MS Abstracts 01a-2g5

Background
Sex related differences in the course and severity of Multiple Sclerosis (MS) could be mediated by the sex Hormones.

Objective
To investigate the relation between Serum sex Hormone concentrations and characteristics of tissue damage on conventional Magnetic Resonance Imaging (MRI) in men and women suffering from Relapsing/Remitting MS.

Results
Serum Testosterone was significantly lower in women with MS than in controls. The lowest levels were found in women with a greater number of Gadolinium enhancing lesions.

A positive correlation was observed between Testosterone concentrations and both tissue damage on MRI and clinical disability.

In men, there was a positive correlation between Oestradiol concentrations and Brain damage.

Conclusions
The Hormone related modulation of pathological changes supports the hypothesis that sex Hormones play a role in the inflammation, damage, and repair mechanisms typical of MS.

Background
NeuroFilament Phosphoforms (Nf) are principal components of the AxoSkeleton released during Axonal injury.

CerebroSpinal Fluid (CSF) levels of Nf Phosphoforms might be useful surrogate markers for disability in Multiple Sclerosis (MS), aid in distinguishing clinical subtypes, and provide valuable prognostic information.

Method
Thirty four patients with MS were included in a three year follow up study along with 318 controls with Other Non-Inflammatory Neurological Diseases.

CSF levels of two Nf heavy chain (NfH) phosphoforms (NfH(SMI35), NfH(SMI34)) were quantified at baseline and three year follow up using new ELISA techniques.

Levels of NfH Phosphoforms, the degree of Phosphorylation (NfH(SMI34):NfH(SMI35) ratio).

And, changes in NfH levels between baseline and follow up (DeltaNfH) were related to the clinical phenotype (RR or SP/PP).

To three clinical scales (Kurtzke's EDSS, Ambulation Index (AI), and Nine Hole Peg Test (9HPT)), and to progression of disability.

Results
A significantly higher proportion (59%) of patients with SP/PPMS experienced an increase in NfH(SMI35) levels between baseline and follow up compared with those with RRMS (14%, p < 0.05).

CSF NfH(SMI34) levels at baseline were higher in patients with SP/PP (11 pg/ml) compared with RR (7 pg/ml, p < 0.05).

And, NfH(SMI35) levels were higher at follow up in SP/PP (129 pg/ml) compared with levels below assay sensitivity in RR (p < 0.05).

NfH(SMI35) correlated with the EDSS (r(s) = 0.54, p < 0.01), the AI (r(s) = 0.42, p < 0.05), and the 9HPT (r(s) = 0.59, p < 0.01) at follow up.

Conclusion
The increase in NfH during the Progressive phase of the disease together with the correlation of NfH(SMI35) with all clinical scales at follow up.

Suggests that cumulative Axonal Loss is responsible for sustained Disability and that high NfH(SMI35) levels are a poor prognostic sign.

The effects of Interferon-beta (IFN-ß) used for treatment of Multiple Sclerosis (MS) on the Central Nervous System (CNS) have not yet been elucidated.

The effect of IFN-ß and IFN-γ on Astrocytes as the major component of the CNS was investigated using murine primary Astrocytes and human Astrocytoma U251 cell line.

IL-1ß, IL-6, TNF- and iNOS were analyzed by RT-PCR. Both protein and mRNA levels of IL-6 were increased by IFN-ß. IFN-γ augmented the effect of IFN-ß on IL-6 production.

These results suggest that IFN-ß has an activity to modulate inflammatory and Immune Responses by up-regulating IL-6 in the CNS of MS.

Multiple Sclerosis (MS) is the most common disabling Neurological Disease in young people. Most CNS lesions involve NeuroAnatomically non-eloquent zones that often do not result in symptomatic complaints.

By contrast, tissue-injury mechanisms involving inflammatory DeMyelination can involve more eloquent sites, such as the Optic Nerve and BrainStem.

Which can correspondingly produce the development of well recognized syndromes such as Optic Neuritis and InterNuclear Ophthalmoplegia, respectively.

In this review we discuss the broad landscape of abnormalities that affect the Afferent Visual System and the Ocular Motor Apparatus, and emphasise relevant features, the recognition and treatment of which are of importance to general Neurological practice.

The commonness of Visual Sensory and Eye movement abnormalities in MS highlights the importance of understanding the principles addressed in this review.

Objective
To determine the time course of Brain Atrophy during treatment with once-weekly IM Interferon-beta-1a (IFN-ß-1a).

Methods
The MRI cohort (n = 386) of the European IFN-ß-1a dose comparison study in Relapsing Multiple Sclerosis (MS) was analyzed.

In addition to baseline and three annual scans, a frequent subgroup (n = 138) had two scans before treatment initiation and scans at months 4, 5, 6, 10, and 11.

Brain Parenchymal Fraction (BPF), a normalized measure of Whole-Brain Atrophy.

And, volume of Gd-enhancing lesions (T₁Gd) and T₂ HyperIntense lesions (T₂LL) were evaluated.

Results
BPF decrease was -0.686% (first year), -0.377% (second year), and -0.378% (third year).

Analysis of the frequent subgroup showed that 68% of the first-year BPF decrease occurred during the first 4 months of treatment.

This change was paralleled by a drop in T₁Gd and T₂LL.

In the frequent subgroup, an annualized Atrophy rate was determined by a regression slope for the pretreatment period and from month 4 of treatment onward. Annualized pretreatment rate (-1.06%) was significantly higher than the under-treatment rate (-0.33%).

Conclusions
In the first year of treatment with AntiInflammatory agents, Atrophy measurements are possibly confounded by resolution of inflammatory Edema or more remote effects of previous damage to the CNS.

The Atrophy rate reduction observed after treatment month 4 may reflect a beneficial but partial effect of Interferon-ß-1a and was sustained over the 3-year study period.

Purpose
To use quantitative Magnetization Transfer Imaging (qMTI) in an investigation of T₁-weighted HypoIntensity observed in clinical Magnetic Resonance Imaging (MRI) scans of Multiple Sclerosis (MS) patients.

Which has previously been proposed as a more specific indicator of tissue damage than the more commonly detected T₂ HyperIntensity.

Materials And Methods
A cross-sectional study of 10 MS patients was performed using qMTI.

A total of 60 MTI measurements were collected in each patient at a resolution of 2 x 2 x 7 mm, over a range of saturation pulses.

The observed T₁ and T₂ were also measured. qMT model parameters were estimated using a Voxel-by-Voxel fit.

Results
A total of 65 T₂-HyperIntense lesions were identified; 53 were also T₁ HypoIntense.

In these Black Holes, the qMTI-derived semisolid pool fraction F correlated negatively with T(₁,obs) (r(2) = 0.76; P < 0.0001). The water pool absolute size (PD(f)) showed a weaker correlation with T(₁,obs) (positive, r(2) = 0.53; P < 0.0001).

The Magnetization Transfer Ratio (MTR) showed a similarly strong correlation with F and a weaker correlation with PD(f) (r(2) = 0.18; P < 0.04).

Conclusion
T₁ increases in chronic Black Holes strongly correlated with the decline in semisolid pool size, and somewhat less to the confounding effect of Edema.

MTR was less sensitive than T(₁,obs) to liquid pool changes associated with Edema.

(c) 2005 Wiley-Liss, Inc.

The Immunological mechanisms leading to tissue damage in Inflammatory Brain Diseases are heterogeneous and complex.

They may involve direct CytoToxicity of T-Lymphocytes, specific AntiBodies and activated Effector Cells, such as Macrophages and Microglia.

Here we describe that in certain inflammatory Brain lesions a pattern of tissue injury is present, which closely reflects that found in Hypoxic conditions of the Central Nervous System.

Certain inflammatory mediators, in particular reactive Oxygen and Nitrogen species, are able to mediate Mitochondrial dysfunction.

And, we suggest that these inflammatory mediators, when excessively liberated, can result in a state of HistoToxic Hypoxia.

This mechanism may play a major role in Multiple Sclerosis, not only explaining the lesions formed in a subtype of patients with Acute and Relapsing course, but also being involved in the formation of diffuse "NeuroDegenerative" lesions in Chronic Progressive forms of the disease.

This study investigated the relationship between clinical symptoms and Cognitive Dysfunction in Multiple Sclerosis.

Cognitive Dysfunction and Visual Evoked Potentials (VEPs) were studied in patients free of physical disability and mildly to moderately disabled patients with Multiple Sclerosis (MS).

Disability-free patients (EDSS < /= 1.5; n = 13),mildly to moderately disabled patients (EDSS ranging from 2 to 6; n = 13).

And, a healthy matched control group (n = 16) were examined with respect to Attention, Verbal and NonVerbal Memory and Early Visual Processing (VEPs).

Disability-free patients showed mild impairments on phasic alertness and divided attention.

Deficits were more pronounced in mildly to moderately disabled patients who were additionally impaired with respect to Non-Verbal Memory.

Despite adequate Visual Acuity, one half of all patients showed abnormal VEP latencies for both eyes at the same time.

The findings suggest that Cognitive Deficits are already present in Multiple Sclerosis even in the absence of physical disability.

Even with normal Visual Acuity, perceptual impairments should be considered as part of the CNS affection.

Recent studies suggest that ExcitoToxicity may contribute to Neuronal damage in NeuroDegenerative Diseases including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis.

Activated Microglia have been observed around degenerative Neurons in these diseases, and they are thought to act as Effector Cells in the degeneration of Neural Cells in the Central Nervous System.

Neuritic Beading, focal bead-like swellings in the Dendrites and Axons, is a NeuroPathological Sign in Epilepsy, Trauma, Ischemia, Aging and NeuroDegenerative Diseases.

Previous reports showed that Neuritic Beading is induced by various stimuli including Glutamate or Nitric Oxide and is a Neuronal response to harmful stimuli.

However, the precise physiologic significance of Neuritic Beading is unclear.

We provide evidence that Neuritic beading induced by activated Microglia is a feature of Neuronal Cell dysfunction toward Neuronal death.

And, the NeuroToxicity of activated Microglia is mediated through N-Methyl-D-Aspartate () Receptor signaling.

Neuritic beading occurred concordant with a rapid drop in IntraCellular ATP levels and preceded Neuronal death.

The actual Neurite beads consisted of collapsed CytoSkeletal proteins and motor proteins arising from impaired Neuronal transport secondary to cellular energy loss.

The drop in IntraCellular ATP levels was due to the inhibition of Mitochondrial respiratory chain complex IV activity downstream of NMDA receptor signaling.

Blockage of NMDA receptors nearly completely abrogated Mitochondrial dysfunction and NeuroToxicity.

Thus, Neuritic Beading induced by activated Microglia occurs through NMDA receptor signaling and represents Neuronal Cell Dysfunction preceding Neuronal death.

Blockage of NMDA receptors may be an effective therapeutic approach for NeuroDegenerative Diseases.

Optic Nerve Sheath dilatation or Gadolinium-enhancement on Magnetic Resonance Imaging in acute Optic Neuritis have been previously reported but have been thought to be rare occurrences.

This study recruited 33 patients with acute Unilateral Optic Neuritis. All had their Optic Nerves imaged with fat-saturated Fast Spin-Echo (FSE) imaging, and 28 had imaging before and after triple-dose Gadolinium-enhanced fat-saturated T₁-weighted imaging.

Follow-up imaging was performed on 20 patients (15 following Gadolinium). A dilated SubArachnoid Space at the anterior end of the symptomatic Optic Nerve on FSE imaging was seen in 15/33 cases.

In three of these cases, dilatation was visible on short-term follow-up. Optic Nerve sheath enhancement was seen in 21/28 cases acutely: seven at the anterior end of the lesion only, five at the posterior end only and nine at both ends.

Optic Sheath enhancement was seen in 13 patients on follow-up. This study suggests that Optic Nerve Sheath dilatation on FSE images and Optic Nerve Sheath enhancement on triple-dose Gadolinium-enhanced images are common findings in Acute Optic Neuritis.

Optic Nerve Sheath dilatation may be due to inflammation of the Optic Nerve, with its associated swelling, interrupting the communication between the SubArachnoid Space of the diseased Optic Nerve and the Chiasmal Cistern.

Optic Nerve Sheath enhancement suggests that Meningeal inflammation occurs in Optic Neuritis, in agreement with pathological studies of both Optic Neuritis and Multiple Sclerosis.

Object
The authors sought to evaluate the initial response of Trigeminal Neuralgia (TN) to gamma knife surgery (GKS) based on the number of shots delivered and radiation dose.

Methods
Between September 1998 and September 2003, some 63 patients with TN refractory to medical or surgical management underwent GKS at Upstate Medical University.

Ten patients had Multiple Sclerosis and 25 patients had undergone prior invasive treatment. Gamma knife surgery was delivered to the Trigeminal Nerve Root entry zone in one shot in 27 patients or two shots in 36 patients.

The radiation dose was escalated to less than or equal to 80 Gy in 20 patients, 85 Gy in 21 patients, and greater than or equal to 90 Gy in 22 patients.

Pain before and after GKS was assessed using the Barrow Neurological Institute Pain Scale and the improvement score was analyzed as a function of dose grouping and number of shots.

Sixty patients were available for evaluation, with an initial overall and complete response rate of 90% and 27%, respectively.

There was a greater improvement score for patients who were treated with two shots compared with one shot, mean 2.83 compared with 1.72 (p < 0.001).

There was an increased improvement in score at each dose escalation level: less than or equal to 80 Gy (p = 0.017), 85 Gy (p < 0.001), and greater than or equal to 90 Gy (p < 0.001).

Linear regression analysis also indicated that there was a greater response with an increased dose (p = 0.021).

Patients treated with two shots were more likely to receive a higher dose (p < 0.001). There were no severe complications. Five patients developed mild facial numbness.

Conclusions
Gamma knife surgery is an effective therapy for TN. Initial response rates appear to correlate with the number of shots and dose.

Background And Purpose
In the early stage of Multiple Sclerosis (MS), conventional MR imaging parameters such as T₂ lesion load fail to explain the clinical status of patients.

In the present work, we aimed to determine the ability of Magnification Transfer Imaging to better reflect the relationship between local tissue damage and functional status of MS patients.

Methods
We performed a comparative statistical mapping analysis on Brain tissue Magnetization Transfer Ratio (MTR) data measured in 18 patients with Clinically Isolated Syndrome Suggestive of MS (CISSMS) and 18 matched control subjects.

Results
In the patients with CISSMS, a pattern of significant low MTR values was observed in the White Matter, Corpus Callosum, Bilateral OccipitoFrontal Fascicles, Right Fornix, Right Parietal White Matter, External Capsule, Right Superior Longitudinal Fasciculus (SLF), Right Inferior Longitudinal Fasciculus, Optica Radiata, Parietal White Matter, Right Cingulum, Gray Matter, Bilateral Thalamus, Bilateral Caudate, Right Insula, and left Brodmann Area (BA) 8.

No correlation was found between local MTR decrease and Expanded Disability Status Scale score. Significant correlations between MTR and MS Functional Composite scores (Spearman rank test, P < .05) were observed in the left BA40, right SLF, Right Frontal White Matter, Splenium, and Anterior Corpus Callosum.

Local MTR values correlated with Paced Auditory Serial Addition Test scores in the left BA40, right BA4, right SLF, and Splenium.

Conclusion
Statistical mapping analysis of Brain MTR data provides valuable information on the relationship between the location of Brain tissue damage and its functional impact in patients with MS, even in the earliest stage of the disease.