Multiple Sclerosis Abstracts 7a-2g

Background And Purpose
Magnetization Transfer (MT) imaging and measurements of the Magnetization Transfer Ratio (MTR) have extended our capability to depict and characterize pathologic changes associated with Multiple Sclerosis (MS).

We wanted to investigate whether the analysis of other MT parameters, such as Magnetization Transfer Rate, (k-for), and relative measure of water content (T₁ (free)), adds insight into MS-related tissue changes.

Methods
Quantitative MT imaging by use of phase acquisition of composite echoes was performed in nine patients with Clinically Definite Relapsing/Remitting MS and eight healthy control subjects on a 1.5-T MR system.

We analyzed a total of 360 regions of interest and compared control White Matter with various types of lesions and Normal-Appearing White Matter in MS.

Results
We found a strong correlation between the MTR and k-for, but this relation was non-linear.

A slight but significant reduction of the MTR in Normal-Appearing White Matter of patients with MS was attributable to a reduced transfer rate only.

Whereas, a lower MTR was associated with both a reduction of k-for and an increase of T₁ (free) in regions of dirty White Matter.

Moreover, areas such as Edema and T₁-IsoIntense lesions had a similar MTR but could be differentiated on the basis of T₁(free).

Conclusion
Estimates of k-for and T₁ (free) appear to complement MTR measurements for the understanding of MT changes that occur with different types of MS abnormalities in the Brain.

Macrophage inflammatory products including Tumor Necrosis Factor (TNF) and InterLeukin-12/p40 are implicated in DeMyelinating Diseases such as Multiple Sclerosis (MS), Guillain-Barre Syndrome, and animal models Experimental AutoImmune EncephaloMyelitis and Neuritis.

The Macrophage product Angiotensin Converting Enzyme (ACE) is released during Inflammation. ACE can also be elevated in MS.

We investigated the ability of central (CNS) and Peripheral Nervous System (PNS) Myelin to stimulate TNF, InterLeukin-12, and ACE production by murine Macrophages.

Both CNS and PNS Myelin and purified Myelin Basic Protein and P2 protein induced release of these products.

Direct stimulation by Myelin may represent a mechanism of inducing release of Macrophage products in inflammatory DeMyelination or Neural injury.

Emotional disturbances are common in MS and consist of disturbances of Mood and disturbances of Affect.

The important Mood Disorders are Major Depressive Disorder, Dysthymic Disorder, Bipolar Disorder, Panic Disorder, and Generalized Anxiety Disorder.

Their relationship to MS is multi-factorial and complex, and the extent to which they are direct consequences of the disease process or psychological reactions to it remains unclear.

Whatever their cause, however, the symptoms of Mood Disorders in people with MS are no different from the symptoms of Mood Disorders in people without MS, and respond just as well to standard treatments.

The disorders of affect are Euphoria, Pathological Laughing and Weeping, and other Frontal Lobe Syndromes.

These disorders result from DeMyelination, are some of the most characteristic symptoms of MS, and have the same implications for treatment as do other aspects of the disease.

Mood and Affective Disturbances can cause enormous pain and suffering and lead to significant disruption of family, work, and social life.

Physicians who can identify, diagnose, treat, and manage Mood and Affective Disturbances effectively and who can help their patients and family members acknowledge these difficulties, talk about them, and accept Psychiatric consultation and treatment can have a dramatic impact on the quality of their lives.

This paper outlines the symptoms and diagnostic criteria for Mood Disorders and Affective Disturbances, reviews current treatment options, summarizes data from Epidemiologic and PathoPhysiological Studies, and suggests areas for future research.

One of the most frequent disorders of the BrainStem in Multiple Sclerosis (MS) is InterNuclear Opthalmoplegia (INO).

The aim of this study is to show how it is possible to monitor the course of MS grading INO on the basis of Electro-Oculographic findings.

We selected 130 patients with a diagnosis of Clinically Defined Multiple Sclerosis (78 males and 52 females, mean age 43.5 years) from a population of 354 MS patients.

Both Saccadic Eye movements and spontaneous, Vestibular (VOR), Visuo-Vestibular (VVOR) and Optokinetich Nystagmus (OKN) were assessed.

Slowing of the adducting Eye was considered as a sign of lesion of the InterOcular Pathways.

Statistical analyzes showed that the most sensitive test was VVOR, the least sensitive being randomized Saccades. An impairment of random Saccades was always associated with abnormal results on all other tests.

It seems thus possible to grade the involvement of the Medial Longitudinal Fasciculi (MLF) in MS from an abnormality limited to the VVOR test up to an impairment of randomized Saccadic movements.

Grading BrainStem involvement in MS is particularly important in therapeutic trials and during rehabilitation.

The frequency of Multiple Sclerosis (MS) with clinical onset before 16 years of age in different regions of Russia fluctuates from 2 to 10% of all MS patients. One of the most frequent signs of MS manifestation and/or exacerbation at this age is Optic Neuritis (ON).

Forty-seven children with MS were observed in Moscow. Diagnosis of MS in every case was clinically definite and proved by serial MRI.

Clinico-tomographic dissociation was noticed: numerous large lesions, typical for MS on T2 images were often seen in children with mild or moderate residual Neurological symptoms.

All patients had Relapsing/Remitting MS course, mean EDSS was 2.24+/-0.26. Thirty-eight children (80%) had ON at least once, ten (21.3%) - twice or more times.

In several cases ON had subclinical course or might be missed and the damage of the Optic Nerve with partial Atrophy was found only after complex Ophthalmological investigation including Visual Evoked Potentials.

Thus, the clinical course of MS and ON have some peculiarities in children and may be Genetically based. Analyzes of allelic polymorphisms of HLA-DR and TNF loci on Chromosome 6 was performed.

Data from children with MS were compared with data from their parents, healthy controls and other MS patients from the same ethnic group.

Children with MS had increased frequency of DR2(15) and TNF-a11, but not TNF-a9 as adult MS patients from the same ethnic group. The presence of TNF-a7, rare in adult patients, could be proposed as a marker of early MS onset.

Geographically MS describes three frequency zones. High frequency areas (prevalence 30+ per 100 000) now comprise most of Europe, Israel, Canada, northern US, southeastern Australia, New Zealand, and easternmost Russia.

Medium frequency areas include southern US, most of Australia, South Africa, the southern Mediterranean basin, Russia into Siberia, the Ukraine and parts of Latin America. Prevalence rates under 5 per 100 000 are found in the rest of Asia, Africa and northern South America.

Migrants from high to lower risk areas retain the MS risk of their birth place only if they are at least age 15 at migration.

Those from low to high increase their risk even beyond that of the natives, with susceptibility extending from about age 11 to 45.

Thus MS is ordinarily acquired in early adolescence with a lengthy latency before symptom onset.

MS occurred in epidemic form in North Atlantic islands: probably in Iceland and the Shetland-Orkneys; clearly in the Faroe Islands.

In the Faroes first symptom onset was in 1943, heralding the first of four successive epidemics at 13 year intervals.

The disease was presumably introduced by occupying British troops during World War II, with the postwar occurrences representing later transmissions to and from consecutive cohorts of Faroese.

What was transmitted is thought to be a specific, widespread, persistent infection called PMSA (the primary Multiple Sclerosis affection) which only rarely leads years later to clinical MS.

Search for PMSA is best attempted on the Faroes where there are regions still free of MS after 50 years.

Proton MR Spectroscopy allows in vivo measurement of N-AcetylAspartate in White Matter, providing a biochemical index of Axonal integrity.

Several recent studies of patients with Multiple Sclerosis and other White Matter Disorders have shown both transient and sustained decreases in N-AcetylAspartate in White Matter lesions and in Brain regions appearing normal on conventional MRI.

These data have emphasised that a substantial amount of Axonal damage or loss (presumably secondary to Myelin pathology) is consistently present in most of these disorders.

Recent post-mortem studies support these results. In contrast to changes seen with conventional MR imaging, decreases in N-AcetylAspartate have shown a close correlation with changes in Neurological status.

This suggests that Axonal Damage may be more relevant than DeMyelination for determining chronic functional impairments in primary White Matter Diseases.

Thus, serial measurement of Brain N-AcetylAspartate with Proton MR Spectroscopy can provide a reliable and clinically-relevant monitor of disease evolution.

As pathological changes responsible for long-term morbidity are logically important targets for therapeutic agents, early treatment directed at Axonal protection should be useful in these disorders.

Magnetization Transfer Imaging (MTI) is a Magnetic Resonance Imaging (MRI) technique that has a higher specificity than conventional T₂-weighted scans to the heterogeneous pathological substrates of Multiple Sclerosis (MS) lesions.

This review outlines the contribution of MTI in the study of lesion evolution and in the assessment of disease burden in MS.

MTI studies of individual MS lesions confirm the pathological Heterogeneity of T₂-weighted MRI abnormalities and the potential role of unenhanced T₁-weighted HypoIntensities as specific markers of localized severe White Matter disruption.

Correlative cross-sectional and longitudinal studies using MTI and Gadolinium (Gd)-enhanced MRI reveal that MTI findings may vary in Lesions with different patterns of enhancement.

And that MTI abnormalities are closely related to the onset and recovery of Blood-Brain Barrier disruption in new MS plaques.

Measures obtained from MTI scans using whole-Brain Histogram analysis are highly correlated with the extent of MS abnormalities on conventional MRI scans and predict patients' clinical disability well.

Since they are sensitive to the amounts of both Macro- and Microscopic MS disease burden in the whole Brain and in specific regions.

To verify the possible role of Human HerpesViruses as triggering or aggravating factors in Relapsing/Remitting Multiple Sclerosis (RRMS) clinical acute attack, we studied the prevalence of some HerpesViruses in the Peripheral Blood MonoNuclear Cells (PBMCs) collected from 22 MS patients during an MS relapse and in a stable phase and from 18 healthy controls (HC).

DNA belonging to Herpes Simplex Virus type 1 (HSV-1) and type 2 (HSV-2), Human CytoMegaloVirus (HCMV), Epstein-Barr Virus (EBV) and Human Herpes Virus 6 (HHV-6) has been searched by specific nested Polymerase Chain Reaction (n-PCR).

EBV and HHV6 DNA has been detected with high frequency in acute and stable MS and in healthy controls without significant differences.

HCMV DNA was observed both in acute and stable MS but not in HC, and, more interestingly, HSV-1 DNA was only found in 13% of acute MS, while both stable MS and healthy controls were negative.

On the basis of these results we focused on HSV-1, and to confirm them and to demonstrate that HSV-1 is actively replicating in MS patients during clinical relapse, we searched both messenger RNA (mRNA) and DNA of HSV-1 in the PBMCs of 15 acute MS patients and 15 healthy controls.

We found HSV-1 mRNA and DNA in a significant number of acute MS patients but not in the control group.

On the whole these data indicate that HSV-1 reactivate in the peripheral blood of MS patients during clinical acute attack and probably play a role in the triggering of MS relapses.

It has been suggested that Human HerpesVirus 6 (HHV-6) might be involved in the PathoGenesis of Multiple Sclerosis (MS).

However, studies of the association between HHV-6 and MS are hindered by the difficulty in discriminating between latent and active infection.

We undertook a study to determine whether HHV-6 establish a systemic active infection in the course of MS, and to investigate possible roles of HHV-7, a HerpesVirus closely related to HHV-6.

To discriminate between latent and active infection, we analyzed Viral transcription.

The results indicate that both Viruses are prevalent in PBMCs of MS patients as in healthy controls, and that Viral sequences are maintained in a non-trascriptional state.

These observations indicate that further studies should define the state of Viral persistence in the Central Nervous System.