Modeling and Treating the Pathophysiology of Demyelination in Multiple Sclerosis

A quantum leap forward in our understanding of MS pathophysiology was provided by the
discovery of myelin by Louis Ranvier in 1878, and by Pierre Marie who first suggested in 1892
that demyelination represented a critical element in MS pathology.1 In 1925 Lord Edgar
Douglas Adrian reported the first electrical recordings of nerve transmission.2 Ultimately
six Nobel prizes were awarded for contributions directly related to the characterization of
the nerve impulse and the role played by myelin, a monumental achievement of modern biology.

While working at the University of Otago in New Zealand, Dr. W. Ian McDonald (who passed away
on December 13, 2006) was the first to provide objective evidence that demyelination in MS
was associated with a corresponding change in the transmission of electrically coded messages
within nerve axons.3-5 He noted that the disruption of myelin led to a reduction in axonal
cross sectional area and thereby a reduction in conduction velocity, loss of saltatory
conduction, with a predilection to conduction block. Understanding this conspicuous aspect of
MS pathophysiology allows us to predict many of the reversible symptoms described by our
patients, particularly those that are provoked or intensified by elevated ambient or core
body temperature, exercise, and infection. Such processes appear to compromise the safety
threshold for high fidelity nerve transmissions. This phenomenon was also recognized
clinically by Wilhelm Uhthoff in 1899, when he evaluated optic neuritis patients who
experienced reversible and stereotypic alterations in vision after exercise or exposure to
heat.6 MS exacerbations (via inflammation, edema, and demyelination) and sustained
progression of disability (via gliosis, sustained demyelination, and neurodegeneration)
represent formidable challenges of the disease process that have partially yielded to a
series of disease modifying therapeutic strategies.7 However, in most patients, bona fide
exacerbations typically occur infrequently (perhaps a few per year, even in those not using
treatment), and disability progression takes time (many years in most). Alternately,
fluctuations in neuronal activity can be induced by a variety of factors with great frequency
and variability (provoked over minutes, hours, days, or weeks) and correspondingly results in
a compromise of functional capabilities such as vision, reading, driving, walking, work
performance, cognitive processing, and the execution of activities of daily living. In
essence, these frequent, transient, typically stereotypic and reversible physiologic changes
constitute a major component of MS related disability.

Notwithstanding the important achievement of validating the favorable effects of disease
modifying agents in MS, a major and recalcitrant challenge, that should be at the forefront
in MS therapeutics, is a focus on reducing the consequences of symptoms collateral to the
disease process. Such symptoms include fatigue, weakness, gait dysfunction, spasticity, heat
intolerance, pain, cognitive changes, sensory disturbances, bowel, bladder, sexual
dysfunction, depression, and hopelessness.8 While the underpinnings of these complaints are
manifold, changes in axonal conduction mechanisms now represent a well-recognized and
cardinal feature of MS pathophysiology.

A deeper understanding on how novel interventions might serve to enhance the axonal 'safety
factor' to thermal perturbations (ambient, surface, and core body temperature) could lead to
the identification of new treatment strategies for enhancing physiologic performance in CNS
pathways involved in the organization of physical and intellectual capabilities. An important
randomized controlled study systematically demonstrated the long-term benefits of acute and
chronic cooling on objective as well as patient reported measures of neurologic function.9 It
would be important to also understand how active heating impacts upon similar measures, and
whether preemptive cooling is protective in response to a heat stress.

We propose that neuro-ophthalmologic hallmarks of MS, INO (an ocular motor syndrome) and
optic neuritis (a visual sensory syndrome), can be studied with objective methods (infrared
oculography and VEPs respectively) to better understand the factors that provoke or prevent
the reversible conduction changes in demyelinated axons, within highly discrete tract systems
and whether a specific drug treatment, ACTHAR Gel, can mitigate heat induced worsening of
ocular motor and anterior visual system dysfunction. Such studies would appear to be germane
to the development of new treatment approaches focused on optimizing the fidelity of axonal
conduction in demyelinated pathways, and providing elusive outcome measures for some Phase II
trials. Education efforts to inform patients and health care providers on the pervasive
nature of thermally induced symptoms in MS (and the potential impact on daily activities),
could lead to effective strategies to enhance performance and safety. There has been a
paucity of research and education on this very conspicuous and important aspect of MS and its
impact upon patients, families, and the workplace.

Inclusion Criteria:

1. Subject has clinically or laboratory supported Multiple Sclerosis with evidence of INO
by quantitative neurophysiologic criteria or has a history of ON.

2. Subject is between the ages of 18-65.

3. Subject is able to understand the demands of the protocol, has had any questions
answered and has voluntarily signed the informed consent prior to any study
procedures.

4. Subject has a peak saccadic acceleration ratio (abducting eye/adducting eye) of
greater than 2S.D. above the mean derived form a normal control group.

5. Subject is otherwise in good health, based on complete medical history and physical
examination, including vital signs and ECG.

Exclusion Criteria:

1. Subject is a pregnant female (as determined by a urine pregnancy test), a lactating
female, or a female of child-bearing potential, not sterilized and not using one of
the following methods of birth control: oral or injectable contraceptive agent,
implantable contraceptive device, or barrier method.

2. Subject has a history of hypertension or diabetes.

3. Subject has known allergy to ACTH.

4. The subject has any medical condition, including psychiatric disease that might
interfere with the interpretation of the results or with the conduct of the study.

5. Subject has a history of drug or ethanol abuse within the past year.

6. Subject has a history of ischemic heart disease.

7. Subject has received an investigational drug within 30 days of screening.

8. In opinion of investigator, subject is unlikely to complete study for any reason.

9. The subject has abnormal clinical laboratory values or an abnormal ECG, without
approval of the study monitor.