Demyelinating Diseases: MS, Transverse Myelitis, Neuromyelitis Optica Flashcards
What is MS?
A chronic, inflammatory disease of the central nervous system (CNS) - the brain and the spinal cord that occcurs when the myelin (made by oligodendrocytes), and neurons & axons, are destroyed
When the myelin is lost in multiple areas, plaques (inflammation and sclerosis [scar tissue]) occur resulting in periodic loss of neurological function (known as a relapse) and often progressive disability
What is the most common form of MS?
‘relapsing remitting”, in which patients develop periodic loss of neurological function.
Over time, MS plaques accumulate in the CNS and patients develop progressive disability.
Let’s meet our first patient.
She is 37 years old.
At age 19 (college freshman – this is a true story), while studying for exams she has vision loss in her right eye (This is her 1st relapse).
It worsened over the course of the day, and was associated with a headache behind the eye and PAIN WITH EYE MOVEMENT.
It also worsened when she went outside in the heat.
Over the next 20 years (approximately), she had multiple episodes (each is a relapse) of left sided tingling (neurological term = paresthesias) that resolved over 2 weeks.
During the last relapse, she became numb from the umbilicus distally and her gait changed. She improved, but did not quite return to normal.
MS symptoms that worsen during an increase in body temperature is known as what?
Uhthoff’s phenomena – this is very common in MS patients. This occurs because of poor electrical conduction along demyelinated axons.
This patient will help us define relapsing remitting MS. What is an MS relapse?
A relapse is a new neurological disability that lasts at least 24 hours. Its onset is SUBACUTE, which separates it from stroke, which is ACUTE.
MS, by clinical definition, is a disease that is separated by time and space.
Time is two relapses that occur during two different times in a person’s life.
Space is two different areas of the CNS. In this patient it was an episode of optic neuritis followed by multiple episodes of transverse myelitis.
The clinical exam is noted on this slide.
MS plaques can be visualized by MRI and is used to diagnose MS.
The spinal fluid shows an inflammatory profile.
Note that CSF protein may be normal in MS. It is the IgG index and oligoclonal bands which are consistent with a diagnoses of MS.
Also note that lymphocytes may be present, but never neutrophils in classic MS.
On this spin echo image of the brain, cortex is light gray, white matter is dark gray.
The bright white (hyper-intense) areas are the MS plaques. The red arrow points to one. There are several others within the white matter adjacent to ventricles.
This is an MRI of the brain (at the same level as the previous image) following intravenous administration of gadolinium.
Gadolinium does not normally enter the brain parenchyma.
In this image, the red arrow shows a ‘gadolinium enhancing’ MS plaque. There are several others within the white matter.
This is an acute (new) MS plaque in which there is active inflammation and breakdown of the blood brain barrier which allows gadolinium to enter the brain parenchyma.
Remember, MS also affects the spinal cord.
This is an MRI of the cervical spinal cord. The spinal fluid is white surrounding the spinal cord parenchyma. The red arrow shows large white (hyper-intense) plaque within the dark grey spinal cord parenchyma.
As shown on the right panel, oligoclonal bands were present in the spinal fluid, but not the plasma.
Oligoclonal bands are IgG’s of similar molecular weight. They are present in the CSF of MS patients, as well as patients with infections of the central nervous system.
Thus, they are not specific for MS, but are very helpful when you have ruled out infectious processes.
The visual evoked response (also known at VEP) measure how quickly the occipital cortex detects light input from the retina. Normally, this takes 100 msecs. Thus the term P100.
As shown here, this patient has a normal VEP on the left, and an absent P100 (above) or delayed P100 (bottom) on the right. This is seen in MS
These are the classic diagnostic criteria for MS – also described in the literature as “CLINICALLY DEFINITE MULTIPLE SCLEROSIS”.
They describe the first patient accurately. She has clinically definite MS.
Please note there is another kind of MS called primary progressive MS (bullet 3, sub-bullet 2).
Now that we have an idea of what an MS patient looks like, let’s review the pathology of the disease.
Again, MS plaques are periventricular (red arrow).
At autopsy, the plaques are located in the deep white matter and periventricular areas (red arrows).
Recent data on MRI shows that many are present in regions adjacent to the cortical gray matter. This is termed Juxtacortical (blue arrow) and is important when evaluating an MRI for MS.
Luxol fast blue stains normal myelin blue.
Notice the area of demyelination (white) (“damaged”), at the upper right of the slide.
Within the plaque, particularly at its edge, is a robust inflammatory response.
Monocytes (upper) within a blood vessel is a perivascular cuff, show staining for T-cells, B-cells, and macrophages, but NOT neutrophils.
Note some of the cells are entering the brain parenchyma.
Axons are also damaged. This axon should be contiguous. Here it is damaged, as shown by disrupted staining and an abnormal spheroid at its end (‘damaged’ – left red arrow). This is indicative of a transected axon.
What causes MS?
We do not know the cause of MS.
A single virus or environmental agent has never been proven to cause MS.
Most scientists believe a virus acts as a trigger in a genetically susceptible person, that results in an autoimmune response in the central nervous system.
People with a genetic predisposition to MS associated with exposure to a yet unknown environmental factors, develop CNS inflammation followed by demyelination and axonal loss (the latter also known as ‘neurodegeneration’).
This is a model of the pathogenesis of MS within the CNS.
Note that lymphocytes (labeled TH1) within a blood vessel are activated in the systemic circulation. They then cross the blood brain barrier and initiate an autoimmune response within the CNS. Note that the TH1 lymphocytes stimulate (green arrows) B-cells to make antibodies, and macrophages to make substances that can demyelinate or cause axonal damage. Note that TH2 cells tend to regulate the process and reduce (red arrows) the pro-inflammatory response of the TH1 cells. Many believe that the CNS becomes its own immune organ (i.e., like a lymph node) in MS patients.
Like all autoimmune diseases, MS is more common in women.
This is true for relapsing remitting MS (RRMS). In primary progressive MS (PPMS) the gender distribution is about equal.
- The peak age of onset for MS is the third decade of life. Most cases strike between ages 15 and 45.1
- Women outnumber men by a ratio of greater that 2:1, which is seen in many autoimmune diseases.2
- Although the cause of MS is unknown, studies support a complex interaction of environmental and genetic factors.3
- One of the more puzzling aspects of MS is the increase in prevalence with distance from the equator, which is noted in both hemispheres and similar in Europe and the U.S.4
- There are between 8,500 and 10,000 new cases of MS diagnosed in the U.S. each year, and the disease affects a total of approximately 350,000 people.2
lPeople with MS usually fit into one of two general categories according to the predominant course of the disease:
–Relapsing
–Progressive
This describes relapsing remitting MS, like the patient presented earlier.
If MS is progressive from onset, it is called primary progressive MS.
The gender distribution in primary progressive MS is equal.
These patients usually develop spastic paraparesis over a period of years.
On exam, they will have evidence of corticospinal dysfunction (spasticity, weakness), sensory disturbance and urinary symptoms.
These symptoms are referable to the ‘long tracts’ of the CNS.
Work up will show an MRI and CSF just like relapsing remitting MS, yet they never relapsed!
We do not know why this occurs.
This type of MS is very difficult to treat.
There are no FDA approved medications to treat this type of MS.
The medicines to treat MS are for RRMS.
If patients develop progressive disease FOLLOWING a relapsing remitting stage, this is called SECONDARY progressive MS. This will be discussed in few minutes.
- Approximately 85% of patients present with relapsing-remitting disease at onset. The remainder generally have primary-progressive or progressive-relapsing disease.
- A large number of patients with relapsing-remitting MS eventually progress to a secondary-progressive course. The latter is associated with significant disability, thus early treatment with an immunomodulating agent is crucial.
- Approximately 50% of patients require walking aids within 15 years of diagnosis.
Each graph denotes a different clinical type of MS.
Graph one shows the natural history of benign MS. These patients have a few relapses, but never progress. This is rare.
Graph two shows relapsing remitting MS. This has already been described.
Graph three shows secondary progressive MS. Over time, as the number of plaques increases within the CNS, patient’s worsen even when the relapses stop.
Graph four shows the natural progression of primary progressive MS. Patients worsen without relapses. Usually they lose the ability to ambulate due to spastic paraparesis and other symptoms referable to CNS systems that affect gait (balance, sensory input, etc).
Natural History
Natural history studies, conducted prior to the availability of immunomodulatory therapy, showed the following:
Mortality from MS is low (life expectancy is at least 25 years after diagnosis; most patients die of unrelated conditions).
Average is 1 relapse per year, fewer over time.
25% of patients never lose ability to perform ADL, but 15% become severely disabled within a short time.
Median time to reach EDSS of 6 is 15 years; to reach EDSS of 8 is 46 years
(moderate disability:, assistance with walking is needed; severe disability, patients are confined to bed or chair and perform self-care only with help).
You’ve already seen several MRI scans of MS patients.
MRI is used to diagnose MS.
Cerebrospinal fluid (CSF) examination and evoked potentials can also be helpful.
Typically only visual evoked potentials (VEPs) are used.
Any combination of these symptoms can occur in an individual patient.
However, there are some that occur more frequently.
These are the most common symptoms that MS patients experience.
Note that onset of these symptoms are SUBACUTE, which separates them from stroke (acute) and other neurodegenerative diseases like Parkinson’s disease which are CHRONIC.
Symptoms usually occur over hours to days.
Remember that myelin allows for very fast saltatory conduction down an axon. Note that demyelination as well as axon loss will lead to symptoms experienced by MS patients.
The location of the demyelinating lesions influences the types of symptoms patients develop.
In a study conducted at the University of British Columbia, Paty et al determined that the initial symptoms in 1721 patients with clinically definite MS were as follows on the slide:
Over the disease course, symptoms are highly variable in both frequency and severity.
Fatigue is the most common symptom in 80% of patients with MS.
Again, MS plaques are periventricular (red arrow).
CSF in MS patients.
Protein is usually normal. Lymphocyte count is usually MILDLY elevated. It too may be normal.
The markers for MS in the CSF are increased IgG index and the presence of oligoclonal bands as shown here. (Oligoclonal bands are IgG’s of similar size) They are not normally present in normal CSF. They are present in serum.
Their presence suggests MS in a patient who has no other signs of systemic illness, but they can be elevated in other diseases such as lyme disease, syphilis and lupus.
Evoked response can also assist in diagnosing MS.
This is a visual evoked response- Light is flashed in front of the patient. It takes 100 msec for the light to pass from retina through optic nerve and chiasm to occipital cortex. The wave that results from the light is called the P100 (see OS=normal in both panels).
If the optic nerve is demyelinated from MS, there will be a delay of the P100 (bottom panel) or a complete absence of it (upper panel).
Other evoked responses can also be measured. We can measure how long it takes for a click to be heard from the ear to the auditory cortex (this is a brainstem evoked response) and how long it takes for an electrical stimulus to travel from the finger and toes to the sensory cortex via the ascending sensory fibers (somatosensory evoked response). Demyelination of these pathways will show abnormal wave forms, just like the VER
Now let’s meet our second patient.
Here is her presentation.
This is her diagnostic work up.
Note on the middle image, there are hyperintense lesions (plaques) located in the periventricular and juxtacortical areas, just like we saw on the pathology.
There are multiple lesions (plaques) on the image on the right also.
Several enhance with gadolinium (GAD) as shown by the yellow arrows on the left. Gadolinium is given to the patient intravenously during the scan, and enters the brain in areas of blood brain barrier breakdown and inflammation. This shows an examples of a newly formed, gadolinium enhancing (inflammatory) MS plaque.
Note that she has APD = afferent pupillary defects. This is the pathway. It was discussed in previous lectures.
An APD is consistent with a demyelination and axon damage on the side of the lesion.
This patient has clinically isolated syndrome, a syndrome that suggests MS.
CIS is defined in this slide.
Traditionally, we would wait for the second attack to diagnose this patient with MS.
However, now we use MRI to determine lesions in ‘time’ and ‘space’.
You do NOT need to memorize this.
This is used only to emphasize how MRI is used to diagnose people who only had ONE clinical attack (see yellow arrow).
Sorry for all of the jargon, but it’s in the literature:
LESION = PLAQUE
ATTACK = RELAPSE
MONOSYMPTOMATIC DISEASE = ONE ATTACK = ALSO CALLED ‘CLINICALLY ISOLATED SYNDROME”
Take home message: MRI can be used to help determine time and space. For instance, if an MRI at time one had 5 lesions and MRI 3 months later has 6 lesions, that patient had another attack, thus we have satisfied ‘time’.
Also, if a patient has an optic neuritis which we know occurs from demyelination of the OPTIC NERVE, yet has 15 lesions within her brain, thus there are lesions in two different areas of the CNS, thus we have satisfied ‘space’.
The newest criteria allows us to diagnose a patient at the first clinical visit.
As shown on the table on the right, this patient has MS plaques in periventricular (PV), juxtacortical (JX) and the posterior fossa (PF) AND HAS BOTH GAD ENHANCING AND NON-GAD ENHANCING LESIONS AT THE SAME TIME.
Since GAD ENHANCEMENT IS A SIGN OF A NEW PLAQUE, AND SOME PLAQUES DO NOT ENHANCE, THEN THESE TWO KINDS OF PLAQUES OCCURRED AT DIFFERENT TIMES IN THE PATIENT’S LIFE. Thus, she has dissemination in time (gad and non-gad lesions) and space (lesions in multiple areas).
So how many lesion on MRI do you need if a patients presents to you with ONE SYMPTOM = MONOSYMPTOPMATIC MS = CLINICAL ISOLATED SYNDROME = ‘CIS’?
Wow, only 1!.
If you have no MRI lesion, your risk of getting MS is about 20% at 14years.
Yet if you have 1-3, 4-10, or > 10 lesions, your chance of getting MS is about 90%!
Here are other conditions that can mimic MS.
Many are ruled out by MRI and blood tests.
Just like the patients presented today, here is the work up.
You do not need to order all of these labs.
Usually the labs in the first line are enough. Then add others if you are clinically suspicious.
Here are some of the medications used to treat MS.
Steroids are used for acute relapses, but have NEVER been shown to alter the natural history of disease.
We also treat symptoms with some of the medications listed on the left.
The medications on the right are FDA approved medications that reduce the risk of: relapse, new plaque formation and neurological progression.
Here are the brain MRIs of our first patient.
Note the gadolinium enhancing lesions on the upper two scans (pre-treatment), compared to the scans at 3 and 5 years.
This is not a cure, the old plaques are still there, but the new gadolinium enhancing plaques are not present
Our next patient has a spinal cord syndrome not related to epidural compression.
Note that she did NOT have back pain.
Note early urinary retention = suggests a spinal cord lesion!
Here is her neurological exam.
Is this a neurological emergency?
Note that the lesion within the spinal cord is limited to 1-2 vertebral body segments (arrows)
This is the definition of transverse myelitis.
It can be an early sign of multiple sclerosis, but also exists alone.
There is approximately a 30% chance of developing MS following an episode of transverse myelitis
Note the clinical presentation of this patient.
Severe thoracic pain, bouts of optic neuritis, acute paraparesis with urinary retention.
There are some important clues to the diagnosis, even before the positive test for aquaporin-4.
This includes a spinal MRI lesion at least 3 vertebral body segments long, neutrophils in the CSF, and a normal brain MRI (distinguishes it from MS)
IT can be even more severe, encompassing almost the entire spinal cord! (as shown by the arrow on the LEFT in sagittal view. The arrow on the right shows involvement of almost the entire thoracic spinal cord in the transverse plane.
Pathology,….eosinophils, neutrophils, hyalinized vessels distinguishes NMO from MS Pathology
Distinguishing factors: brain MRI, 3 VB segments, PMNs, OCBs more common in MS (no time to form in NMO)
Note differences, contiguous (NMO) vs. segmental (MS)
Review of INO.
The lesion is on the side of the ADDUCTION deficit.
