Viking voyages: the origin of multiple sclerosis? An essay in medical history.

Multiple sclerosis is most frequently found in Scandinavia, Iceland, the British Isles and the countries settled by their inhabitants and their descendants, i.e. the United States, Canada, Australia and New Zealand. This suggests that the Vikings may have been instrumental in disseminating genetic susceptibility to the disease in those areas, as well as in other parts of the world. The Vikings raided most European countries and settled in Normandy and in Sicily and southern Italy. They engaged in trade with the Arabs along the river routes to the Caucasus, to the Black and Caspian Seas, and penetrated Persia, India and probably China. They also migrated to the East and established the Russian state. Under the name Varangians, they became part of the Byzantine army and were active in all the military activities of the Byzantine Empire. They participated in the Crusades. Russians, many of Scandinavian origin also constituted a regiment of the Mongol army and roamed throughout that Empire as well. The custom of capturing and keeping or selling women and children, which was widespread in the early Middle Ages, as well as the flourishing slave trade in men, were important factors in this genetic dissemination.

Exacerbations, activity, and progression in multiple sclerosis.

The introduction of evoked response studies has disclosed the presence of asymptomatic lesions in multiple sclerosis (MS). This also raises an important question regarding the actual date of onset of the disease and the concept of disease activity. Close study of clinical exacerbations reveals that the recurrences of previously experienced symptoms are considerably more common than the appearance of new ones, and emphasizes the major role of physiologic and psychophysiologic alterations on the clinical course of the disease. The common practice of relating disease process activity to clinical symptoms is questioned in view of the nature of exacerbations and the poor anatomical correlation between demonstrable areas of activity revealed by radionuclide and contrast-enhanced CT scans and the patient's signs and symptoms. Symptomatic progression of MS may be due, in part, to relatively minor and subtle metabolic alterations of the interior millieu affecting the function of a nervous system with increased vulnerability.

Dysmyelination revisited.

Dysmyelination describes an inborn error of metabolism affecting myelinogenesis that causes it to be abnormal, arrested, or delayed. Abiotrophy or myelin as defined by Gowers, due to metabolic failure of the myelin maintenance system, is yet another feature of dysmyelination. In addition to the leukodystrophies, genetically determined conditions such as infantile amaurotic idiocy, hematosidosis, Niemann-Pick's disease and several of the aminoacidopathies are examples of dysmyelinating diseases. In order to reconcile morphological and neurochemical data in these conditions, it is necessary to reexamine a number of pathogenetic hypotheses based on known enzymatic deficiencies, and the interpretation of fragmentary biochemical analyses. The obligatory role of the neuron and axon in myelin formation and maintenance is reviewed. The hypothesis is advanced that gangliosides and their degradative products constitue precursors for the synthesis of the characteristic myelin sphingolipids cerebrosides, sulfatides, and sphingomyelin. Alterations in axoplasmic flow and of ganglioside metabolism must be condidered as important factors in the pathogenesis of dysmyelination.

Syphilitic meningomyelitis. A case report.

A 58-year-old man was admitted with a progressive, subacute asymmetrical paraparesis. The patient denied a previous syphilitic infection, but spinal fluid examination disclosed a lymphocytic pleocytosis, hypoglycorrhachia, and a positive serologic test for syphills. Clinical improvement resulted from a 14-day course of penicillin. Syphilitic involvement of the nervous system appears to be increasing in the United States and should be included in the differential diagnosis of progressive paraparesis.

Recurrent disseminated vasculomyelinopathy.

The monosymptomatic (recurrent infantile hemiplegia) and the polysymptomatic forms of disseminated vasculomyelinopathy that follow various infections and antigenic challenge to the nervous system were seen in two cases. These cases emphasize the importance of vasculopathy as the initial and obligatory component of the postinfectious and postimmunization neurologic syndromes as well as the clinical and pathological variability of the secondary effects on the nervous system. Recurrent infantile hemiplegia occurred in the first patient. In the second patient, after two episodes of postinfectious myelinoclastic encephalopathy, concurrent acute hemorrhagic leukoencephalopathy and an acute Guillain-Barré syndrome following swine flu vaccination developed.

Psychological profiles in patients with multiple sclerosis. A preliminary investigation.

Most psychological and psychiatric studies of patients with multiple sclerosis (MS) have failed to take into account the varying demographic and disease-related factors that may be expected to play a role in patients' adjustment to this disease. We describe the psychological response of patients to MS as a function of age, sex, educational level, disease state, length of disease, physical disability, manual dexterity, and abstract reasoning. Several resulting response patterns are discussed.

Steroid treatment for experimental autoimmune myasthenia gravis.

Short-term, high-dose steroids (prednisolone sodium succinate) were given to female Lewis rats in the chronic stage of experimental autoimmune myasthenia gravis (EAMG). Abnormally low amplitude miniature endplate potentials (MEPPs) persisted, and were even slightly lower than those seen in saline-treated animals with chronic EAMG. The MEPPs were also studied in normal female Lewis rats treated with short-term, high-dose steroids, and no significant change was noted when compared with normal controls. Previous investigators have reported normalization of the abnormally low amplitude MEPPs within 24 hours of high-dose steroid treatment. Our different results might be explained by our higher dose of receptor, addition of pertussis to the inoculum, and study of a different muscle. A survey of endplate ultrastructure revealed some definite postsynaptic membrane abnormalities in both steroid-treated and saline-treated rats with EAMG, but clear distinction among the groups studied was not possible by direct visualization.

Amino acid residues of serum and CSF protein in multiple sclerosis. Clinical application of statistical discriminant analysis.

Statistical discriminant analysis of the amino acid compostion of serum and cerebrospinal fluid (CSF) proteins provides an objective method for distinguishing between normal controls and patients with multiple sclerosis (MS). This method also results in a high degree of specificity in separating MS patients from those with other diseases of the nervous system. The CSF protein serine residue is highly correlated with the CSF IgG and holds promise for a more sensitive diagnostic test for MS than the currently used CSF IgG. Finally, the serum/CSF protein serine ratio seems to correlate best with clinically determined degree of activity for the disease, the most active cases having the lowest ratio. These results suggest that investigation of the amino acid composition of serum and CSF protein in multiple sclerosis and, possibly, in other diseases might lead to the development of clinically useful tests of diagnosis and degree of activity of MS.

Cognitive function in patients with multiple sclerosis.

The performance of patients with multiple sclerosis on selected psychological tests was examined to ascertain the usefulness of such examinations to diagnosis. Cognitive impairment was studied in relationship to disease-related factors, physician's identification of cerebral involvement, and psychological adjustment. The results indicate that half the subjects exhibited cognitive impairment. Levels of neurologic involvement, physical impairment, and depression were not predictive of cognitive impairment. Of the subjects who were judged on neurological examination to have intact mentation, half were actually impaired. Impaired cognitive functioning, which is often not detected through routine examination, may occur early in the disease. These deficits may represent manifestations of otherwise undetectable plaques in the subcortical white matter.

Multiple sclerosis or HTLV-I myelitis?

Several authors have demonstrated the presence of antibodies against the HTLV-I retrovirus in patients with MS. Considerable controversy exists regarding the etiologic significance, if any, of this finding, but the presence of these antibodies in the blood or CSF of MS patients has led to reconsideration of that diagnosis in certain cases. It is recommended that, before the diagnosis of MS is changed to that of HTLV-I-associated chronic myelitis, at least 2 of the following abnormalities be present: (1) clinical or electrophysiologic involvement of peripheral nerve or muscle; (2) the presence of oligoclonal bands in the serum; (3) the presence in blood or CSF of lymphocytes with multilobed nuclei; (4) a positive serologic test for syphilis; (5) the presence of a sicca syndrome; and (6) the presence of pulmonary lymphocytic alveolitis.

Recurrent optic neuromyelitis with endocrinopathies: a new syndrome.

We report a new syndrome that we call "recurrent optic neuromyelitis with endocrinopathies" in eight Antillean women from Martinique and Guadeloupe Ocular involvement was either monocular or binocular, whereas myelopathy was acute or subacute. In seven patients, myelopathic symptoms recurred, and in six patients, visual problems recurred. Spinal cord involvement was a consistent band-like pseudo-syringomyelic dissociated sensory loss. All eight patients had endocrinopathies consisting of amenorrhea, galactorrhea, diabetes insipidus, hypothyroidism, or hyperphagia. Spinal cord MRI revealed cavitation-like images. Various immunosuppressant treatments had little effect on the uniformly deteriorating course, ending in blindness and paraplegia. Six patients died within 5 years of onset, and an autopsy in one patient showed multiple demyelinizing lesions of the spinal cord with thickened blood vessels walls without evidence of inflammation. These cases appear to constitute a syndrome distinct from MS and from classic Devic's syndrome, not only because of the association with endocrinopathies but because of the stereotypy of the recurrences, the absence of MRI lesions in the cerebral white matter, and the unusual image of cavitation of the spinal cord. The syndrome is also distinct from HTLV-I-associated paraparesis, which is endemic in the West Indies.

Late onset of Guillain-Barré syndrome.

The Guillain-Barré syndrome (GBS) usually occurs within one month of the precipitating cause. It is the purpose of this paper to show that typical cases may, however, appear weeks to months later. We have reviewed the collected data on these cases and suggest that they provide evidence which is in favour of a humoral, rather than a cell-mediated, aetiology for GBS.

Schilder's myelinoclastic diffuse sclerosis.

The term "Schilder's disease" has been used to describe conditions as disparate as adrenoleukodystrophy, myelinoclastic diffuse sclerosis, and postinfectious and postvaccinal encephalomyelitis. The eponymic designation should be reserved for instances of myelinoclastic diffuse sclerosis that correspond to the case described by Schilder in 1912. The diagnosis cannot be made unless adrenoleukodystrophy has been ruled out by analysis of the long-chain fatty acids of plasma cholesterol esters. Schilder's myelinoclastic diffuse sclerosis, a variant of multiple sclerosis, is a very rare disease that occurs in children and adults of both sexes and appears to respond to vigorous treatment with corticosteroids and/or corticotropin. A case of this disease is reported and the recent literature of cases that have been called Schilder's disease is reviewed.

Diagnostic techniques in multiple sclerosis.

Although multiple sclerosis (MS) has been an area of great interest and effort in numerous scientific disciplines, its etiology, pathogenesis and therapy remain mysterious. Perhaps the most significant advances have resulted from the ability to be more precise in establishing the diagnosis of MS. Among the most important of the new diagnostic tools are electrophysiological techniques for examination of the visual and oculomotor systems. Tests such as the visually evoked potential (VEP) can confirm the existence of clinically suspected lesions and document the presence of asymptomatic ones. Various electrophysiological techniques for detection and evaluation of MS, as well as CSF analysis, psychological and neuroradiological procedures, and immunological observations are described. The relationship between optic neuritis and MS is reviewed, as are therapeutic regimens in use and under study.

Trauma and multiple sclerosis. An hypothesis.

An obligatory event in the pathogenesis of the multiple sclerosis plaque appears to be an increase in the permeability of the blood-brain barrier. Neuropathological observations of the brain of persons suffering from concussion after relatively minor head injury, as well as of animals subjected to experimental brain injury, have shown that alterations of the blood-brain barrier constitute a common result of such trauma. It is postulated that the alterations of the blood-brain barrier secondary to trauma of the brain or spinal cord of patients with already established multiple sclerosis may result in an exacerbation or recurrence of a previously symptomatic plaque, in the appearance of symptoms from a silent lesion, or in the formation of a new plaque in such an area of selected vulnerability. In other persons injury to the nervous system may cause the development of multiple sclerosis plaques in the previously damaged areas when the disease has its onset after the trauma. There is no evidence to support the idea that trauma ever causes multiple sclerosis.

Neuroimaging and the lesion of multiple sclerosis.

In a patient with long-standing multiple sclerosis (MS), a double-dose delayed contrast-enhanced CT scan obtained during exacerbation revealed many areas of enhancement. Vigorous treatment with corticotropic hormone was followed by almost complete disappearance of these abnormalities. No areas of low attenuation were seen on a later unenhanced CT scan. Finally, MR imaging showed only a single area compatible with a plaque of MS. It is suggested that pathologic alteration of the blood-brain barrier seen in MS is not necessarily followed by demyelination and plaque formation. Restoration of the integrity of the blood-brain barrier may thus possibly prevent the formation of plaques in some MS patients, in particular if this can be accomplished early in the course of the exacerbation.

Magnetic resonance imaging in asymptomatic disseminated vasculomyelinopathy.

Two cases of disseminated vasculomyelinopathy (one of acute disseminated encephalomyelitis (ADEM), the other of acute transverse myelitis), are reported because of the persistence, 3 years and 5 months respectively, of abnormalities of magnetic resonance imaging (MRI). These abnormalities remained although in the first case the disease had been essentially asymptomatic from the onset except for one seizure, the patient remaining neurologically intact, whereas in the second case, the patient had made a complete recovery from very serious neurologic dysfunction. The first case illustrates the fact that ADEM may rarely occur without any symptoms, even in the presence of severe imaging abnormalities in both CT and MRI. Neither the persistence of a blood-brain barrier permeability alteration nor gliosis can satisfactorily explain the MRI changes, and thus the pathological significance of areas of increased signal intensity in MRI remains poorly understood and a matter of uncertainty. This report emphasizes the futility of attempting to correlate any kind of clinical observation, laboratory parameter, or effect of therapeutic regimens with changes, or lack thereof, in the MRI in multiple sclerosis and disseminated vasculomyelinopathy.

Notes on the pathogenesis of subacute sclerosing panencephalitis.

In the original description by van Bogaert and De Busscher of subacute sclerosing leukoencephalitis (SSLE), great emphasis was placed upon the involvement of the white matter, a feature that, in addition to the absence of inclusion bodies, differentiated it from subacute inclusion body encephalitis (SIBE) of Dawson. Subsequently, the common features, primarily clinical, electroencephalographic and immunological led to the consolidation of both into the entity known as subacute sclerosing panencephalitis (SSPE). The white matter lesions of SSLE are identical to those that are seen in progressive rubella encephalitis, subacute AIDS encephalomyelitis, tropical spinal paraparesis due to HTLV-1, and visna of Icelandic sheep, but, more importantly, are characterized by the perivascular edema, inflammation and demyelination known in acute, immune-mediated post-infectious and post-vaccinal acute disseminated encephalomyelitis (ADEM). Furthermore, in SSLE and in the other conditions resulting from a persistent viral infection, deposits of immune complexes can be demonstrated in the walls of small cerebral blood vessels. There is therefore strong evidence to suggest that in SSLE as well as in the other persistent viral infections, in addition to the actual invasion by the virus, there is a contemporaneous immune-mediated response to this virus which is responsible for most, perhaps even all of the disseminated, extensive demyelination observed in these conditions. It is also suggested that SSLE and SIBE, sharing a common etiology, may represent two different phenotypic expressions of the same process.(ABSTRACT TRUNCATED AT 250 WORDS)

The pathogenesis of multiple sclerosis. Additional considerations.

Multiple sclerosis (MS) is acquired as a systemic "trait" by individuals who are genetically susceptible. This condition does not involve the central nervous system (CNS) and is characterized by a state of hyperactive immunocompetent responsiveness. It develops as the result of an antigenic challenge by a viral protein, either from a viral infection or a vaccination. In order for MS to become a disease affecting the CNS, it is necessary for the blood-brain barrier's (BBB) impermeability to be altered. This is now a fully recognized fact. As a result of this change, the MS lesion, which consists of edema and inflammation occurs. It may but need not lead to demyelination. Several mechanisms can cause this increased permeability of the BBB. The role of the immune system, and in particular of T lymphocytes in initiating and continuing the process of lesion formation remains extremely controversial. In fact, there are unanswered questions regarding the actual target of MS: is it the myelin sheath itself or its forming cell, the oligodendrocyte, or is it the BBB itself leading to bystander demyelination? The role of mild, concussional trauma to the CNS in producing the alteration of the BBB and therefore acting as a trigger or facilitator in the development or enlargement of MS lesions in the CNS, is based on considerable clinical, neuropathological and experimental evidence. Along with another viral infection, it must be one of the commonest causes of progression of MS, and quite often leads to the onset of the clinical manifestations of an hitherto asymptomatic condition.

Multiple sclerosis. Observations and reflections--a personal memoir.

The pathogenesis of MS has become better understood as a result of recent advances in several areas, particularly in epidemiology and neuro-imaging. A number of epidemiologically based conclusions need to be revised, most importantly the putative direct relationship between prevalence and latitude, and the concept that epidemics of MS have occurred in some parts of the world. It is now clear that genetic factors play a much more important role in the genesis of the disease than environmental factors, although the latter cannot be ignored. The existence of a genetic susceptibility, coupled with either protective or enhancing factors, which may be genetic or environmental, is recognized as being most important in individuals of northern European origin. Much evidence suggests that the disease is initiated by a viral illness (or possibly a vaccination) at some time before puberty. This first antigenic challenge results in the development of what is called the "MS trait", a systemic condition that may never develop into the actual disease and may be observed as well in the unaffected siblings of MS patients. The trait is almost certainly a manifestation of an alteration of the immune system; its most important effect is to render the blood-brain barrier more vulnerable to a variety of agents that will increase its permeability. In order for MS to involve the central nervous system, loss of integrity of the blood-brain barrier is an obligatory step, an observation which has now been amply confirmed by neuroimaging studies. This effect upon the blood-brain barrier appears to be non-specific, since it may result from such diverse causes as a viral infection, a vaccination, or mild trauma. Edema and inflammation follow, but myelinoclasia is not always a consequence; thus plaque formation may not occur and the initial lesion of MS may disappear without leaving a trace. The actual mechanism of myelinoclasia, and the role played in it by lymphocytes, remain unknown. Although the disease does affect the central nervous system, it may remain asymptomatic for a long time after the actual plaque is formed, even for the person's entire life.