MS Abstracts 10c-2g

Background
Susac Syndrome is characterized by the triad of branch Retinal Arterial Occlusions, Encephalopathy and Cochlear MicroAngiopathy.

The underlying process is believed to be a small vessel Vasculitis causing MicroInfarcts in the Retina, Brain and Cochlea.

Methods
Analysis of two male and two female cases of Susac Syndrome recognized in Australia.

Results
In this series the epidemiology, mode of presentation, Ophthalmologic features, Neurologic and CochleoVestibular features, Radiologic characteristics, CerebroSpinal Fluid findings, therapeutic interventions, clinical course and outcome of Susac Syndrome is examined.

Key Ophthalmologic differential diagnoses include Systemic Lupus Erythematosis (SLE), Behcet's Syndrome and other Vasculitides such as Sarcoidosis, Tuberculosis, Syphilis and Lymphoma.

NeuroOtologic features are most frequently misdiagnosed as Multiple Sclerosis.

Conclusion
Susac Syndrome, first described in 1979, is becoming an increasingly recognized condition.

Early recognition of the syndrome is important because treatment with systemic ImmunoSuppression may minimize permanent Cognitive, Audiologic and Visual sequelae.

Therapy for Multiple Sclerosis (MS) that prevents exacerbation of the disease and slows the progression of disability has not diminished the importance of treating symptoms.

Because the new agents are not curative and rarely reverse existing deficits, many patients under treatment have or will have persistent symptoms.

Many Neurologic symptoms are seen in patients with MS, but it is important to recognize that some NonNeurologic symptoms, such as Pain, Fatigue, and Mood Disturbance, are common and may cause significant disability.

The first and most important step in the management of symptoms is to discuss the symptoms with the patient on an ongoing basis.

The second step is to recognize treatable symptoms and to apply the appropriate strategies for management.

There have been promising results with experimental agents, primarily Potassium Channel Blockers, that may improve function in DeMyelinated fiber pathways and that offer the possibility of treatment for a range of symptoms.

At present, the management of symptoms varies, depending on the symptom, and it involves the coordinated application of a range of treatment approaches including medication, lifestyle changes, rehabilitation, and, in some cases, surgery.

Given our current knowledge, there is a need for the early institution of ImmunoModulatory therapy, especially for patients with poor prognostic factors (Motor and Cerebellar Symptoms, frequent disease exacerbations, and a high level of activity on Magnetic Resonance Imaging ).

Patients who progress despite ImmunoModulatory therapy should be reevaluated in terms of diagnosis, development of Neutralizing AntiBodies, or compliance.

If a patient has a partial response to ImmunoModulatory therapy but his or her disease, as assessed by clinical and MRI criteria, remains very active, every effort should be made to modify disease progression by searching for an ImmunoSuppressive therapy regimen before irreversible and considerable disability has accumulated.

For the majority of patients, Multiple Sclerosis (MS) is a chronic condition.

Therefore, until a curative treatment has been developed, the available repertoire of ImmunoSuppressive or ImmunoModulatory treatments should be assessed with respect to the possibility of long-term use.

This is particularly important for new ImmunoSuppressive drugs, such as Cladribine or Mitoxantrone, or for invasive procedures, such as total Lymphoid irradiation or autologous Bone Marrow Transplantation.

For the latter treatments, experience with long-term administration is not available or the potential side effects (eg, CardioToxicity with Mitoxantrone) limit the cumulative dose.

These considerations may limit long-term administration and thus the general usefulness of some drugs. Even with proven efficacy, we need to define the next step once treatment has to be discontinued.

We should also address whether exacerbating disease by discontinuing an effective therapy is a potential hazard. What other therapeutic options remain once the current treatment is discontinued?

Answers are not readily available at the moment, but the question should influence our decisions in the selection of traditional, well-studied or new, potentially promising therapies.

Patients with acquired forms of Nystagmus may suffer from Oscillopsia and Blurred Vision; abolishing or reducing Nystagmus ameliorates these symptoms.

Ideally, treatment of Nystagmus should be directed against the PathoPhysiologic mechanism responsible.

Identification of Nystagmus pattern is important in directing therapy and occasionally requires electronic eye movement recording for precise characterization.

Patients with acquired Pendular Nystagmus, particularly those with Multiple Sclerosis, often benefit from Gabapentin, a drug with few side effects.

Scopolamine, Clonazepam, and Valproate are also useful in some patients. A new drug, Memantine, was effective in treating Pendular Nystagmus in one study, but it has not yet been approved for use in the United States.

Periodic alternating Nystagmus usually responds to Baclofen. Central Vestibular Nystagmus, including downbeating and upbeating forms, can be treated with Baclofen or Clonazepam.

In some patients, treatment of an underlying condition, such as Periodic Ataxia, Whipple's Disease, and Chiari Malformation, abolishes Nystagmus and improves vision. If pharmacologic therapy fails, Optical devices can be considered in selected patients.

Injections of Botulinum Toxin and surgery to weaken ExtraOcular muscles are prone to induce Diplopia and may precipitate plastic-adaptive Ocular Motor changes that eventually negate the beneficial effect.

In acute Monosymptomatic Optic Neuritis, treatment with oral Prednisone alone should be avoided.

Therapy with intravenous MethylPrednisolone (1 g/day for 3 days) followed by 11 days of oral Prednisone (1 mg/kg with a short taper) should be considered instead.

This is particularly true if a patient considers accelerated Visual recovery to be particularly urgent or if Magnetic Resonance Imaging (MRI) demonstrates three or more signal abnormalities consistent with DeMyelination.

In patients without a diagnosis of Clinically Definite Multiple Sclerosis (CDMS), an MRI should be considered to assess the prognosis for developing Multiple Sclerosis (MS) and to eliminate other causes of Optic Neuropathy.

Foregoing an MRI or Steroid treatment is an acceptable option. Chest x-ray, blood tests, and Lumbar Puncture are not necessary in evaluating patients with typical clinical features of Optic Neuritis.

These tests may be appropriate, however, for patients who are about to undergo CorticoSteroid therapy, which could complicate or mask an unrecognized condition.

In Multiple Sclerosis (MS) Gadolinium (Gd)-enhanced MRI activity correlates weakly with Immunological markers of disease activity.

We, therefore, tested the hypothesis that the poor correlation could be partly explained by the temporal profile of Gd enhancement.

We measured Urinary Neopterin:Creatinine ratios (Neopt.:Creat.(urine)) in 5 patients with active MS undergoing weekly Gd-enhanced MRI studies of the Brain.

The Neopt.:Creat. (Urine) associated with new Gd-enhancing lesions (< 8 days) was significantly higher than the ratio not associated with new Gd-enhancing lesions [mean (geometric) Neopt.: Creat.(urine) = 413 mumol/mol (range = 207-521) vs. 250 mumol/mol (range = 132-492), p = 0.03].

Pro-inflammatory Immunological markers, which are probably produced early on in the life cycle of an active MS lesion, should preferably be correlated with newly enhancing lesions (< 8 days).

Failure to do this may explain the poor and unpredictable correlations between Immunological markers and Gd-enhanced MRI activity, which cannot be accurately aged in cross-sectional and serial monthly MRI studies.

Copyright 2000 S. Karger AG, Basel

We assessed serial Event-Related Potentials (ERPs) as well as NeuroPsychological and clinical test findings in a group of Multiple Sclerosis (MS) patients (n = 14) treated with Interferon-ß-1b (IFN-ß-1b) compared to normal controls (n = 14).

All investigations were done within 1 week before IFN-ß-1b therapy was started and 12 months later. An Auditory oddball paradigm was employed.

No significant differences in the N100, P200, N200 or P300 latencies between patients and control group were found.

But 3 out of 14 MS patients developed abnormal P300 latencies (more than 2 standard errors from the mean) after 1 year of IFN-ß-1b therapy.

This was not reflected by the respective Neurological impairment as assessed by the Expanded Disability Status Scale score.

ERPs might be a useful tool in clinical studies in order to evaluate drug effects on Cognition, but for a final statement, the analysis of ERPs in a larger group of patients is required.

Copyright 2000 S. Karger AG, Basel

In the past 5 years, around 350 patients have received Haematopoietic Stem Cell (HSC) transplantation for an AutoImmune Disease.

With 275 of these registered in an international data base in Basel under the auspices of the European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation(EBMT).

Most patients had either a Progressive form of Multiple Sclerosis (MS; n = 88) or Scleroderma (now called Systemic Sclerosis; n = 55).

Other diseases were Rheumatoid Arthritis (Ra n = 40), Juvenile Idiopathic Arthritis (JIA; n = 30), Systemic Lupus Erythematosus (SLE; n = 20), Idiopathic ThromboCytopenic Purpura (ITP; n = 7) and others.

The procedure-related mortality was around 9%, with between-disease differences, being higher in Systemic Sclerosis and JIA and lower in RA (one death only).

Benefit has been seen in around two-thirds of cases.

No one regimen was clearly superior to another, with a trend toward more infectious complications with more intense regimens. Prospective, controlled randomized trials are indicated and being planned.

Objective
To determine the pathologic basis of areas not exhibiting signal of the short-T₂ component of the T₂ relaxation distribution in MS, as studied in Formalin-fixed Brain.

Background
A Myelin-specific MRI signal would be of great importance in assessing DeMyelination in patients with MS.

Evidence indicates that the short-T₂ (10 to 50 millisecond) component of the T₂ relaxation distribution originates from water in Myelin Sheaths.

The authors present two cases of MS in which the anatomic distribution of the short-T₂ component was correlated with the pathologic findings in postmortem Formalin-fixed Brain.

Method
One half of the Formalin-fixed Brain was suspended in a Gelatin-Albumin mixture cross-linked with Glutaraldehyde, and scanned with a 32-echo MRI sequence.

The Brain was then cut along the center of the 5-mm slices scanned, photographed, dehydrated, and embedded in paraffin.

Paraffin sections, stained with Luxol fast blue and ImmunoCytoChemically for 2',3'-Cyclic Nucleotide 3'-Phosphohydrolase for Myelin and by the Bielschowsky technique for Axons, were compared with the distribution of the amplitude of the short-T₂ component of the comparable image slices.

Results
The anatomic distribution of the short-T₂ component signal corresponded to the Myelin distribution. Chronic, silent MS plaques with Myelin loss correlated with areas of absence of short-T₂ signal.

The numbers of Axons within lesions were reduced, but many surviving Axons were also seen in these areas of complete loss of Myelin.

Conclusion
In Formalin-fixed MS Brains the short-T₂ component of the T₂ relaxation distribution corresponds to the anatomic distribution of Myelin.

Chronic, silent DeMyelinated MS Plaques show absence of the short-T₂ component signal. These results support the hypothesis that the short-T₂ component originates from water related to Myelin.

MTR and T₁ relaxation times are abnormal in MS lesions and NAWM, and may reflect tissue damage such as DeMyelination and Axonal loss.

Their relationship and potential to provide complementary information in tissue characterization is explored.

The aim of this study was to document the relationship between Magnetization Transfer Ratio (MTR) and T₁ relaxation time in Multiple Sclerosis (MS) lesions.

And, Normal-Appearing White Matter (NAWM) in order to determine whether the combination provides a more comprehensive tissue characterization than either parameter in isolation.

Ten patients with Relapsing/Remitting MS and 10 age matched healthy controls underwent imaging using a protocol which included the measurement of both MTR and T₁ relaxation times.

The MTR and T₁ values were compared statistically using a commonly adopted correlation approach and a mixed-model regression approach.

There was a strong correlation between MTR and T₁ in MS Lesions (r=0.74). The correlation was seen equally in T₁ HypoIntense and IsoIntense lesions.

The relationship was much weaker in MS NAWM (r=0.24) and no correlation was found in control White Matter (r=0.06).

Mixed-model regression analysis confirmed that the relationship between T₁ and MTR is strongly dependent upon tissue type (MS lesion, MS NAWM, or control White Matter).

The relationship between MTR and T₁ relaxation time measurements varies markedly between pathological and normal tissue types.

In MS, the complementary information obtained from MTR and T₁ is most apparent in NAWM.

The results emphasise the potential for combinations of MR parameters to improve tissue characterization, which in turn should improve understanding of disease pathology and treatment monitoring.

Multiple Sclerosis (2000) 6 327 - 331