CNS demyelinating Disease: A clinical Correlate Flashcards
Pathophysiology
• MS is a disease which results in neurologic dysfunction due to degradation of myelin
o Myelin is fatty substance which surrounds the nerve axon allowing signal to be
transmitted from one location in the CNS to another distant location with greater speed
and efficiency
• This autoimmune process causes focal areas of demyelination with associated inflammation that
slows down or completely interrupts transmission of neural activity
MS is a life-long disease which presents in two distinct forms: Relapsing Remitting MS (RRMS)
▪ This is the most common form of MS and is defined as distinct acute exacerbations of demyelinating disease that result in transient neurologic dysfunction lasting days to weeks, before typically resolving completely, leaving the patient at or very near to their previous neurologic baseline ▪ RRMS accounts for >90% of all MS cases ▪ Patients with longstanding RRMS will often transition into a Secondary Progressive MS (SPMS) disease category many years after initial symptom onset • SPMS is defined as incomplete return to baseline in patients following exacerbation with a history of longstanding RRMS. • Approximately half of RRMS will become SPMS at some point
MS is a life-long disease which presents in two distinct forms: Primary Progressive MS (PPMS)
▪ PPMS is the rarer form of MS and is defined as distinct acute exacerbations of
demyelinating disease that result in permanent neurologic dysfunction. The
patient may show some subtle signs of improvement but they fail to return to
their previous neurologic baseline
Epidemiology and Risk Factors
• MS affects greater than 350,000 patients in the US alone
o Prevalence of ~10-20/100,000 in the population
• There are clear associations with both genetics and environment
o Individuals in northern climates develop MS at a strikingly high frequency than those
who were raised in southern areas
▪ Some postulate a link to Vit. D deficiency but this has never been fully
supported in the literature
• Onset of symptoms is typically noted between the ages of 20 and 40, but the disease can occur
at nearly any age.
• Females carry a 2-3x risk of developing MS compared to males
• Those with first degree relatives carry a 20-40x risk of developing disease compared to general
population
o There is also a slightly elevated risk of developing MS if other autoimmune diseases are
present in first degree relatives
Prototypical Presentations of MS
I will begin this section with the preface that MS can present with nearly any imaginable
neurologic impairment, ranging from monocular blindness to ataxia to tremor to even
quadriplegia. The disease examples below represent the most common initial presentations of
demyelinating diseases and are by no means all encompassing. I am specifically seeking to
provide the most frequently seen and tested clinical presentations so that you will be familiar
with them when they encountered in the clinic or in a question stem.
Prototypical Presentations of MS: Optic Neuritis
o Very common clinical syndrome resulting from MS
o This is defined as acute demyelination of the optic nerve
▪ Typical anterior to the chiasm and only involving one of the optic nerves (left or
right), but has been known to involve both nerves and/or the chiasm in rarer
presentations
▪ Symptoms of a typical optic neuritis are as follows:
• Gradually progressive monocular vision loss often described as hazing or
blurring. Many patients will described the sensation of looking through
“dirty dishwater” or a “dense screen”
o Symptoms usually worsen over hours to a day
o If vision loss is very abrupt (i.e. over seconds to a minute) you
should be thinking vascular (stroke of the retina) not
demyelinating
• There is loss of brightness and clarity of color. This is termed color
desaturation.
• Patients will often described a dull ache when looking up, down, left or
right.
▪ Exam findings will be remarkable for an afferent pupillary defect and decreased
visual acuity in the affected eye. One may also appreciate optic disc edema on
funduscopic exam, but this usually takes a couple of days following symptom
onset to be readily apparent.
▪ Symptoms usually resolve to previous baseline within weeks, but the afferent
pupillary defect may remain a permanent exam finding
Prototypical Presentations of MS: Intranuclear ophthalmoplegia (INO)
o An INO results from a lesion within the brainstem, most specifically within the pons.
o INO is defined as an impairment in horizontal gaze where the affect side has failure of
medial gaze (towards the nose) when looking away from the side of the lesion (see
below)
▪ The INO results from a disconnection of the abducens nucleus to the
oculomotor nucleus due to demyelinating disease occurring in the medial
longitudinal fasciculus (MLF). The impaired connection results in dis-conjugate
gaze with nystagmus in the good eye
Prototypical Presentations of MS: Transverse Myelitis
o Transverse Myelitis is demyelination of the spinal cord.
o As you may recall the spinal cord is formed by various tracks, which house fibers with
vastly different functions (i.e. corticospinal fibers carry motor input from the brain to
the body). Keeping this knowledge of spinal cord anatomy in mind, you will understand
why a transverse myelitis can result in a wide ranging of neurologic symptoms ranging
from hemi-sided weakness, sensory deficit (of different types), bowel/bladder
dysfunction or some combination of all of the above depending on the location and size
of the demyelinating plaque.
Diagnosing MS
• No single test of clinical feature in isolation is significant enough to establish or exclude the
diagnosis of MS
• MS often requires extensive history, neuroimaging, and at times additional work-up with
cerebrospinal fluid analysis, and prolonged clinical monitoring to establish the diagnosis.
• The diagnosis of MS hinges on the principal of “separation of lesions in time and space”
o The diagnosis of MS is reliant on a patient having more than one clinical symptom which
is consistent with demyelinating disease. These clinical symptoms must be separated in
time. It also is necessary that those two or more clinical symptoms localize to different
places in the central nervous system
o The term “separated in time and space” is the main principal for the McDonald Criteria
which is used to clinically make the diagnosis.
o A single episode of demyelinating disease without history of prior transient neurologic
deficit is considered a clinically isolated syndrome. This is NOT diagnostic for MS (only a single clinical event, not multiple as is required by the McDonald Criteria), however there is most certainly an increased risk that the patient will develop MS in the next five years compared to the baseline population.
• Neuroimaging is mainly focused on the results of magnetic resonance imaging (MRI) rather than CT. In general CT imaging is not helpful in diagnosing MS.
o MRI’s give very detailed
imaging that can reveal current as well as older evidence of demyelination which is extremely useful in supporting the diagnosis of MS
o Typical features present on MRI include multiple ovoid or confluent white (hyperintense) areas on the T2 Flair sequence that are often location along the ventricles, corpus callosum, in the brainstem, and cerebellum.
▪ Frequent monitoring and follow-up MRI is important in patients who have had a clinically isolated syndrome so that the diagnosis of MS is not delayed.
Diagnosing MS: Neuroimaging
Neuroimaging is mainly focused on the results of magnetic resonance imaging (MRI) rather than
CT. In general CT imaging is not helpful in diagnosing MS.
o MRI’s give very detailed imaging that can reveal current as well as older evidence of
demyelination which is extremely useful in supporting the diagnosis of MS
o Typical features present on MRI include multiple ovoid or confluent white (hyperintense)
areas on the T2 Flair sequence that are often location along the ventricles,
corpus callosum, in the brainstem, and cerebellum.
Diagnosing MS: Cerebrospinal Fluid Analysis
o Obtaining CSF and analyzing is for the presence of abnormalities that can be seen in MS
can aid in establishing the diagnosis, but are not diagnostic in isolation (meaning it’s just
one “piece of the pie” that can support the conclusion that MS is the etiology of the
patient’s symptoms
o Abnormalities which can be seen in the CSF of a patient with MS include: oligoclonal
banding, abnormally high IgG/albumin ratio, and elevated IgG synthesis rate
o The CSF findings are often absent early in the disease course and present only in
approximately 80% of those who suffer with MS
▪ Key point: If the findings of abnormal CSF are present they are helpful, if they
are absent it definitely does not exclude the diagnosis of MS.
Treatment of the acute exacerbation
o When a patient presents with an acute MS exacerbation, which may clinically appear as
an optic neuritis, intranuclear ophthalmoplegia, transverse myelitis or any number of
other neurologic deficits, one must keep in mind the basic pathophysiology of the
underlying disease. Specifically you must remember that inflammation around the
affected part of the nerve is large component of what contributes to the clinical
presentation
o Understanding the role that inflammation plays helps to rationalize why we use high
dose corticosteroids to treat MS flare-ups.
Figure 3. Multiple T2 Flair MRI
examples of white (hyper-intense)
foci which represent areas of
demyelination
o Although we know that patients who have RRMS do get better on their own, often
returning to their previous neurologic baseline within weeks to months, we also know
that offering treatment with steroids will likely increase the speed of recovery
significantly.
o Typically patients are given 3-5 days of very high dose IV methylprednisolone treatment
at the onset of certain significantly symptomatic MS exacerbations such as those clinical
presentations listed above. More minor complaints, such as mild sensory impairments,
may be treated with lower doses of oral steroids or just monitored clinically for
resolution on their own as the risk of side effects from the steroids does not outweigh
the benefits of a more rapid recovery
Selected Long Term Treatment- Disease Modifying Therapy
o The theory that MS is an inflammatory autoimmune condition guides the mechanisms
of action for the available disease modifying therapies.
o These drugs only work in the setting of relapsing remitting MS; there are no available
treatments to alter the course of primary progressive MS at this time.
o There are six main disease modifying therapies available to treat MS (three of which are
interferon beta agents)
Interferon beta treatments
▪ The exact mechanisms for the interferon beta agents are unknown aside for
some action on decreasing T-cell migration. All interferon therapies have been
shown to decrease the number of clinical exacerbations and to slow the
creation of new T2 Flair hyper-intense lesions in the brain. The interferon beta
agents are detailed below.
▪ Individual drugs (no need to memorize)
• Interferon beta-1b (Betaseron™)-subcutaneous injection 3x weekly
• Interferon beta 1a (Rebif™)- subcutaneous injection 3x weekly
• Interferon beta 1a (Avonex™)-intramuscular injection 1x weekly
o Less efficacious in aggressive disease compared to the above
two choices
▪ All the interferon treatments have side effects of flu-like symptoms (headaches,
arthralgia, myalgia, and injection site reactions.)
Glatiramer Acetate (Copaxone™)
▪ This drug most likely acts in the inflammatory process by interacting at the level
of the major histocompatibility complex.
▪ Given as a daily subcutaneous injection
▪ Fewer side effects than the interferons betas, but this drug is also found to be
less effective in aggressive disease compared to the subcutaneously
administered interferon beta drugs
