Genetically determined failure of activation-induced apoptosis of autoreactive T cells as a cause of multiple sclerosis

I postulate that multiple sclerosis is an autoimmune disease that involves genetically determined failure of activation-induced apoptosis of autoreactive T cells in the central nervous system. Activation of central-nervous-system-reactive T cells in peripheral lymphoid organs by exposure to crossreacting antigens or superantigens derived from common infectious agents may trigger attacks of multiple sclerosis. In normal individuals these activated T cells are deleted by activation-induced apoptosis, but in individuals predisposed to multiple sclerosis they survive, proliferate, and damage the central nervous system. The clinical course of multiple sclerosis may vary according to the antigens in the central nervous system being targeted: targeting of myelin antigens leads to a relapsing-remitting course of clinical recovery due to remyelination or other mechanisms; targeting of axonal antigens leads to a progressive course from onset because axonal regeneration is limited in the central nervous system. This hypothesis can account for many characteristics of multiple sclerosis and has predictions that can be tested.     

Fibrinolytic treatment with ultra-high streptokinase infusion via the dorsalis pedis vein offers no advantage over systemic infusion via the brachial vein in patients with deep vein thrombosis of the leg

BACKGROUND: Diagnosis of intraparenchymal brain lesions has usually required invasive diagnostic procedures, because too few cells are shed into cerebrospinal fluid to permit cytologic diagnosis. Polymerase chain reaction technology makes it possible to identify cell populations that are present at a much lower frequency than traditional techniques. CASE REPORT: A young woman presented with multiple brain lesions raised the question of primary central nervous system lymphoma. Polymerase chain reaction analysis of cerebrospinal fluid showed evidence of a monoclonal B-cell population heightening suspicion of lymphoma. Brain biopsy showed acute demyelination most consistent with multiple sclerosis. CONCLUSION: Although T-cell restriction has been demonstrated in multiple sclerosis lesions, the finding of a monoclonal B-cell population was unexpected and to our knowledge has not been previously reported. This case emphasizes that monoclonality is not always indicative of a neoplastic process, particularly in the central nervous system.     

Spontaneous and induced remyelination in multiple sclerosis and the Theiler's virus model of central nervous system demyelination

Remyelination in the central nervous system, originally thought to occur rarely, if ever, is now an established phenomena in multiple sclerosis patients. However, the extent of myelin repair is incomplete and limited. Experimental models of central nervous system demyelination provide an opportunity to study the cellular and molecular events involved in remyelination. These models may provide some clue to why remyelination in multiple sclerosis is incomplete as well as suggest potential methods to stimulate central nervous system repair. In this review we examine the morphological aspects of central nervous system remyelination and discuss both spontaneous and induced remyelination in multiple sclerosis and experimental models of central nervous system demyelination. We give special emphasis to the Theiler's virus model of central nervous system demyelination and its usefulness to identify therapeutic agents to promote remyelination. The role of immunoglobulins in promoting remyelination in both the Theiler's model system and in multiple sclerosis is discussed. Finally, we examine the potential physiological role of demyelination and remyelination and its relationship with clinical manifestations of central nervous system disease.     

Late-onset multiple sclerosis and serum monoclonal gammopathy: an incidental association?

Four patients older than 45 years with a central nervous system demyelinating disease associated to a monoclonal gammopathy are reported. The neurologic disease met the diagnostic criteria of multiple sclerosis, with the particularity of a late onset. Monoclonal paraproteinemia was also present in the cerebrospinal fluid, associated with an intrathecal immunoglobulin synthesis. The clinical data and the course of the disease were comparable to the previous reports of late onset multiple sclerosis. A causal link between the dysglobulinemia and the neurological disease may not be demonstrated. However, such an association may underline the role of humoral processes in multiple sclerosis.     

Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria

At the recent tuberous sclerosis complex consensus conference, the clinical diagnostic criteria for tuberous sclerosis complex were simplified and revised to reflect both new clinical information about tuberous sclerosis complex and an improved understanding of the disorder derived from molecular genetic studies. Based on this new information, some clinical signs once regarded as pathognomonic for tuberous sclerosis complex are now known to be less specific. No single sign is present in all affected patients, and there is no proof that any single clinical or radiographic sign is absolutely specific for tuberous sclerosis complex. Accordingly, the clinical and radiographic features of tuberous sclerosis complex have now been divided into major and minor categories based on the apparent degree of specificity for tuberous sclerosis complex of each feature. A definitive diagnosis of tuberous sclerosis complex now requires two or more distinct types of lesions, rather than multiple lesions of the same type in the same organ system. Although diagnosis on purely clinical grounds can continue to be difficult in a few patients, there should be little doubt about the diagnosis for those individuals who fulfill these strict criteria. Couples with more than one child with tuberous sclerosis complex, no extended family history, and no clinical features of tuberous sclerosis complex are more likely to have germline mosaicism for tuberous sclerosis than nonexpression of the mutation. Germline mosaicism, while fortunately rare, will not be suspected from either diagnostic criteria or molecular testing until a couple has multiple affected children. Genetic counseling for families with one affected child should include a small (1% to 2%) possibility of recurrence, even for parents who have no evidence of tuberous sclerosis complex after a thorough diagnostic evaluation.     

Glucagonoma as a tumor found by the therapist

An analysis was performed of features of incipient manifestations of multiple sclerosis in 648 patients with a primary diagnosis having been made at the Ukrainian Centre for Study of Demyelinating Diseases over 1992-1996. Incipient manifestations of disseminated sclerosis revealed themselves predominantly as sensory, motor, visual, and coordination impairment against the background of pain sensations, paresthesias and pronounced asthenia of the nervous system. Knowledge of disseminated sclerosis debut is important for the diagnosis of the condition to be made and treatments to be administered in a timely fashion.     

The role of nuclear magnetic resonance monitoring in early clinical-instrumental diagnosis of multiple sclerosis

Nucleo-magnetic resonance tomography (NMRT) facilitated considerably early diagnosis of multiple sclerosis. Yet, there appeared data indicating the existence of NMRT negative forms. These were found in 15 patients of 82 ones examined using NMRT only which failed to defect foci of demyelinization in spite of a clear-cut clinical picture. NMRT monitoring during 3 years (from 2 to 5 NMRT investigations) permitted to visualize the foci of demyelinization located primarily in the periventricular cerebral region. The conclusion was made that a presence of clear clinical symptoms as well as a remitting character of the pathologic process confirmed by visualization of multiple foci of CNS demyelinization by means of NMRT monitoring, gave full chance for a reliable diagnosis of multiple sclerosis. A lack of such confirmation may be explained by the fact, that clinical debut of the disease reflected only the phase of multiple sclerosis and forestalled forming of a focal demyelinizating process, pathognomonic for this disease.     

Relative value of three laboratory methods in the diagnosis of multiple sclerosis

We compared three methods of analysis for IgG in cerebrospinal fluid, using samples from 158 patients with clinically suspected multiple sclerosis and from 200 neurological controls. The tests were: search for oligoclonal bands, calculation of rate of synthesis of IgG in the cerebrospinal fluid, and determination of the IgG/albumin ratio. Paired cerebrospinal fluid and serum samples were collected and their IgG and albumin concentrations measured. Oligoclonal bands were detected by electrophoresis on agarose. Positive results were obtained in 94, 75, and 67% of patients with probable or definite multiple sclerosis by the three respective methods. In contrast, for patients for whom the clinical diagnosis of multiple sclerosis was considered possible, positive results were obtained in 10, 43, and 13%, respectively. Evidently, detection of oligoclonal bands remains the best single test for the presence of abnormal IgG in suspected multiple sclerosis patients. A combination of the first two tests is most sensitive for both probable and definite multiple sclerosis (97%) and possible multiple sclerosis (50%). Some infectious or immunologic disorders can also produce these IgG abnormalities, but they can usually be distinguished from multiple sclerosis by other clinical and laboratory data.     

Delusion of mercury poisoning in multiple sclerosis

We confirmed the diagnosis of multiple sclerosis in a 54-year-old man. The patient rejected this diagnosis and was completely convinced that all his symptoms resulted from a chronic mercury intoxication. We found evidence that this delusional disorder was an independent illness, and not a "symptomatic psychosis in multiple sclerosis." So far, little notice has been taken in psychiatry of delusions of environmental poisoning, which cause difficulties in applying common criteria of delusion.     

Sudden hearing loss as the initial monosymptom of multiple sclerosis

Hearing loss is an uncommon symptom in multiple sclerosis. We report two patients in whom unilateral sudden hearing loss was the first monosymptomatic manifestation of multiple sclerosis. We confirmed the initial central auditory dysfunction suggested by audiometric findings and brainstem auditory evoked potentials by MRI, which showed a unilateral pontine lesion in one patient and a lesion in the medulla oblongata in the other.     

Clinical, neurodiagnostic, and MR findings in children with spinal and brain stem multiple sclerosis

PURPOSE: To describe the clinical, neurodiagnostic, and MR findings in seven children with brain stem and spinal multiple sclerosis. METHODS: Spinal or brain stem multiple sclerosis was diagnosed in seven children between 1986 and 1992. All patients had neurologic and MR examinations as well as neurodiagnostic testing, including spinal fluid analysis and brain stem and auditory evoked potentials. RESULTS: Three children had clinical findings and masslike lesions in the brain stem (two) or spinal cord (one) suggestive of neoplasm, which prompted biopsy (two) or radiation therapy (one). Five of six patients with spinal involvement had cord swelling with increased signal on T2-weighted images over at least three cord segments, and two children had essentially holocord involvement. Three children had normal cranial MR at presentation. CONCLUSIONS: Multiple sclerosis involvement of the brain stem and spinal cord may be associated with extensive swelling and MR signal changes suggestive of neoplasm without typical cerebral white matter abnormalities. Serial clinical and neuroimaging examinations may be necessary to make a definitive diagnosis of multiple sclerosis in children.     

Neuropsychological aspects of multiple sclerosis

Twenty-six persons (five males and 21 females) with the neurological diagnosis of multiple sclerosis, and an equal number of control subjects matched on age, sex, and education were given a battery of tests designed to assess motor and intellectual functioning. Subjects in the multiple sclerosis group displayed marked deficits on all tests of motor skill except grip strength. Although verbal intelligence was not impaired in subjects with multiple sclerosis, these subjects performed more poorly than control subjects on two different tests of memory even though these tasks required minimal motor responsivity. Correlational analyses on the several motor and cognitive tasks revealed that correlations between motor and memory performance were consistently higher in persons with multiple sclerosis than in controls. These results suggest that whereas multiple sclerosis may not have mch effect on the utilization of stored verbal information, the processing and storage of new verbal material are disrupted by the disease to a degree that is paralleled by the extent of motor impairment. This finding is consistent with the view that the memory impairments observed are secondary to the primary motor deficit, but the alternative explanation that memory functions, like motor functions, are especially vulnerable to the demylination process of multiple sclerosis is equally viable at present.     

Magnetic resonance imaging of disseminated sclerosis

Multiple sclerosis is a chronic demyelinating disease. Paraclinical examinations may contribute to the diagnosis of multiple sclerosis. Magnetic resonance imaging (MRI) has a very high sensitivity concerning multiple sclerosis, and has made it possible to visualize multiple sclerosis plaques in vivo, to follow each plaque over the course of time and in this way to obtain information about the pathogenesis. MRI has shown that the size of plaques may vary considerably, and that plaques are dynamic structures with the ability to change in size over few weeks. By using MRI and the contrast agent Gadolinium-DTPA, it is possible to distinguish a newly developed plaque from an older one. Therefore, MRI has become an important examination in therapeutic trials. Just now, MRI with Gadolinium-DTPA is being used to evaluate the efficacy of plasmapheresis and immunoglobulin treatment in a joint study between Rigshospitalet and Hvidovre Hospital.     

Case report of unusual leukoencephalopathy preceding primary CNS lymphoma

A previously healthy 35 year old woman presented with bilateral uveitis associated with multiple, evolving, non-enhancing white matter lesions consistent with a progressive leukoencephalopathy such as multiple sclerosis. Thirty months after her initial presentation, she was diagnosed with primary CNS lymphoma and died 14 months later. The unusual clinical course preceding the diagnosis suggests that a demyelinating disease may have preceded, and possibly heralded, the development of primary CNS lymphoma. Cases of "sentinel lesions" heralding the diagnosis of primary CNS lymphoma have been reported, and this case further corroborates such instances and raises further issues regarding possible neoplastic transformation occurring in inflammatory diseases such as multiple sclerosis.     

Paroxysmal itching in multiple sclerosis

In three women with multiple sclerosis, paroxysmal attacks of itching occurred. There were several similarities between these attacks and other types of paroxysmal phenomena previously described in multiple sclerosis. The attacks were brief, but usually lasted several minutes, they started and ended abruptly, and recurred several times a day. The were controlled effectively by carbamazepine. It is suggested that paroxysmal itching is caused by transversely spreading ephaptic activation of axons within a partially demyelinated lesion in pain-conducting fibre tracts in the central nervous system.     

Anger expression and incident hypertension

OBJECTIVE: To determine the incidence and prevalence of multiple sclerosis in the Lothian and Border Health Board Regions of south east Scotland. METHODS: Incidence study: all patients were identified in whom a diagnosis of Poser category probable or definite multiple sclerosis was made by a neurologist between 1992 and 1995. Prevalence study: all patients known to have multiple sclerosis who were alive and resident in the study area on 15 March 1995 were recorded. RESULTS: The crude annual incidence rates of probable or definite multiple sclerosis per 100000 population were the highest ever reported: 12.2 (95% confidence interval (95% CI) 10.8-13.7) in the Lothian Region and 10.1 (95% CI 6.6-13.6) in the Border Region. A total of 1613 patients with multiple sclerosis were resident in the study area, giving standardised prevalence rates per 100000 population of 203 (95% CI 192-214) in the Lothian Region and 219 (95% CI 191-251) in the Border Region. Prevalent cases were more likely than expected to have a Scottish surname (risk ratio 1.24, 95% CI 1.14-1.34). CONCLUSION: Orkney and Shetland were previously thought to have by far the highest prevalence of multiple sclerosis in the world: about double that found in England and Wales. However, the prevalence in south east Scotland is equally high, suggesting that the Scottish population as a whole has a genetic susceptibility to the disease, and undermining the hypothesis that patterns of infection specific to small sparsely populated island communities are important in the causation of multiple sclerosis.     

MRI in the study of multiple sclerosis

Magnetic resonance imaging (MRI) has provided considerable insight into the pathological process and disease activity and progression in multiple sclerosis. MRI has become an important tool for the diagnosis of multiple sclerosis, and increasingly for monitoring treatment trial. The growing use of MRI calls for careful consideration in applications so that the technology is not misused. Here we propose a summary of the literature on MRI in application in clinical neurology.     

Determinant spreading associated with demyelination in a nonhuman primate model of multiple sclerosis

Definition of the immune process that causes demyelination in multiple sclerosis is essential to determine the feasibility of Ag-directed immunotherapy. Using the nonhuman primate, Callithrix jacchus jacchus (common marmoset), we show that immunization with myelin basic protein and proteolipid protein determinants results in clinical disease with significant demyelination. Demyelination was associated with spreading to myelin oligodendrocyte glycoprotein (MOG) determinants that generated anti-MOG serum Abs and Ig deposition in central nervous system white matter lesions. These data associate intermolecular "determinant spreading" with clinical autoimmune disease in primates and raise important issues for the pathogenesis and treatment of multiple sclerosis.     

Childhood multiple sclerosis

Multiple sclerosis begins before the age of 17 years in 0.4 to 0.5% of the cases, but the diagnosis is exceptionally made before the age of 10 years. Female predominance is more marked in early onset multiple sclerosis. The general features of the disease (clinical expression, progression, prognostic) and the findings of complementary explorations are comparable with those found when the disease begins in adulthood although acute onset and signs of brain stem involvement have been reported. The diagnosis must be made with prudence, especially when progression is slow from the beginning. An analysis of the influence of infective environmental factors and puberty has not provided new insight. Corticosteroids can be used in case of flare-ups. Management requires a multidisciplinary approach to maintain appropriate educational activities.     

The use of the auditory evoked potential in the diagnosis of multiple sclerosis

Auditory evoked potentials, both early and middle components, were recorded from 227 patients with a variety of conditions including multiple sclerosis, brain stem vascular disease, intracranial tumours and Arnold-Chiari malformation. Abnormalities were found in a substantial proportion of patients with definite multiple sclerosis and a smaller proportion of those in the less definite clinical categories of this condition. There was a high correlation between clinical evidence of brain stem involvement and an abnormal auditory evoked potential in multiple sclerosis. Abnormalities were also found in a few patients presenting with an isolated episode of central nervous system dysfunction involving the brain stem. The auditory evoked potential was abnormal in other patients with known diagnoses including half of those with Arnold-Chiari malformation. Tumours involving the brain stem caused abnormalities of the brain stem evoked potentials in some cases and more frequently distortion of the middle components. The specificity of these auditory evoked potential abnormalities to multiple slcerosis is discussed.