Remyelination in demyelinating disease

In multiple sclerosis, partial remyelination is conspicuous in many lesions, and is thought to contribute significantly to lasting recovery from acute relapse. However, myelin repair ultimately fails during progression of the disease, as disability and handicap accumulate. In this chapter we explore the biological background to myelin repair in CNS demyelinating disease, and the reasons underlying the failure of more widespread and lasting remyelination in multiple sclerosis. Experimental studies provide clear evidence that therapies promoting myelin repair can be highly successful in the CNS, and we discuss the clinical approaches which might allow the translation of these laboratory studies to neurological practice, together with some of the potential hazards and pitfalls likely to arise.     

The spectrum of chronic inflammatory demyelinating polyneuropathy

Research criteria for the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) were proposed by an Ad Hoc Subcommittee of the American Academy of Neurology (AAN) in 1991, and since then these criteria have been widely used in clinical studies. We have been impressed by the frequent finding of electrophysiological changes of a demyelinating neuropathy in patients whose clinical presentation does not conform to the usually accepted clinical phenotype of CIDP. To determine the clinical spectrum of CIDP, we conducted a retrospective review of patients of the peripheral electrophysiology laboratory of the University of Miami-Jackson Memorial Medical Center. Diagnostic criteria for acquired demyelination of an individual nerve were adapted from the AAN research criteria for the diagnosis of CIDP (1991). Patients were accepted for inclusion when such evidence was demonstrated in at least one motor nerve or at least two sensory nerves. We then reviewed the clinical phenotype and the underlying etiology of the neuropathy in these cases. Eighty-seven patients, 63 male and 24 female, age of onset 4-84 (mean 49.3) years, met these inclusion criteria. Forty-seven patients (54%) had distinct features outside the usual clinical presentation of CIDP. Of these, 15 (17%) had predominantly distal features, 13 (15%) had exclusively sensory polyneuropathy; seven (8%) had markedly asymmetric disease, seven (8%) had associated CNS demyelination, four (5%) had predominant cranial nerve involvement, and one (1%) had only the restless legs syndrome. An associated medical condition that may have been responsible for the acquired demyelinating neuropathy was present in 60% of the patients. We conclude that spectrum of CIDP is broader than would be indicated by the strict application of the AAN research criteria, and that many of the cases meeting more liberal criteria frequently respond to immunosuppressive therapy.     

Atypical demyelinating disease

A 17 year old girl died after an illness characterized by progressive mental deterioration and severe myoclonic jerks. Extensive pathological, virological, and immunological studies failed to support the diagnosis of subacute sclerosing panencephalitis but were compatible with disseminated demyelinating disease. The spinal fluid was positive for measles virus antibodies when examined by the fluorescent antibody technique, by complement fixation, and by haemagglutination inhibition tests, but the antibody titres were not high. The concentration of vaccinia antibody in the serum was consistent with that found in the general population and none was detected in the spinal fluid. Animal and tissue culture studies failed to disclose a viral agent, but pathological sections revealed perivascular cellular infiltration, demyelination, rare inclusion bodies, and multinucleated giant cells. Although these studies were not definitive, a record of procedures used and results obtained, both positive and negative, may be helpful to other investigators interested in defining more accurately the clinical features and the pathogenesis of these diseases.     

Clinical spectrum of chronic acquired demyelinating polyneuropathies

A number of presentations of chronic demyelinating polyneuropathy have been identified, each distinguished by its phenotypic pattern. In addition to classic chronic inflammatory demyelinating polyneuropathy (CIDP), which is characterized clinically by symmetric proximal and distal weakness and sensory loss, several regional variants can be recognized: multifocal motor neuropathy (MMN: asymmetric and pure motor), multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy (asymmetric, sensory, and motor), and distal acquired demyelinating symmetric (DADS) neuropathy (symmetric, distal, sensory, and motor). There are also temporal, pathological, and disease-associated variants. This review describes a clinical scheme for approaching the chronic acquired demyelinating polyneuropathies that leads to a rational use of supportive laboratory studies and treatment options. In addition, we propose new diagnostic criteria for CIDP that more accurately reflect current clinical practice.     

Incidence and outcome of cerebrovascular disease in Perth, Western Australia

We estimated the event rates for stroke and transient cerebral ischemic attacks in a prospective community-based epidemiologic study in a representative segment of the city of Perth, Western Australia, during a 10-month period in 1986. Of 349 persons with an initial diagnosis of stroke or transient ischemic attack, 154 had suffered a first stroke, 75 a recurrent stroke, and 47 a transient ischemic attack; the remaining 73 persons were thought not to have had an episode of acute cerebrovascular disease. Annual event rates for first stroke (age-standardized to the "world" population) were 120 per 100,000 for males and 56 per 100,000 for females. The crude case-fatality ratio at 28 days after the index event for first stroke was 23% and varied from 0% for lacunar infarction to 57% for subarachnoid hemorrhage.     

Computerized tomography in demyelinating disease of the young

We have used computerized tomography (CT) to look for evidence of cerebral demyelination in children with progressive neurologic disorders. Fourteen patients with a clinical diagnosis of a demyelinating disorder were examined by CT, and five had CT findings suggesting cerebral demyelination. In two patients with a so-called myelinoclastic demyelinating disease, CT showed asymmetric, circumscribed areas of diminished radiodensity, and in three patients with a leukodystrophy, scans showed diffuse symmetric areas of low density in the centrum ovale. Autopsy examination in one patient confirmed the diagnosis of sudanophilic leukodystrophy and substantiated the abnormalities suspected from CT.     

Recurrent monofocal demyelinating disease

We describe a patient with recurrent brainstem symptoms and migraine-like headache. Magnetic resonance imaging (MRI) showed a symptomatic hyperintense T2-weighted lesion in the middle cerebellar peduncle and the trigeminal nuclei and an asymptomatic periventricular lesion of Dawson finger shape. The findings were suspicious for a first demyelinating event, possibly representing the first manifestation of multiple sclerosis (MS). Nevertheless, this case report also illustrates several pitfalls in the differential diagnosis of MS.     

Alpha-1 antitrypsin phenotypes in demyelinating disease: an association between demyelinating disease and the allele PiM3

Alpha-1 Antitrypsin, the major circulating protease inhibitor, has more than thirty alleles that can be identified by electrophoresis. In addition to its role as a protease inhibitor, alpha-1 antitrypsin may regulate the immune response. As there is evidence that both the inflammatory polyneuropathies and multiple sclerosis have an immune basis, and that genetic factors influence susceptibility, we have determined the alpha-1 antitrypsin phenotypes (protease inhibitor types) of 63 patients with Guillain-Barré syndrome, 52 patients with chronic inflammatory demyelinating polyneuropathy, and 178 patients with multiple sclerosis. In all 3 groups there was a significant increase in the proportion of patients with the protease inhibitor type M3 allele.     

Destructive lesions in demyelinating disease.

Three cases are presented in which clinical and radiological features suggested the diagnosis of glioma but surgical biopsy revealed a demyelinating process, with tissue destruction and cyst formation in two. One patient had clinically definite multiple sclerosis. Two had probable acute disseminated encephalomyelitis. Treatment with high dose steroids is appropriate when there is clinical or investigative evidence to suggest the presence of demyelinating disease, before deciding on biopsy.     

Cerebrospinal fluid lipids in demyelinating disease

Summary The lipid composition of CSF, serum and lymphocytes from patients without demyelinating disease (controls) as well as from patients with acute and chronic MS is analyzed. Individual lipid fractions are isolated by TLC and their fatty acid composition determined. Lipid and fatty acid composition of normal CSF resembles the results found in lymphocytes and it is deduced that CSF lipids are derived mainly from lymphocytes rather than white matter (myelin) or serum.There is an increase of CSF sphingomyelin in patients with acute MS (showing pleocytosis) which is apparently derived from disintegrated lymphocytes; there is also an increase of linoleic acid concentration which could come from serum because of dysfunction of the blood-brain barrier. The role of the CNS in contributing to CSF lipids is considered negligible both in controls and in patients with demyelination.

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Zusammenfassung Gegenstand der Untersuchungen war die Lipidzusammensetzung des Liquors, des Serums und der Lymphocyten von Patienten ohne Entmarkungskrankheiten (Kontrollen) und MS-Patienten im akuten Schub, im schubfreien Intervall und mit vorwiegend chronischem Verlauf. Die einzelnen Lipidklassen wurden dünnschichtchromatographisch getrennt und ihre Fettsäurezusammensetzung gaschromatographisch bestimmt.Hierbei zeigte der Vergleich bei den Normalliquores eine große Ähnlichkeit im Lipidprofil der Cerebrospinalflüssigkeit und der Lymphocyten, die darauf schließen läßt, daß ein großer Anteil der Liquorlipide, vor allem die Sphingolipide, aus devitalisierten Liquorzellen stammen, weniger aus dem Serum oder gar dem Zentralnervensystem.Patienten im akuten Schub einer MS (mit leichter Zellzahlerhöhung im Liquor) zeigen daher auch eine mäßige Sphingomyelinerhöhung im Liquor mit einer Fettsäurezusammensetzung, die eindeutig ihre Herkunft aus Lymphocyten ausweist. Als Ausdruck der Schrankenstörung findet sich darüber hinaus im Liquor auch in der Mehrzahl ein deutlicher Anstieg der aus dem Serum stammenden Linolsäure.Gegenüber früheren Vermutungen scheint demnach der Anteil von etwa aus dem Nervensystem stammenden Liquorlipiden auch bei MS-Patienten im akuten Schub allenfalls sehr gering zu sein.

     

Neuroimaging in infections and demyelinating disease

Computerized tomography and magnetic resonance imaging continue to illuminate the changes that occur in the central nervous system in infections and demyelinating disease. Imaging in the acquired immune deficiency syndrome helps to better understand neurological complications. Magnetic resonance imaging also helps to be specific about the diagnosis of cryptococcal meningitis and toxoplasmosis. Major contributions have been made to the understanding of the diagnosis and the living pathology of multiple sclerosis. Experimental studies have identified the mechanism of blood-brain barrier disruption in inflammatory disease.     

Dissecting the multifactorial nature of demyelinating disease

Chondroitin sulfate proteoglycan-4(CSPG4) is a surface component of two key cell types(oligodendrocyte progenitor cells(OPCs) and myeloid cells) present in lysolecithin-induced lesions in mouse spinal cord.Two types of CSPG4 manipulations have been used to study the roles of these cells in myelin damage and repair:(1) OPC and myeloid-specific ablation of CSPG4,and(2) transplantation of enhanced green fluorescent protein(EGFP)-labeled progenitors to distinguish between bone marrow-derived macrophages and resident microglia.Ablation of CSPG4 in OPCs does not affect myelin damage,but decreases myelin repair,due to reduced proliferation of CSPG4-null OPCs that diminishes generation of mature oligodendrocytes for remyelination.Ablation of CSPG4 in myeloid cells greatly decreases recruitment of macrophages to spinal cord lesions,resulting in smaller initial lesions,but also in significantly diminished myelin repair.In the absence of macrophage recruitment,OPC proliferation is greatly impaired,again leading to decreased generation of myelinating oligodendrocytes.Macrophages may promote OPC proliferation via phagocytosis of myelin debris and/or secretion of factors that stimulate OPC mitosis.Microglia are not able to substitute for macrophages in promoting OPC proliferation.An additional feature of lesions in myeloid-specific CSPG4 null mice is the persistence of poorly-differentiated platelet-derived growth factor receptor α(PDGFRα) + macrophages that may prolong damage.     

Periaxin mutations cause a broad spectrum of demyelinating neuropathies

Previous studies have demonstrated that apparent loss-of-function mutations in the periaxin gene cause autosomal recessive Dejerine-Sottas neuropathy or severe demyelinating Charcot-Marie-Tooth disease. In this report, we extend the associated phenotypes with the identification of two additional families with novel periaxin gene mutations (C715X and R82fsX96) and provide detailed neuropathology. Each patient had marked sensory involvement; two siblings with a homozygous C715X mutation had much worse sensory impairment than motor impairment. Despite early disease onset, these siblings with the C715X mutation had relatively slow disease progression and adult motor impairment typical of classic demyelinating Charcot-Marie-Tooth neuropathy. In contrast, a patient with the homozygous R82fsX96 mutation had a disease course consistent with Dejerine-Sottas neuropathy. The neuropathology of patients in both families was remarkable for demyelination, onion bulb and occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate-like junctions between the terminal loops and axon. Our study indicates a prominent sensory neuropathy resulting from periaxin gene mutations and suggests a role for the carboxyl terminal domain of the periaxin protein.     

Optimizing the management of neuromyelitis optica and spectrum disorders in resource poor settings: Experience from the Mangalore demyelinating disease registry

Background:

In resource-poor settings, the management of neuromyelitis optica (NMO) and NMO spectrum (NMOS) disorders is limited because of delayed diagnosis and financial constraints.

Aim:

To device a cost-effective strategy for the management of NMO and related disorders in India.

Materials and Methods:

A cost-effective and disease-specific protocol was used for evaluating the course and treatment outcome of 70 consecutive patients.

Results:

Forty-five patients (65%) had a relapse from the onset and included NMO (n = 20), recurrent transverse myelitis (RTM; n = 10), and recurrent optic neuritis (ROPN; n = 15). In 38 (84.4%) patients presenting after multiple attacks, the diagnosis was made clinically. Only 7 patients with a relapsing course were seen at the onset and included ROPN (n = 5), NMO (n = 1), and RTM (n = 1). They had a second attack after a median interval of 1 ± 0.9 years, which was captured through our dedicated review process. Twenty-five patients had isolated longitudinally extensive transverse myelitis (LETM), of which 20 (80%) remained ambulant at follow-up of 3 ± 1.9 years. Twelve patients (17%) with median expanded disability status scale (EDSS) of 8.5 at entry had a fatal outcome. Serum NMO-IgG testing was done in selected patients, and it was positive in 7 of 18 patients (39%). Irrespective of the NMO-IgG status, the treatment compliant patients (44.4%) showed significant improvement in EDSS (P ≤ 0.001).

Conclusions:

Early clinical diagnosis and treatment compliance were important for good outcome. Isolated LETM was most likely a post-infectious demyelinating disorder in our set-up. NMO and NMOS disorders contributed to 14.9% (45/303) of all demyelinating disorders in our registry.Key Words: Demyelinating disease registry, immunosuppression, India, neuromyelitis optica, neuromyleitis optica spectrum disorders     

Researching psychiatry in Western Australia

OBJECTIVE: To provide an overview of the development, approaches and main research projects of the Centre for Clinical Research in Neuropsychiatry (CCRN) in Perth, Western Australia. METHOD: Discursive. RESULTS: Underlying concepts, methods and selected findings of recent research into the neurobiology and epidemiology of schizophrenia, autism and other psychotic disorders are presented. CONCLUSION: CCRN, one of Australia's youngest centres of psychiatric research, has invested fruitfully in research areas such as molecular genetics, neuropsychology, neurophysiology, behavioural pharmacology, diagnostic assessment procedures and record linkage epidemiology.     

Human demyelinating disease and the polyomavirus JCV

Many human neurological diseases involve demyelination of the central and/or peripheral nervous systems. These include the hereditary leukodystrophies--which have a genetic basis; multiple sclerosis (MS)--where the underlying cause of demyelination remains unknown; and progressive multifocal leukoencephalopathy (PML)--where the etiology is well-established as being viral. The human neurotropic polyomavirus--JC virus (JCV)--is the etiologic agent of PML, a fatal demyelinating disease of the central nervous system that occurs mainly in immunosuppressed patients, especially those with HIV/AIDS. JCV belongs to the polyomavirus family of tumor viruses that are characterized by non-enveloped icosahedral capsids containing small, circular, double-stranded DNA genomes. Serological studies have shown that JCV is widespread throughout the human population, but infections are usually restricted by the immune system, particularly cell-mediated immunity, causing the virus to enter a latent phase. An important corollary of this is that situations of severe immunosuppression may permit JCV to replicate and are thus a risk factor for PML.     

Autosomal-recessive forms of demyelinating Charcot-Marie-Tooth disease

Autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT) account for less than 10% of the families in the European CMT population but are more frequent in the Mediterranean basin and the Middle East because of more widespread consanguinity. Until now, demyelinating ARCMT was more extensively studied at the genetic level than the axonal form. Since 1999, the number of localized or identified genes responsible for demyelinating ARCMT has greatly increased. Eight genes, EGR2, GDAP1, KIAA1985, MTMR2, MTMR13, NDRG1, PRX, and CTDP1, have been identified and two new loci mapped to chromosomes 10q23 and 12p11-q13. In this review, we will focus on the particular clinical and/or neuropathological features of the phenotype caused by mutations in each of these genes, which might guide molecular diagnosis.