Demyelinating Diseases (Cohen)

Question 1

Demyelinating Diseases

Answer 1

Demyelination (damage or destruction of the myelin sheath of axons) of the brain, optic nerves and spinal cord

Multiple Sclerosis
Devic Disease: Neuromyelitis Optica (NMO)

Demyelination of the peripheral nervous system:
Guillain Barre Syndrome

Question 2

Why is demyelination so damaging?

Answer 2

There is a loss of saltatory conduction in neurons because of diminished nodes of Ranvier

Question 3

Multiple Sclerosis

Answer 3

The most common nontraumatic cause of neurologic disability in young adults

• visual loss, diplopia, dysarthria, ataxia, weakness (especially of both legs), sensory loss, bladder dysfunction, and later in the course there may be loss of cognitive abilities
• Primarily a disease of MYELIN DESTRUCTION in oligodendrocytes, but eventually AXONS are destroyed, too in severe cases
  1. Loss of axons may correlate best with overall disability

Mean age of first attack THIRTY YEARS-OLD, with 70% or more of first attacks between ages 20 and 40
Rare in patients under age 10 or over age 55

Question 4

MS Epidemiology

Answer 4

Increasingly common as one moves north of the equator, in Europe and North America
Location in the first 15 years seems to matter most
Somewhat increasingly common as one moves south of the equator, in the southern hemisphere, although uncommon in much of central Africa
Prevalence is early 1/1000 adults in the northern US and in Canada and about 1/100,000 in southern US, Mexico
Much less common in Asians and Africans than in Europeans

Question 5

Genetics of MS

Answer 5

Not Mendelian autosomal or recessive at all
Sex-linked somehow, since @ 70% of patients are female
Twin studies: more common in monozygotic twins as in dizygotic twins, but always less than 50% in monozygotic twins
Human Leukocyte Antigen Associations:
DR15 phenotype, and less so D3 and D4

Question 6

Pathology of MS

Answer 6

An auto-immune disorder involving T-cell mediated attacks on CNS myelin, with formation of plaques (scars)
AXONS ARE ALSO DESTROYED AS THE DISEASE PROGRESSES
Oligodendrocytes are damaged and may be destroyed

Question 7

questions involving the pathology of MS

Answer 7

1. What antigen(s) is the target in myelin? In molecular mimicry, a foreign antigen/virus is attacked, and then a normal component of the body which has molecular similarities, then attacked later by the activated immune system. Is it myelin basic protein or some other component of the myelin?
2. How do T-cells cross the blood brain barrier in large amounts?
3. Specifically, which T-cell subtypes?
4. B-cells are also active, with secretion of antibodies
5. Macrophages and complement play a major role
6. Numerous cytokines and chemokines, such as interferons (beta, gamma), interleukins, necrosis factors, adhesion molecules are secreted by lymphocytes to increase or suppress inflammation
7. What starts the auto-immune process, apparently in childhood? Prior infections with viruses such as HSV, mumps, Epstein-Barr, CMV? Lack of sunlight and low serum levels of vitamin D in northern locations?

Question 8

Four clinical courses of MS

Answer 8

1. Benign MS
2. Relapsing remitting MS
3. Secondary chronic progressive
4. Primary progressive

Question 9

Multiple Sclerosis: Clinical course

Answer 9

Extremely VARIABLE course in every patient
Approximately 80% of patients have periodic attacks, or exacerbations at first: RELAPSING/REMITTING MS
Primary progressive for some patients, who continuously worsen right from the start
Secondary progressive for some patients after a period of relapsing/remitting; continuing and worsening signs, and very limited treatments for this
“Benign MS” is rare: patients have a small number of mild attacks and regain full function eventually

Question 10

Overall prognosis of MS

Answer 10

Extremely variable for patients, perhaps no two patients truly look alike, but more than one attack per year in the first few years suggests a bad outcome
Generally the prognosis is worse when symptoms begin in the 40s and 50s, rather than 20s and 30s
Shortens life expectancy, but perhaps by only 5 – 10 years
A majority will have some permanent impairment of gait, vision or urinary function
Kurtzke’s Rule: 90% of disability in MS patients occurs within 10 years of initial diagnosis

Question 11

Symptoms during first MS attack

Answer 11

Visual loss or double vision 49%
Weakness 42
Paresthesiae (altered sensation) 41
Incoordination 23
Urinary difficulties 10
Depression, dysarthria, tremors < 10

(Total is >100, because some patients presented with multiple symptoms)

Question 12

Clinically Isolated Syndromes (CIS), and how evaluated

Answer 12

These are the most common FIRST ATTACKS of patients with multiple sclerosis, leading to consideration of a diagnosis:

1. Optic neuritis, sudden loss of vision in one or both eyes, often painful
2. Brainstem or cerebellar symptoms/signs, including internuclear ophthalmoplegia
3. Spinal cord deficits (Myelopathies), with paraparesis, sensory level or urinary incontinence

Evaluated with MRIs, and sometimes spinal taps, in hopes of making the diagnosis of MS as early as possible, since early pharmacological treatment improves the ultimate outcome in patients (lessens the ultimate disability)

Question 13

Optic neuritis

Answer 13

Injury to an OPTIC NERVE, usually demyelinating, or unknown pathology
Painful, sudden loss of all or nearly all vision in one eye; painful when moving the eye, due to swelling of the nerve
Occasionally both eyes are affected at one time; many patients will have a recurrent episode of optic neuritis
Patients lose vision in the middle of the visual field for that eye
Pupillary reaction is usually lost; Marcus-Gunn pupillary reaction is seen: when flashlight is quickly moved from the normal eye to the affected eye, it may seem to dilate: PUPILLARY AFFERENT DEFECT
Much of the inflammation is behind the retina, so examiner may not see anything at first; later the disc may be a lighter shade of yellow: PALLOR
Approximately one-half of patients with optic neuritis will ultimately develop multiple sclerosis: increased chance if a brain MRI shows white matter lesions
Time to recovery is shortened by use of intravenous, but not apparently oral, corticosteroids, but majority of patients do recover all of their vision

Question 14

Internuclear Ophthalmoplegia, INO

Answer 14

When looking to one side, the ADDUCTING eye cannot reach the medial edge of the eye, and the ABDUCTING eye goes part-way, but has severe nystagmus
Usually bilateral in multiple sclerosis
Caused by damage to the MEDIAL LONGITUDINAL FASCICULUS in the brain stem, originating in the nucleus of CN VI and reaching the contralateral CN III
Only two causes: multiple sclerosis (prolonged, or permanent impairment), or brain stem stroke (disappears in days)

Question 15

Clinically Isolated Syndrome: myelopathy

Answer 15

Patients lose part or all of their spinal cord function, usually over days or weeks
Weakness of both legs, sensory loss, bladder difficulties, sometimes severe mid-back pain
Reflexes are increased in the legs, Babinski signs
MRI of the cervical or thoracic spine is usually abnormal, although a brain MRI is often normal
Lumbar puncture shows mild elevation of white cells and protein, but not always oligoclonal bands
Patients need to be checked for infections, tumors, systemic lupus erythematosus, even herniated discs
Most will recover; occasionally the only diagnosis that can be made is “transverse myelitis”

Question 16

Diagnosis of MS: not that easy!

Answer 16

In general, multiple attacks in time, and multiple attacks in different locations of the brain, spinal cord or optic nerves Many young patients have symptoms for a few days or weeks, and do not seek medical attention until they are older
Most easily diagnosed when patients have had two or more attacks of CNS dysfunction, in different sites, best explained by MS, rather than any other illness
With the help of MRI scans, the diagnosis can sometimes be made after a first suspected attack if there are lesions in OTHER areas which would not cause the current symptoms/signs: i.e., the patient NOW has a clinical cerebellar deficit, but MRIs of the brain and spinal cord show OLD lesions in other locations

Question 17

Diagnostic criteria for MS

Answer 17

In general, a history of TWO or more known attacks Clinically isolated syndromes) in the brain or spinal cord, at TWO or more distinct times
‘MULTIPLE CNS ATTACKS IN TIME AND SPACE’
No other likely explanation exists for these attacks: a differential diagnosis exists:
A. SLE, vasculitis, Lyme, Anti-phospholipid syndrome, infections, AIDS, HTLV-1, vitamin B12 deficiency, strokes, tumors, cervical spondylosis in older patients
MRI abnormalities in the white matter are common, and may be due to trauma, cerebrovascular disease, trauma, migraines, or no known cause

Question 18

MRI findings in MS

Answer 18

The diagnosis remains a clinical one, but is supported when a brain MRI shows:
At least three lesions in the cerebral white matter
More suggestive if there are brain stem, corpus callosum, optic nerves or cerebellum

Too often, patients are diagnosed solely on the basis of MRI findings, and this has probably led to over diagnosis recently

Consider a cervical or thoracic MRI to look for more evidence of MS; discrete cord lesions are further strong evidence of MS

Question 19

Other diagnostic aids for MS

Answer 19

Lumbar puncture: OLIGOCLONAL BANDS in >90% of patients eventually, so this may be a more specific finding than white matter lesions on MRI
These are IgG bands each specific for one antigen
Multiple sclerosis patients have at least four bands
Increased levels of myelin basic protein, or IgG index
Increased WBCs, but always under 100/mmm

Question 20

Treatment of MS

Answer 20

“DISEASE MODIFYING TREATMENTS”
Indicated for nearly all patients, PERHAPS even with Clinically Isolated Syndromes
Limit the frequency of future attacks, by one-third or more
Probably also limit the eventual disability
Most are for relapsing remitting MS
Formerly all were intramuscular or subcutaneous drugs but now there are ORAL disease modifying treatments, which patients prefer, and they probably cause better patient compliance

Question 21

Mechanisms of DMTs

Answer 21

Interferons: beta interferons may work in vivo to limit the pathologic activity of MS patients. Possible mechanisms:

 1. Suppress release of other chemokines
 2. Blockage of adhesion molecules, so that activated T lymphocytes cannot cross the blood brain barrier and attack myelin
 3. Limit proliferation of lymphocytes

Glatiramer may mimic the sequence of a myelin protein, like a “decoy,” and attract CD4 cells which attack the drug rather than myelin

Question 22

BETA INTERFERONS:

Answer 22

DMT for MS

Avenox, weekly, Interferon beta-1a
Betaseron, every other day, Interferon beta-1b
Rebif, three times a week, Interferon beta 1-a

Question 23

GLATIRAMER ACETATE (Copaxone

Answer 23

All indicated only for relapsing remitting multiple sclerosis, with clear efficacy; reducing further attacks by approximately 30 - 35%

Question 24

Newer DMTs

Answer 24

NATALIZUMAB (Tysabri)

1. Monoclonal antibody which may limit entrance of T cells into the CNS via interference with adhesion molecules
2. Given IV in pre-approved infusion centers only, associated with rare cases of Progressive Multifocal Leukoencephalopathy (PML), a fatal viral infection of the brain, approaching 0.15
   a. for safety, Natalizaumab is occasionally stopped for a few months, and patients need to be checked for possible serum antibodies to the JC virus which causes PML
3. Possibly even greater reductions in future relapses (50%) than are seen with the four older disease-modifying treatments

Question 25

Oral disease modifying treatments

Answer 25

FINGOLIMOD (Gilenya)
It is a once a day capsule which is a sphingosine 1-phosphate receptor modulator
The drug seems to limit the circulation of lymphocytes, so they tend to stay inside lymph nodes and are MUCH LESS LIKELY TO CROSS THE BLOOD BRAIN BARRIER
Adverse effects include cardiac effects such as bradycardia and coronary artery disease, but most patients tolerate the drug better than the injectable DMTs

Question 26

MS Treatment: targeting B cells

Answer 26

Rituximab attacks CD20 B cells

a. Monoclonal antibody which can destroy lymphocytes by producing antibody or complement mediated cytotoxicity or apoptosis
b. Long known to be effective for lymphoma and rheumatoid arthritis
c. Can cause neutropenia and numerous infections including hepatitis B

Ocrelizumab
a. Also a monoclonal antibody which targets CD20 B cells, with perhaps fewer adverse effects

Question 27

Symptomatic treatments for MS

Answer 27

Corticosteroids can limit the severity and duration of individual relapses of MS, especially if given in high doses IV
Antispasmodics such as lioresal and tizanidine
Antidepressants for depression and sometimes for fatigue
Fatigue is common, sometimes helped by amantadine or narcolepsy agents
Gabapentin, or pregabalin for pain
Agents for urinary frequency or retention

Question 28

Neuromyelitis optica or NMO

Answer 28

Optic neuritis AND spinal cord demyelination (myelopathy) without brain demyelination
First noted in the late 19th century
Rare disease, affecting perhaps 1/250,000 in the United States
16 cases collected by Devic, in 1894, and thereafter often referred to Devic’s Disease
Generally thought to be a subcategory of multiple sclerosis until the 1990s, perhaps due to use of MRI scanning
More extensive initial axonal damage than MS, and there appears to be much less REMYELINATION than in MS
NOW, IT IS CONSIDERED MORE OF AN INFLAMMATORY THAN A STRICTLY DEMYELINATING DISEASE

Question 29

More about NMO, or Devic Disease

Answer 29

Previously considered a rare form of multiple sclerosis involving only the spinal cord and one or both optic nerves, with no brain involvement
Much less common than multiple sclerosis in the United States and Europe, although in China and Japan, NMO is more common than MS
NMO has significant differences in apparent pathology and in treatment
Spinal cord MRIs show individual lesions EXTENDING THREE OR MORE LEVELS
The optic neuritis may be one or both eyes, occasionally simultaneously
CSF slightly abnormal, with mild elevation of white cells and protein
Therefore, neurologists often are unsure for months or years, after a single attack of either optic neuritis or myelopathy, if patients have multiple sclerosis or the less common Neuromyelitis Optica

Question 30

NMO: Pathology distinct from MS

Answer 30

Much more extensive axonal loss in the spinal cord than that seen in MS, sometimes with large cavities and hemorrhages
Remyelination appears to be far less common than in MS
The pathology appears to be IgG antibodies to AQUAPHORIN-4 CHANNELS, which allow permeability to water through the plasma membranes of astrocytes (glia)
These aquaphorin channels are primarily located in the optic nerves and the spinal cord, and far less commonly in the brain stem
A. Roughly 80 % of patients with NMO have serum antibodies to these aquaphorin channels
Demyelination extends along at least 3 vertebral segments, sometimes the entire cord
Brain is usually uninvolved with few or no lesions seen on a brain MRI

Question 31

The NMO Spectrum

Answer 31

NMO may strike the lower brainstem, where water channels also are found, as opposed to the cerebral hemispheres
The damage is often close to the fourth ventricle
Only a small group of NMO patients will have this, but it is being reported recently

Question 32

NMO Treatment

Answer 32

Clearly, the disease-modifying treatments which work for multiple sclerosis, such as interferons and copaxone, do NOT help patients with NMO
Most NMO patients get high dose corticosteroids with their first attacks, and these do seem to help
The current long term treatments are oral immune suppressing drugs, such as azathoprine (which limits DNA synthesis in dividing cells), or rituximab (which is a monoclonal antibody to B CD20 cells)
Nobody knows how long newly diagnosed NMO patients should be treated with these drugs

Question 33

Peripheral (polyneuropathies)

Answer 33

Damage to peripheral nerves is very common, especially in diabetics (half of whom develop this), patients with hypothyroidism, vitamin B12 deficiency, alcoholics, patients receiving chemotherapy, people with multiple myeloma and gammopathies, and patients with rheumatologic disorders
The damage is either demyelinating or directly axonal in these peripheral neuropathies
Most commonly there is more of a sensory loss, more than weakness, but patients may have disturbing numbness and pain, and are more inclined to fall

Question 34

The Guillain-Barre Syndrome

Answer 34

Acute inflammatory demyelinating polyneuropathy
May cause a RAPIDLY worsening paralysis bringing the patient close to death in a few days, although more commonly over two to four weeks
Auto-immune attack upon the roots of peripheral and sometimes cranial nerves
Usually follows a previous infection in the prior one to three weeks, commonly upper respiratory or gastrointestinal (may be due to Campylobacter jejuni), or surgery, trauma, vaccination, or no prior illness
First described by French physicians during World War I, a time of rampant infections, especially gastrointestinal ones

Question 35

Guillain-Barre Syndrome patient experience

Answer 35

Patients may initially have more sensory complaints, such as paresthesiae in the feet or hands, occasionally the face, sometimes painful…but only the motor roots of peripheral nerves are ultimately involved
The major symptom is progressive weakness, usually ASCENDING from the feet to the hands, trunk and bilateral face, progressing over 4 weeks or less
A. Rarely a descending paralysis
Deep tendon reflexes are nearly or completely lost within one week
Abnormal cardiac function especially arrhythmias, syncope
Death is generally through inhibition of respiration

Question 36

Pathology of GBS

Answer 36

In most cases there is a sudden attack of T cells, immunoglobulins, as well as complement and eventually macrophages, upon the roots of peripheral nerves, generally both the sensory and motor roots at first, then primarily the motor roots
The actual antigenic targets are on Schwann cells, and sometimes axonal membrane gangliosides
There is involvement of the roots of cranial nerves, too, in half of the patients
In the Miller-Fisher variation, the cranial nerves and the cerebellum are affected without any involvement of the peripheral nerves, and people have near total loss of all extraocular movements, facial weakness, and cerebellar deficits including inability to walk safely

Question 37

Diagnosis of Guillain-Barre

Answer 37

Clinical picture is dramatic in severe cases, with a rapid developing weakness of the arms and legs, the cranial nerves, the autonomic nervous system, and even the phrenic nerves, which may bring patients to the brink of death in less than two weeks
Nerve conduction studies and electromyograms show decreased velocity of conduction and delayed F-waves, which measure conduction in a peripheral nerve to the spinal cord, and then back out again to the hand or foot muscle
Lumbar puncture will become abnormal, but usually this takes one week or more:
Normal or slight elevation of white blood cells in CSF, but a SIGNIFICANT ELEVATION OF CSF PROTEIN, or the classic CELLULAR CHEMICAL DISSOCIATION
A. In meningitis and encephalitis BOTH the white cell count and the protein concentration rise

Question 38

Outcome of GBS

Answer 38

Today, less than 5 % of patients die, usually from cardiac or respiratory causes
Perhaps 90 % make a full recovery, which months, sometimes up to two years at most
Younger patients do better than the elderly
There can be permanent weakness and sometimes numbness/tingling and pain in the extremities

Question 39

Treatment of GBS

Answer 39

Two treatments affect the immunoglobulins which seem to cause the disease:
PLASMA EXCHANGE: Plasma is filtered with removal of large proteinaceous components, including immunoglobulins; invasive with a central venous catheter, morbidity due to volume changes

INTRAVENOUS IgG: newer, less invasive, but equally effective; sterile preparation of IgG from healthy volunteers, possibly attacks abnormal IgG causing Guillain-Barre Syndrome

Both treatments are most effective if begun in the first three weeks of the disease

Question 40

Chronic Inflammatory Demyelinating Polyneuropathy

Answer 40

CIDP: some similarities with Guillain Barre Syndrome, in that there is demyelination from white cells, and loss of deep tendon reflexes. However:

1. Much slower time course, generally one month or more, and patients may gain or lose strength over many months, rather than have only a downhill course
2. More likely to be painful than GBS, especially in the legs
3. Cerebrospinal fluid studies are not as dramatic, but the CSF protein is still elevated nearly all of the time

Question 41

CIDP Treatment

Answer 41

Responsive to all of the treatments which help GBS, although in CIDP oral corticosteroids such as prednisone may be very helpful
Plasmapheresis and intravenous IgG for the more severely afflicted patients
The disease may have multiple relapses, unfortunately, which become less responsive to treatment