Multiple Sclerosis Bulk Abstracts

Epidemiological studies were performed in South Estonia to establish the prevalence rate of Multiple Sclerosis (MS) and Motor Neuron Disease (MND). The prevalence day was 31 December 1989. MND incidence was established for the period of 1986-1995.

The case finding method included information from the hospital records of the central hospital in the region-the Univ Hospital (for MS from 1942 to 1989), from all Neurologists in the region, from the Estonian MS Society and Association of Muscular Disorders, and from nursing homes in the region.

The results demonstrated high prevalence rates of MS among native Estonians (55.3 per 100 000), somewhat lower prevalence among native-born representatives of other nationalities (43.6 per 100 000) and the lowest prevalence rate of MS among non-Estonian immigrants (26.6 per 100 000).

The differences were not statistically significant. The results for MND demonstrated the opposite pattern.

The mean annual incidence rate of MND for 10 years was statistically significantly higher among people of other nationalities (2.5 per 100 000) and Russians (2.6 per 100 000), and lower in native-born Estonians (1.1 per 100 000).

No differences in health care or clinical picture were established. The reasons for the demonstrated differences in MND incidence remain unclear.

Eur J Neurol 6:187-193 Copyright 1999 Lippincott Williams & Wilkins

In normal subjects, the steady-state ElectroRetinoGram in response to contrast reversing gratings (PERG), is spatially band-pass tuned in amplitude, with a maximum at intermediate spatial frequencies and an attenuation at lower and higher ones.

The amplitude attenuation at low spatial frequencies is believed to reflect center-surround antagonistic interactions in the receptive fields of Inner Retinal Neurons.

The aim of this study was to evaluate the PERG spatial tuning in Multiple Sclerosis (MS) patients without a previous Optic Neuritis history.

Steady- state PERGs in response to counterphase-modulated (8 Hz) sinusoidal gratings of variable spatial frequency (0.6, 1.0, 1.4, 2.2 and 4.8 c/deg), were recorded from 18 patients with definite or probable MS and no history of Optic Neuritis (ON-).

Nine of them had no signs of subclinical Optic Nerve DeMyelination (asymptomatic) in either eye, while nine had symptoms or signs of optic pathways involvement (symptomatic) in one or both eyes.

Results were compared with those obtained from 10 MS patients with a previous history of Optic Neuritis (ON+) in one or both eyes, as well as from 21 age-matched controls. The amplitudes and phases of the responses' 2nd harmonics were measured.

Compared with the controls, asymptomatic ON- patients showed selective losses in mean PERG amplitudes at medium and high (1.0-4.8 c/deg) spatial frequencies.

Symptomatic ON- patients and ON+ patients had reductions in mean PERG amplitudes, with respect to controls, involving the whole spatial frequency range, but with greater losses at medium-high (1.0-4.8 c/deg) than at lower spatial frequencies.

In all patients' groups, the average PERG spatial tuning function differed significantly from that of the controls, assuming a low-pass instead of the normal band-pass shape. The PERG phase was delayed in ON+ but not in ON- patients, as compared to controls.

However, the phase delay was independent of spatial frequency. In both ON- and ON+ patients, losses in PERG amplitude and spatial tuning tended to be associated with corresponding abnormalities in perimetric sensitivity, Visual Acuity, colour vision and transient Visual Evoked Potential (VEP) latency.

The results indicate that abnormalities of the spatial tuning of steady-state PERG can be found in MS patients without either Optic Neuritis or signs of subclinical Optic Nerve DeMyelination.

These changes may reflect a Retinal Dysfunction, developing early in the course of MS, due to a loss of specific subpopulations of Inner Neurons, changes in lateral interactions of their receptive fields, or both.

Eur J Neurol 6:151-162 Copyright 1999 Lippincott Williams & Wilkins

We have established spontaneously formed B-LymphoBlastoid cell lines from long-term cultured peripheral blood MonoNuclear Cells (PBMNCs) from Multiple Sclerosis (MS) patients.

The MS cell lines actively produce RetroVirus-like particles as well as Epstein-Barr Virus (EBV).

Using three different variations of the highly sensitive polymerase chain reaction (PCR)-based assays for the detection of Reverse Transcriptase (RT) activity, we have verified the RetroViral origin of the RetroVirus-like particles that are produced in very low amounts by the MS cell lines.

Spontaneous ReMyelination of previously DeMyelinated Axons is found in a substantial minority of acute and chronic lesions in Multiple Sclerosis.

In the rodent, central ReMyelination restores Saltatory Conduction and helps restore limb function, and it seems likely that endogenous Myelin repair contributes to Neurological recovery in Multiple Sclerosis.

However, the identity of the ReMyelinating cell remains enigmatic. Fully differentiated Oligodendrocytes have very limited capacity for recapitulating their developmental activities and re-engaging Myelination pathways.

Proliferative Oligodendrocyte Progenitors - often known as O-2A cells because of their ability to differentiate in vitro into either Oligodendrocytes or ("type 2") Astrocytes - are, in contrast, extremely efficient at Myelin repair either spontaneously, or after transplantation into the De- or DysMyelinated CNS.

Oligodendrocyte Progenitors are present in both developing and adult rodent CNS. We have previously demonstrated that proliferative Oligodendrocyte Progenitors are present in cultures prepared from the adult human CNS.

Here, using fresh tissue print preparations, we report that cells with processes and the A2B5⁺ ImmunoPhenotype of proliferative Oligodendrocyte Progenitors are present in situ in adult human White Matter.

This technique also reveals the occurrence of A2B5⁺ Astrocytes, a cell also not previously identified in the normal adult human CNS.

In the light of the rodent data showing the importance of Oligodendrocyte Progenitors in Myelin repair, our findings suggesting the presence of Progenitors in the adult human Brain may have significant implications for spontaneous ReMyelination in Multiple Sclerosis and other DeMyelinating conditions.

Brain-Derived NeuroTrophic Factor (BDNF) has potent effects on Neuronal survival and plasticity during development and after injury.

In the Nervous System, Neurons are considered the major cellular source of BDNF. We demonstrate here that in addition, activated human T-Cells, B-Cells, and Monocytes secrete bioactive BDNF in vitro.

Notably, in T helper (Th)1- and Th2-type CD4⁺ T-Cell lines specific for Myelin AutoAntigens such as Myelin Basic Protein or Myelin Oligodendrocyte Glycoprotein, BDNF production is increased upon Antigen stimulation. The BDNF secreted by Immune Cells is bioactive, as it supports Neuronal survival in vitro.

Using anti-BDNF MonoClonal AntiBody and polyclonal antiserum, BDNF Immunoreactivity is demonstrable in inflammatory infiltrates in the Brain of patients with Acute Disseminated Encephalitis and Multiple Sclerosis.

The results raise the possibility that in the Nervous System, inflammatory infiltrates have a neuroprotective effect, which may limit the success of nonselective ImmunoTherapies.

Nitric Oxide (NO) produced in inflammatory lesions may play a major role in the destruction of Oligodendrocytes in Multiple Sclerosis and Experimental Allergic EncephaloMyelitis.

The transformed murine Oligodendroglial line N20.1 is much more resistant than primary Oligodendrocytes to killing by the NO generator S-Nitroso-N-Acetyl-DL-Penicillamine (SNAP).

This observation prompted investigation of the mechanisms leading to Cell Death in the N20.1 cells and comparison of SNAP with another NO donor, Sodium NitroPrusside (SNP).

We observed that N20.1 cells were 30 times more sensitive to SNP than to SNAP. The specific NO scavenger 2-Phenyl-4,4,5,5-TetramethylimIdazoline-1-oxyl-3-Oxide (PTIO) protected against SNP only, not against SNAP.

However, Dithiothreitol protected against both SNAP and SNP, indicating that S-Nitrosylation of Cysteines plays a major role in the cytotoxicity of both NO donors.

We did not observe any formation of Peroxynitrite or increase of Ca²⁺ concentration with either SNAP or SNP, thus excluding their involvement in the mechanisms leading to N20.1 Cell Death.

Based on two observations
1. Potentiation of the cytotoxic effect of SNP when coincubated with FerriCyanide or FerroCyanide, but not Sodium Cyanide
2. Protection by Deferoxamine, an Iron Cyanide Chelator

Finally, SNP but not SNAP induces some Apoptosis, as shown by DNA laddering and protection by a caspase-3 inhibitor.

These results suggest that low levels of NO in combination with increased Iron content lead to Apoptotic Cell Death rather than the Necrotic Cell Death seen with higher levels of NO generated by SNAP.

The analysis of complex sound features is important for the perception of environmental sounds, Speech and Music.

And may be abnormal in disorders such as specific Language Impairment in children, and in common adult lesions including Stroke and Multiple Sclerosis.

This work addresses the problem of how the human Auditory System detects features in complex sound, and uses those features to perceive the Auditory world.

The work has been carried out using two independent means of testing the same hypotheses; detailed psychophysical studies of neurological patients with central lesions, and functional imaging using Positron Emission Tomography and Functional Magnetic Resonance Imaging of normal subjects.

The psychophysical and imaging studies have both examined which Brain areas are concerned with the analysis of Auditory Space, and which are concerned with the Analysis Of Timing information in the Auditory system.

This differs from many previous human Auditory studies, which have concentrated on the analysis of sound frequency.

The combined lesion and functional imaging approach has demonstrated analysis of the spatial property of sound movement within the Right Parietal Lobe.

The timing work has confirmed that the Primary Auditory Cortex is active as a function of The Time Structure Of Sound, and therefore not only concerned with frequency representation of sounds.

Mouse Hepatitis Virus (MHV) A59 infection which causes Acute Encephalitis, Hepatitis, and Chronic DeMyelination, is one of the experimental models for Multiple Sclerosis.

Previous studies showed that lethal infection of ß2-MicroGlobulin 'knockout' (beta2M(-/-)) mice required 500-fold less Virus and Viral clearance was delayed as compared to infection of Immunocompetent C57Bl/6 (B6) mice.

To investigate the mechanism of the increased susceptibility of ß2M(-/-) mice to MHV-A59, we studied organ pathology and the distribution of Viral Antigen and RNA during acute and chronic infection.

A59-infected ß2M(-/-) mice were more susceptible to acute Encephalitis and Hepatitis, but did not have increased susceptibility to DeMyelination.

Viral Antigen and RNA distribution in the Brain was increased in Microglia, Lymphocytes, and small vessel Endothelial Cells while the distribution in Neurons and Glia was similar in ß2M(-/-) mice and B6 mice.

Acute hepatitis and thymus Cortical hypoplasia in ß2M(-/-) mice were delayed in onset but pathologic changes in these organs were similar to those in B6 mice.

The low rate of DeMyelination in ß2M(-/-) mice was consistent with the low dose of the Virus given. A less neurotropic Virus MHV-2, caused increased Parenchymal inflammation in beta2M(-/-) mice, but without DeMyelination.

Thus, CD8⁺ cells were important for Viral clearance from Endothelial Cells, Microglia and inflammatory cells, but not from Neuronal and Glial Cells. In addition, CD8⁺ cells played a role in preventing the spread of Encephalitis.

Therapeutic trials in Multiple Sclerosis, in part because of the marked intra- and inter-individual variability of its clinical course, are prone to serious flaws in both design and interpretation.

As a consequence, it has been a common historical pattern that treatment regimens, which are enthusiastically recommended at one point in time, are later proven to be ineffective by more definitive studies.