MS Abstracts 6b-2g1

Nitric Oxide generated by the inducible form of Nitric Oxide Synthase (iNOS) may contribute to the PathoGenesis of Multiple Sclerosis (MS).

In this report, we studied postmortem tissues of MS patients for the expression of iNOS by In Situ Hybridization and ImmunoCytoChemistry.

ImmunoCytoChemistry for NitroTyrosine, a putative footprint for Peroxynitrite formation was also performed.

In acute MS lesions, intense reactivity for iNOS mRNA and protein was detected in reactive Astrocytes throughout the lesion and in adjacent Normal-Appearing White Matter.

Staining of Macrophages, inflammatory cell infiltrates, and Endothelial Cells was variable from case to case, but generally detected only in acute lesions.

In chronic MS lesions reactive Astrocytes at the lesion edge were positive for iNOS whereas the lesion center was nonreactive.

Normal-Appearing White Matter demonstrated little reactivity, as did tissues from noninflamed control Brains.

Staining for NitroTyrosine was also detected in acute but not chronic MS lesions, and displayed a diffuse Parenchymal, Membranous, and PeriVascular pattern of ImmunoReactivity.

These results support the conclusion that iNOS is induced in multiple cell types in MS lesions and that Astrocyte-derived Nitric Oxide could be important in orchestrating inflammatory responses in MS, particularly at the Blood-Brain Barrier.

The presentation of Multiple Sclerosis (MS) in childhood has traditionally been thought to be rare.

However, more paediatric cases are now being reported, as a result of progress in diagnostic techniques with the use of sensitive imaging modalities of the Brain and Spinal Cord.

Management from an early age and the availability of new treatment options have changed the outcome of paediatric MS.

Drugs currently available for treatment, such as Interferon-ß, Copolymer-1 and IntraVenous ImmunoGlobulin G, have been found to reduce relapse rate, disease severity and progression to disability in adults, but have not been investigated in children and adolescents.

The overall outcome of MS in children is apparently no worse than in adults and the disease may even be less aggressive in children.

In juvenile MS, disease progression does not appear to be related to age of onset, severity of Neurological involvement or Mono/PolySymptomatic involvement at presentation.

The potential to treat MS has significantly changed the prognosis. Early Diagnose is important, as early treatment can prevent or delay the development of disability.

Ocular adverse effects of Interferon are described during the treatment of malignant diseases and chronic Viral Hepatitis with Interferon-alpha.

At this time, there is no report of these effects during Multiple Sclerosis treatment with IFN-ß-1b. The authors report a bilateral Retinopathy during this treatment.

The production of Neutralizing AntiBodies during Interferon-ß-1b treatment leads to a decreese in diminution of therapeutic efficacy. When treatment failure occurs, Neutralizing AntiBodies are to be tested.

Twenty-five children at the ages of 3 to 18 years with an initial diagnosis of Acute Disseminated EncephaloMyelitis were followed in the Clinic of Child Neurology for a period of 2 to 8 years.

In 10 children, there were data for Clinically Definite or Laboratory-Supported Definite Multiple Sclerosis. The other 15 children in our study were considered as having Suspected Multiple Sclerosis.

Brain Magnetic Resonance Imaging (MRI) performed in 15 children disclosed multiple HyperIntense lesions on T₂-weighted imaging in 13 children: 10 with Definite Multiple Sclerosis and 3 with Suspected Multiple Sclerosis.

The clinical manifestations did not always correspond to the size and location of the MRI lesions of DeMyelination.

Follow-up revealed normalization of the Neurologic Examination in 18 patients (72%) and abnormal neurologic findings in 7 patients (28%) (6 children with definite Multiple Sclerosis and 1 with suspected Multiple Sclerosis).

Magnetic Resonance Imaging follow-up in children with Definite Multiple Sclerosis disclosed:

1. A reduction in the size of the lesions in 3
2. Enlargement or new lesions were established in the other 7 cases
3. 2 cases were without clinical signs of new attacks

Correlation was done concerning the findings of the CerebroSpinal Fluid Examination, Transcranial Magnetic Stimulation, Evoked Potentials, Computed Tomography, and MRI.

The role of MRI for an early diagnosis of Multiple Sclerosis in children is discussed.

The dynamic follow-up of the pathologic changes is of prognostic significance for the course of the disease.

That could be a definite cessation of the process in Acute Disseminated EncephaloMyelitis cases or transition to Multiple Sclerosis.

Although the presence of OligoClonal IgG with abnormal kappa/lambda light-chain ratio in Multiple Sclerosis (MS) has been known for many years, this finding has not been put to diagnostic use in most routine clinical laboratories.

In a retrospective study we report differences in the OligoClonal banding patterns between Multiple Sclerosis and non-MS patients.

We had sufficient CerebroSpinal Fluid (CSF) on 36 from 71 patients with OligoClonal Bands for ImmunoFixation for kappa and lambda light chains, and for free kappa and free lambda.

Thirteen out of 14 patients with clinically confirmed MS had predominantly IgG (kappa) banding.

In contrast, in seven out of eight patients with diagnoses other than MS the Ig G was linked to both kappa and lambda light chains in approximately equal proportions.

Nine out of 14 patients with Probable/Possible/Suspected MS showed predominantly IgG (kappa) banding; five others in this group had both IgG (kappa) and IgG (lambda) and free lambda light chains.

The finding of IgG (kappa) bands in CSF samples with OligoClonal Bands supports a Diagnosis of MS.

We report here a nine-year-old girl with Multiple Sclerosis having consciousness disturbance at admission.

Neurological Examination revealed drowsiness, unstable emotion, decreased Visual Acuity, disturbance of convergence, and clumsy coordination movements.

Her CerebroSpinal Fluid IgG and Myelin Basic Protein were increased. ElectroEnCephalogram showed intermittent, high voltage slow waves predominant in the Frontal Lobes.

Magnetic Resonance Imaging (MRI) found multiple DeMyelinating plaques in the BrainStem, Thalamus, Periventricular White Matter. The BrainStem Reticular Formation was involved.

Since she had had bilateral acute Optic Neuritis and Papillitis two years before the admission, the diagnosis of Multiple Sclerosis was made.

MethylPrednisolone pulse therapy improved her Neurological symptoms and MRI findings.

Multiple Sclerosis in children, unlike that in adults, may present with symptoms mimicking an Encephalopathy.

Our case suggested that consciousness disturbance in childhood Multiple Sclerosis results from lesions in the BrainStem activating Reticular Formation including the Thalamus.

Data, initially anecdotal, but recently supported on more solid experimental evidence, suggest that CannaBinoids might be beneficial in the treatment of some of the symptoms of Multiple Sclerosis (MS).

Despite this evidence, there are no data on the possible changes in CannaBinoid CB(1) or CB(2) receptors.

The main molecular targets for the action of CannaBinoids, either in the postmortem Brain of patients with MS or in animal models of this disease.

The present study addressed this question using the model of Experimental Allergic EncephaloMyelitis (EAE) in Lewis rats generated by inoculation of guinea pig Myelin Basic Protein in Freund's adjuvant.

After inoculation, animals were examined daily to detect the appearance of Neurological signs. The first signs appeared around day 10 after inoculation.

Reaching the highest degree by day 13, when animals were sacrificed and their Brains removed and used for analysis of CB(1) receptor binding, mRNA levels, and activation of GTP-binding proteins.

CB(1) receptor binding and mRNA levels were not affected in EAE rats in Brain areas such as the Hippocampus, Limbic structures, and Cerebellum .

However, there was a marked decrease in both parameters in the Caudate-Putamen, both in the Lateral and Medial parts.

Although this decrease did not correspond with decreases in binding in the Nuclei recipient of Striatal output Neurons, which suggests that changes in CB(1) receptors are exclusively located in the cell bodies of Striatal Neurons.

In addition, CB(1) receptor binding, but not mRNA levels, also decreased in the Cerebral Cortex, both in the deep and the superficial layers.

The analysis of [(35)S]GTPgammaS binding after activation of CB(1) receptors with WIN55,212-2, a synthetic agonist, revealed that, despite the decrease in the number of CB(1) receptors in EAE rats.

These were more efficiently coupled to GTP-binding protein-mediated signaling mechanisms in both the Caudate-Putamen and the Cerebral Cortex of these animals.

In summary, these data suggest that the generation of EAE in Lewis rats would be associated with changes in CB(1) receptors in Striatal and Cortical Neurons.

Which might be related to the alleviation of some motor signs observed after the treatment with CannaBinoid receptor agonists in similar models of MS in rodents.

Copyright 2001 Wiley-Liss, Inc.

Mice infected with Mouse Hepatitis Virus (MHV) strain JHM develop primary DeMyelination.

Herein we show that Axonal damage occurred in areas of DeMyelination and also in adjacent areas devoid of Myelin damage.

ImmunoDeficient MHV-infected RAG1-/- mice (mice defective in recombinase activating Gene 1 expression) do not develop DeMyelination.

Unless they receive Splenocytes from a mouse previously immunized against MHV (G. F. Wu, A. Dandekar, L. Pewe, and S. Perlman, J. Immunol. 165:2278-2286, 2000).

In the present study, we show that adoptive transfer of T-Cells was also required for the majority of the Axonal injury observed in these animals.

Both DeMyelination and Axonal damage were apparent by 7 days PostTransfer.

Recent data suggest that Axonal injury is a major factor in the long-term disability observed in patients with Multiple Sclerosis.

Our data demonstrate that Immune System-mediated damage to Axons is also a common feature in mice with MHV-induced DeMyelination.

Remarkably, there appeared to be a minimal, if any, interval of time between the appearance of DeMyelination and that of Axonal injury.

Patients with signs and symptoms consistent with acute MonoSymptomatic Optic Neuritis should undergo evaluation with Gadolinium-enhanced MRI of the Brain and Orbits.

To determine whether or not they are at high risk for the development of Clinically Definite Multiple Sclerosis (CD/MS).

The presence of two or more White Matter lesions (3 mm or larger in diameter, at least one lesion PeriVentricular or Ovoid) suggests high risk for CD/MS, and should prompt immediate treatment as follows:

Intravenous MethylPrednisolone Sodium Succinate (1 g intravenously per day for 3 days) followed by oral Prednisone (1 mg/kg per day for 11 days) with a 4-day taper (20 mg on day 1, 10 mg on days 2 and 4).

IFN-ß-1a, which has been demonstrated to significantly reduce the 3-year probability of the development of CD/MS and the development of clinically silent MRI lesions.

In high-risk patients with acute Optic Neuritis, should be considered following IV MethylPrednisolone treatment (30 &mgr;g IntraMuscularly weekly).

In MonoSymptomatic patients with fewer than two White Matter lesions by MRI, and in patients for whom a diagnosis of CD/MS has been established, treatment with IV MethylPrednisolone followed by oral Prednisone (as outlined).

Should be considered on an individual basis and may hasten Visual recovery, but has not been demonstrated to affect long-term Visual outcome.

Background
Emotional distress is higher in persons with Multiple Sclerosis (MS) than in other chronic illnesses.

Not known is whether personal attributes of the person with MS and/or the presence of social support will function as mediating and/or moderating variables between emotional distress and adaptation to the illness.

Objectives
Determine if personal attributes and social support function as mediating and/or moderating variables between emotional distress and ADL functioning in persons with MS.

Methods
Secondary analyzes of data obtained from 686 persons with MS through self-report measures of emotional distress, personal attributes, social support, and ADL functioning was conducted.

Separate mediation and moderation models were tested using stepwise and hierarchical multiple regression. Demographic variables of education, age, and length of MS illness, were controlled in all analyzes.

Results
Personal attributes and social support functioned as mediator variables between emotional distress and ADL functioning.

Additionally, personal attributes and not social support functioned as a moderator. Significant main effects were shown for social support and emotional distress in the moderator model.

Conclusion
Personal attributes and social support mediated the effects of emotional distress by decreasing its impact on ADL functioning.

Personal attributes, as a moderator variable, demonstrated that higher levels were associated with low levels of emotional stress and moderate or lower levels of personal attributes were associated with increased emotional distress.

Suggesting that personal attributes may intervene between emotional distress and ADL functioning by attenuating or preventing a stress appraisal response.

Twenty one MS patients suffering from a Relapsing/Remitting (four patients), a Secondary/Progressive (12 patients) or a Primary/Progressive form of the disease (five patients) were assessed using a Cognitive battery specifically devoted to Executive and Memory processes.

Results showed that, patients without significant depressive state evaluated by the MADR scale, exhibited significant impairments in Executive Processes, Working, Episodic and Procedural Memories.

Whereas Short Term Memory, Language and Global Intellectual efficiency were normal. The preliminary data suggest an Impairment of Encoding, a process previously underestimated in this disease.

In addition, the battery was easily administered to the patients and relevant for the Cognitive assessment of MS.