Levin - MS Flashcards
What is MS?
- Chronic inflammatory disease of CNS (brain and spinal cord)
- Myelin (made by oligodendrocytes) destroyed and underlying axons and neurons damaged
- When myelin in lost in multiple areas, plaques (inflam and sclerosis/scar tissue) occur
- Periodic loss of neuro function (aka, relapse), and often progressive disability -> most common form, “relapsing remitting”
- Most common demyelinating disease in humans
What is Uhthoff’s phenomena?
- MS symptoms that worsen during an INC in body temp
- Very common in MS pts, and occurs due to poor electrical conduction along demyelinated axons
- NOTE: remember example from lecture where pt had vision loss and pain with eye mvmt (+ headache) that was aggravated by going outside into the heat (her 1st relapse) -> over time (maybe in a year), this pt may have recurrence of this symptom or a new symptom (like weakness and numbness in legs)
What is a relapse?
- A new neuro disability that lasts >24 hours
- Onset is usually subacute
Why does it matter that MS symptoms present in a subacute manner?
- This distinguishes these symptoms from the ACUTE symptoms of stroke
What does it mean that MS is a disease separated by time and space?
- CLINICAL DEFINITION:
1. Time = 2 relapses that occur during 2 different times in a person’s life
2. Space = 2 different areas of the CNS (example in lecture was woman with instance of optic neuritis, then subsequent trasverse myelitis)
What tests can you do help dx MS?
-
MRI: looking for plaques
1. Hyperintense on T2/FLAIR: see attached image (white matter dark gray and gray matter light gray) -
LP: spinal fluid shows inflammatory profile
1. CSF protein may be normal, but IgG index and oligoclonal bands are consistent with dx of MS
2. Lymphos may be present, but NEVER polys in classic MS
How is IV gadolinium used in MS mgmt?
- Gadolinium does NOT normally enter brain parenchyma
- In this MRI of brain after IV admin of gadolinium, arrow shows gadolinium enhancing MS plaque (there are several others in the white matter)
- This is an acute (new) MS plaque in which there is ACTIVE INFLAMMATION and BREAKDOWN of BBB, allowing gadolinium to enter brain parenchyma
What do you see here?
- MS plaque in the cervical spinal cord
- Spinal fluid surrounding parenchyma is white
- Arrow shows large white (hyperintense) plaque in dark grey spinal cord parenchyma
Are oligoclonal bands in the CSF specific for MS?
- No: they are present in CSF of MS pts, and those with infections of CNS -> useful when you have RULED OUT infection
1. Oligoclonal bands are just IgG’s of similar molecular weight - IMAGE: oligoclonal bands in spinal fluid, but not plasma
In addition to MRI and LP, what is another test you can do for MS? How does it work?
- Visual evoked response (VEP): measures how quickly the occipital cortex detects light input from retina
- Normally, it takes 100msecs (P100) for light flashed in front of pt to pass from retina through Optic N to chiasm and occipital cortex
- IMAGE: pt has normal VEP on the left, and absent (above) or delayed (below) P100 on the right, which indicates demyelinated Optic N from MS
What are the classic dx criteria for MS?
- Clinical evidence for lesions that reflect white matter dysfunction disseminated in time and space in expected age range (18-50 yrs)
- Objective abnormalities on neuro exam, preferably at time of dx
- Dissemination of lesions in time must fit into one of the following patterns:
1. At least 2 clear cut episodes of func significant symptoms each lasting >24 hrs and separated by at least 1 month
2. Slow, progressive deterioration of the same disseminated pattern evolving over at least 6 mos - Dx should be made by a skilled physician
- Must be no better explanation for the dx
- NOTE: described as “CLINICALLY DEFINITE MS”
What is one of the typical distributions of MS plaques?
- PERIVENTRICULAR: see attached image
- Also ovoid in shape
In addition to the classic periventricular plaques, where else in the brain can these be in MS pts?
- JUXTACORTICAL: in deep white matter of regions adjacent to cortical grey matter (see attached image)
- Remember: periventricular also characteristic, and shown in attached image
What is going on in this luxol fast blue stained image?
- Showing MS plaque: see attached image
- Luxol fast blue stains normal myelin blue, so the white area of this image is demyelinated (damaged)
What is going on at a cellular level in these MS plaques?
- Within the plaque, esp. at its edge, is a ROBUST INFLAMMATORY RESPONSE
- IMAGE: monocytes (upper) in blood vessel is called a perivascular cuff
1. Also shown is staining for T-cells, B-cells, and macros (notice that there are NO NEUTROPHILS)
2. Some of the cells are also entering the brain parenchyma
How are axons affected in MS plaques?
- They are DAMAGED
- Axon in attached image should be contiguous, but the staining shows that it is disrupted, and has an abnormal spheroid at its end
1. This is indicative of a transected axon
Describe the pathogenesis of MS.
- Cause uncertain, but immune-mediated inflammatory disease of CNS -> demyelination and axonal loss (aka, neurodegeneration)
1. Leukocytes penetrate BBB and secrete inflam cytokines
2. T-cells, B-cells, macros orchestrate autoimmune attack against myelin antigens - May devo in 1) genetically susceptible ppl who are exposed to undefined 2) envo triggers (most scientists believe virus acts as a trigger)
How are TH1 and TH2 cells involved in MS?
-
TH1 activated in blood vessel in systemic circulation, then cross BBB and initiate immune response in CNS
1. STIMULATE (green arrow) B-cells to make Ab’s, and macros to make substances that can demyelinate or cause axonal damage - TH2 cells tend to regulate the process and REDUCE (red arrows) the pro-inflammatory response of TH1 cells
- Many believe that CNS becomes its own immune organ (i.e., like a lymph node) in MS patients
What is the epi of MS?
- Typically dx’d in young adults bt 15-45 (peak age of onset during 20’s)
-
75% women, or 2:1, F:M (auto-immune diseases more common in women) for RRMS
1. In PPMS (primary progressive), however, gender distribution about equal (M = F) - Incidence INC w/distance from equator (in both hemispheres)
- Complex interaction of envo and genetic factors
What are the clinical types of MS? Describe their basic features.
- Ppl with MS usually fit into 1 of 2 general categories:
1. RELAPSING (RRMS): exacerbations followed by complete or incomplete recovery -> slow, inconsistent accumulation of disability in majority
2. PROGRESSIVE (PPMS): steady progression of disability from onset with few or no exacerbations
What are the features of PPMS?
- PROGRESSIVE MS: steady progression of disability from onset with few or no exacerbations
- M = F
- Usually devo spastic paralysis over period of 2 years
- Evidence of corticospinal dysfunction (weakness, spasticity), sensory disturbance, and urinary symptoms, aka, long tracts of CNS
- MRI and CSF like relapsing MS, but never relapse (do not know why this occurs)
- Very difficult to treat -> no FDA-approved meds (the meds for MS are for RRMS)
- NOTE: if RRMS pts develop progressive disease after RR stage, this is called SECONDARY progressive MS
Describe the natural history of the 4 main types of MS.
- BENIGN MS: few relapses, but never progress -> this is rare
- RRMS: slowly progressive relapse and remissions
- 2o PROGRESSIVE: over time, as # of plaques INC w/in CNS, pts worsen even when relapses stop
- PPMS: pts worsen w/o relapses, and usually lose the ability to ambulate due to spastic paraparesis and other symptoms referable to CNS systems that affect gait (balance, sensory input, etc.)
What are the MOST COMMON symptoms that MS pts experience?
- OPTIC NEURITIS: unilateral, retrobulbar pain with no retinal exudates, disc hemorrhage infrequent, and some recovery
- MYELITIS: partial sensory > motor (ASYMMETRICAL), band-like pressure, Lhermitte’s sign (electrical sensation that runs down back into limbs), bowel and bladder sxs common, acute dystonias
- BRAINSTEM: ocular motor (INO, nystagmus), trigeminal neuralgia, hemifacial spasm, Bell’s palsy, vestibulopathy and other cranial neuropathies
- CEREBELLUM: acute ataxia, tremor, eye mvmt abnormalities
- REMEMBER: onset of these sxs is SUBACUTE (occur over hrs to days), separating them from stroke and o/chronic neurodegenerative diseases like Parkinson’s
Briefly describe why demyelination causes MS symptoms.
- Neuro dysfunc in MS reflects conduction impairment along partially or completely demyelinated segments of myelinated fibers
- Partially or completely demyelinated segments are temperature-sensitive, and less efficient w/INC temp
- Degree of tissue swelling (edema) after breakdown of myelin also contributes to severity of symptoms
- Myelin allows for very fast saltatory conduction down an axon, so demyelination and axon loss leads to MS symptoms
What might you find in the CSF of MS pts?
- Protein usually normal
- Lymphocyte count MILDLY elevated, and may be normal
- Markers for MS in the CSF are INC IgG index and presence of oligoclonal bands
- Oligoclonal bands are IgG’s of similar size that are not normally present in CNS, but are in serum
1. Presence suggests MS in pt who has no other signs of systemic illness (but can be elevated in other diseases, like lyme, syphilis, and lupus)
36-y/o F w/loss of vision. Woke up with blurry vision OS and pain w/eye mvmt. Worsened throughout day to almost complete loss of vision.
No hx of other episodes, medical exam normal, neuro exam shows L afferent pupillary defect (APD). MRI attached. VER delay on L. Labs (-). IgG index and 1 oligoclonal band in CSF. Tx’d with 3d of IV steroids, and vision returned.
What is going on with her?
- CLINICALLY ISOLATED SYNDROME (CIS): a clinical episode suggestive of an MS pt’s first relapse
1. Optic NN: optic neuritis
2. Brainstem: INO, bilateral; disorder of conjugate lateral gaze in which 1 eye fails to adduct
3. Spinal cord: PARTIAL transverse myelitis
4. Lasts at least 24 hours
5. Typically age 20-45 years
6. No evidence of infection, fever, or encephalopathy - NOTE: APD consistent with demyelination and axon damage on the side of the lesion
Why are the McDonald criteria so useful in MS dx?
- McDonald criteria: clinical exam + specific MRI criteria to aid in early dx of MS, as opposed to waiting for 2nd relapse
- This criteria allows dx of pt at 1st clinical visit
- IMAGE: pt with MS plaques in paraventricular, juxta-cortical, and posterior fossa and BOTH gad-enhancing and non-gad enhancing lesions at same time
1. Since gad enhancement is sign of new plaque, and some plaques do NOT enhance, these 2 kinds of plaques occurred at different times in pt’s life -> dissemination in time (gad and non-gad) and space (lesions in multiple areas)
How many lesions on MRI do you need if pt presents with one symptom (CIS)?
- Only 1
- IMAGE: bottom line is for 0 lesions, and other are for subsequent #’s above 0
1. If you have no MRI lesion, your risk of getting MS is about 20% at 14 yrs
2. If you have 1-3, 4-10, or >10, your chance of getting MS is bt 80 and 90%
What are some conditions you need to exclude in suspected MS? How can you do this?
- Many are ruled out by MRI and blood tests
What is the workup for MS?
- You do not need to order all of the labs -> usually the labs in the first line are enough (add others if clinically suspicious)
- Can usually make dx after history/PE and MRI
What txs are available for people with MS?
- Steroids are used for acute relapses, but have NEVER been shown to alter natural history of disease
- Treat symptoms with some of the meds listed on the left
- Meds on the right are FDA-approved to reduce risk of relapse, new plaque formation, and neuro progression
Can tx “cure” MS?
- No: note in these MRI’s from case that old plaques are still there, but new gadolinium enhancing plaques are not present
37-y/o woman with acute onset of numbness below waist. Also patchy areas of numbness at torso and upper abdomen. Initially, not weak, but over 24 hours the pt developed lower extremity weakness and urinary retention.
Neuro exam: HIF normal, CN full and symmetric, DEC pin prick from mid-chest distally. Paraparesis L > R and great difficulty walking. Hyperreflexic w/extensor plantar response and DEC rectal tone. Post-void residual of 250cc.
Imaging attached. Hyperintense on T2 weighted images and acutely enhances with gadolinium.
What might be going on?
- Transverse myelitis: spinal cord syndrome not related to epidural compression
- No back pain
- Early urinary retention suggests spinal cord lesion
- Limited to 1 or 2 vertebral bodies
- This is a NEURO EMERGENCY
45-y/o F with severe thoracic pain and paresthesias and weakness of lower extremities. Several years earlier, she had recurrent optic neuritis OD tx’d with steroids. Initial clinical exam revealed sensory level at T4 and 3+/5 paraparesis + urinary retention. Visual acuity OD: 20/200.
Thoracic spine MRI with lesion in spinal cord T1-T7, with enhancing signal T1-T3. Brain MRI normal. VEP’s prolonged bilaterally. CSF: 110 WBC (50% N), protein 100, glu 50, and (-) oligoclonal bands.
IV steroids and long-term immunosuppression to control disease. Serum Ab test for aquaporin-4 (+); NMO IgG. MRI attached.
What is going on?
-
Neuromyelitis Optica:
1. Spinal MRI of at least 3 contiguous vertebral segments long (to distinguish from transverse myelitis)
2. Neutrophils in CSF
3. Normal brain MRI (to distinguish from MS) - VEP’s always abnormal in these pts
- NMO IgG used for dx: serum test
What are some of the pathological features of NMO that distinguish it from MS?
- Eosinophils: NEVER seen in MS -> pathological sign of NMO
- Neutrophils: NEVER seen in MS
- Hyalinized vessels also distinguish from MS
What is the mechanism of NMO?
- Antibody-mediated demyelination, axonal injury, and necrosis
- Antibodies to AQP4 attack these receptors on astrocytes, leading to BBB breakdown, activation of complement, and severe necrosis of spinal cord NN
What are the dx criteria for NMO?
- MRI of brain normal, esp. early on
- NMO IgG = serum Ab test (to AQ4)
What are some of the distinguishing factors bt NMO and MS (chart)?
- Brain MRI: small dots or normal MRI for NMO
- 3 vertebral segments
- PMN’s
- Oligoclonal bands more common in MS (no time to form in NMO)
Which of these are NMO vs. MS? How can you tell?
- MS is first one on the left: SEGMENTAL lesions
- NMO in other two: CONTIGUOUS
1. On T1, may be hypointense lesions indicating necrosis and cavitation, while enhancing with IV gadolinium due to active inflammation
What do you see here?
- Internuclear opthalmoplegia (INO)
- One eye unable to adduct on horizontal gaze
- From damage to MLF -> lesion on side of ADDUCTION deficit
