset bout was significantly reduced during pregnancy while the risk of onset bout in the post-partum period did not differ significantly from the risk during non-pregnancy periods. We also found a decreased risk of multiple sclerosis onset in parous compared with nulliparous women. The association between nulliparity and multiple sclerosis tended to increase with age. Furthermore, the effect of pregnancy on the long-term prognosis in established multiple sclerosis was analysed by comparing the risk of change from a relapsing-remitting to a chronic progressive course and the risk of reaching level 6 of the Disability Status Scale in women with pregnancy after multiple sclerosis onset with that in non-pregnant control patients, matched for neurological deficit, disease duration and age. There was a significantly decreased risk of a progressive course in women who were pregnant after multiple sclerosis onset.

Reversal of alexia in multiple sclerosis by weak electromagnetic fields.

The occurrence of cognitive deficits in patients with multiple sclerosis (MS) has been recognized since 1877 when Charcot first observed "enfeeblement of memory" in his patients. Cognitive deficits have been reported in almost 50% of patients with a relapsing-remitting course and in a significantly higher percentage of patients with a chronic progressive course leading to intellectual disability which is often severe enough to preclude employment. MS is considered a form of subcortical dementia and the occurrence of classical cortical disorders such as aphasia, agnosia and apraxia is reported to be rare in the disease. However, in my experience alexia, a reading impairment unrelated to visual acuity or visual field defects, is common in patients with MS. Recently, I reported that treatment with picotesla range electromagnetic fields (EMFs) is an efficacious modality in the management of both the motor and cognitive symptoms of MS. Three patients with MS who developed alexia as a manifestation of the disease are presented. In all patients the alexia was reversed several months after they began treatment with EMFs. Since alexia usually reflects a disconnection syndrome whereby lesions involving the left visual cortex and the splenium of the corpus callosum disconnect language association areas from visual association areas, it is suggested that reversal of the alexia in these patients by EMFs was related to improved interhemispheric transcallosal transmission of visual information. In addition, it is conceivable that changes in the metabolism of monoamines, which are involved in visual information processing and reading comprehension, may have been important in causing reversal of the alexia. This report further supports the unique efficacy of this treatment modality in reversing specific cognitive deficits in MS.

Spontaneous Resolution of Keratosis lichenoides chronica

Keratosis lichenoides chronica (KLC) is a disorder of keratinization with a chronic progressive course. The nosology of this disorder has been discussed in relation to lichen planus. In this communication a classical case of KLC is presented; however, the lesions involuted spontaneously. The present observation challenges the common belief that KLC has a chronic progressive course.

Clinically isolated lesions of the type seen in multiple sclerosis: a cognitive, psychiatric, and MRI follow up study.

There is a dearth of longitudinal studies on psychometric and psychiatric change in multiple sclerosis (MS) particularly on the evolution of these abnormalities early in the disease process. A 4 1/2 year follow up study documenting magnetic resonance imaging (MRI), psychometric, and psychiatric abnormalities was undertaken in a group of 48 patients with clinically isolated lesions--for example, optic neuritis--which are frequently the harbinger of MS. At follow up about half the subjects had developed clinically definite MS, with memory deficits becoming apparent. Deficits in attention documented at initial assessment were present but unchanged in those subjects who still had a clinically isolated lesion status. However, after MS was categorised into a relapsing-remitting or chronic progressive course, patients with a chronic progressive course were found to have significantly deteriorated with regard to auditory attention tasks. T1 relaxation times in apparently normal white matter correlated with certain indices of cognitive impairment. In developing a model to explain the pathogenesis of intellectual and emotional change in MS, the interaction of organic, psychological, and social factors needs to be emphasised.

Clustering of Residence of Multiple Sclerosis Patients at Age 13 to 20 Years in Hordaland, Norway

Geographic and temporal variation and migration studies point to an exogenous agent in the etiology of multiple sclerosis. If infectious etiology is involved, space-time clustering would also be expected. The authors analyzed 381 patients with a clinical onset of multiple sclerosis between 1953 and 1987 in the county of Hordaland, Norway. Patients within the same birth cohort had lived significantly closer to each other than would be expected during ages 13-20 years, with peak clustering at age 18 years (p = 0.002). Clustering was also shown between patients in pairs comprised of one individual with initial remittent disease and the other with chronic progressive course of disease, suggesting a similar etiology for both clinical patterns. Clustering between cases with widely divergent dates of clinical onset provides evidence of marked variation in latency. No similar clustering was observed in age-, sex-, and area-matched hospital controls without multiple sclerosis, and no clustering was found among the cases when using fixed number of years before onset. These results are compatible with a common infectious agent, such as the Epstein-Barr virus, acquired in adolescence in genetically vulnerable persons who are also not protected by an infection acquired before this age of susceptibility. Susceptibility could be related to the route of transmission or to other age-related covariates or it may be hormonally mediated.

Chronic experimental autoimmune encephalomyelitis induced by the 89‐101 myelin basic protein peptide in B10RIII (H2r) mice

Development of experimental allergic encephalomyelitis (EAE) in the SJL (H-2s) mice is associated with a T cell-dependent autoimmune response to the C-terminal part of the myelin basic protein (MBP). In this study the influence of both H-2 and non-H-2 genetic background on EAE induced with the MBP89-101 peptide is described. Analysis of different H-2q haplotype strains, B10G, B10Q, SWR and NFR/N, showed that the B10 background is relatively resistant to disease induction. Both SWR and NFR/N were susceptible to EAE showing that the H-2q haplotype is permissive for EAE development induced with MBP89-101 and that the T cell receptor (TcR) haplotype or complement C5 deficiency exert no significant influence on disease susceptibility. In a series of H-2-congenic strains on the B10 background only B10RIII (H-2r) mice were susceptible to EAE. The B10RIII mice developed a severe EAE with early onset and chronic progressive or relapsing course of disease. In addition, B10RIII mice treated with Freund's complete adjuvant and pertussis toxin alone showed an early monophasic disease. The clinical observations were confirmed by immunohistopathologic analysis of the central nervous system. In these studies, we also applied antibodies to different TcR V beta elements which showed no specific limitation of the used TcR among infiltrating T cells in the target tissue in any of the strains. It is concluded that an MBP peptide-specific disease can be induced in three different haplotypes and it is possible that shared structures between the As, Aq and Ar molecules are of importance for the trigger of encephalitogenic T cells with different TcR V elements. The presently described chronic EAE model induced in the B10RIII mice will be of value as a model for multiple sclerosis.

Scleredema

We report a classical case of scleredema which pursued a chronic progressive course and was associated with poorly controlled diabetes mellitus.

Chronic progressive multiple sclerosis: serial magnetic resonance brain imaging over six months.

Eight patients in the chronic progressive stage of multiple sclerosis were studied prospectively with magnetic resonance imaging of the head and neurological examination every 2 weeks for 6 months. There were no clinical relapses and disability ratings did not change between the start and completion of the study. Despite the clinical inactivity, a total of 86 active events (new, reappearing, or enlarging lesions) were identified by magnetic resonance imaging over the 6 months, with 50 (51%) of 98 follow-up scans showing evidence of one or more active lesions. New and changing lesions were indistinguishable in appearance, distribution, and temporal pattern from those previously seen in patients who had relapsing and remitting multiple sclerosis. However, as noted previously, the patients in the chronic progressive stage had many more confluent lesions than did the group in relapse. These results strongly suggest that the frequently observed clinical evolution of multiple sclerosis into a chronic progressive course is not accompanied by a fundamental change in the disease process. In fact the chronic progressive stage seems associated with more active changes demonstrated by scans than does relapsing and remitting multiple sclerosis. This study also confirms our previous experience that serial magnetic resonance imaging is much more sensitive than clinical examination in detecting disease activity in multiple sclerosis.

Borrelia burgdorferi antibodies in patients with relapsing/remitting form and chronic progressive form of multiple sclerosis.

Sera of 106 multiple sclerosis patients and 103 closely matched controls were examined for Borrelia burgdorferi antibodies. The prevalence rate in multiple sclerosis patients was 14.2%, in controls 25.2%. Overall prevalence was 20.1%. Mean IgG antibody level was insignificantly higher in controls than in multiple sclerosis patients. Patients with a chronic progressive course of multiple sclerosis had an insignificantly higher mean borrelia antibody level, when compared with those suffering from relapsing/remitting form of disease.

Lysosomal hydrolases in cerebrospinal fluid of multiple sclerosis patients: A follow-up study

The change in activity of lysosomal hydrolases in the brain tissue of patients with demyelinating disease has been suggested to reflect the demyelination process. In this study we measured neutral proteinase (NP), acid proteinase (AP), and β-glucuronidase (BG) activities in CSF of 32 patients with multiple sclerosis (MS) (remitting, remitting and relapsing, or chronic progressive course of the disease), 62 controls, and 4 patients with chronic inflammatory disease of central nervous system (ID). Samples from MS patients were taken at different clinical conditions of the disease during the 22-month follow-up. Elevated NP activity was found in patients with relapsing course of MS and also in patients with ID ( P < 0.05). NP activity correlated with the number of leucocytes in CSF of both MS ( P < 0.005, r = 0.50) and control ( P < 0.05, r = 0.21) patients. AP activity decreased in the MS group, especially in patients with remitting or remitting and relapsing courses of the disease ( P < 0.05), but even more in patients with ID ( P < 0.01). During the follow-up the increase in NP activity seemed to be associated with the clinical relapses of MS patients. Other enzymes did not fluctuate with the disease. This study suggests that the change in activity of lysosomal hydrolases is not specific for MS. The increase in NP activity in CSF is associated with clinical relapse of individual MS patients during the follow-up and may indicate immunological activation of the demyelination process in the brain. The large intra- and interindividual variation in enzyme activities in the CSF, however, makes the use of these enzymes difficult for diagnosis of MS and follow-up of MS activity.