myelination disorders Flashcards
CNS myelin
oligodendrocyte- responsible for axon myelination in the CNS (analogous to schwann cell in the PNS), small round dark nulcei with short processes (oligo
Each oligodendrocyte provides a myelin sheath to several axons, a cytoplasmic process of the oligodendrocyte wraps around the axons and the external surfaces and cytoplasmic surfaces fuse
Myelin components- myelin basic proteins (MBP)- plasma membrane bound, proteolipid protein (PLP structural component of myelin
de and dys myelination
de myelination- destruction of myelin with relative preservation of axons- acquired disorders (ms, acute disseminated encephalomyelitis, central pontine myelinolysis, progressive multifocal leukoencephalopathy (PML), neuromyelitis optica (NMO)
Dysmyelination- failure to form myelin normally- leukodystrophy- discussed in metabolic disease session
MS
most common demyelinating disease of CNS, demyelination is multifocal (disseminated in space) and lesions are of different ages (disseminated in time), epidemiology- prevalence of approximately 1/1000 persons, W>M, peak age of onset 20-40, occurs more frequently in northern climes environmental etiology
Family twin/racial studies- familial rates, lowest in Af am, jap, chi, asians form ind pak
Ms classification
Classic type
Rapidly progressive types- Acute- marburg type, concentric sclerosis (Balos disease)
MS pathology
Grossly plaques of demyelination- depressed, irregular, firm (sclerosis- hard)
Usually occur in - periventicular white matter, optic nerves and chiasm, brainstem and spinal cord tracts, cerebellum, also occur in gray matter
types of MS plaques
active plaque- macrophages with myelin debris, perivascular lympocytes, reactive astrocytes, relative preservation of axons
Inactive plaque- few or no macrophages, few lymphocytes, myelin loss with axonal preservation, fibrillary astrocytes
Shadow plaque- partial myelin absence (either due to incomplete myelin loss or partial remyelination)
acute disseminated encephalomyelitis ADEM
monophasic demyelinating disease, acute onset, associated with recent viral illness, or immunization signs or symtoms occur 1-2 weeks following
also called perivenous encephalomyelitis and post infectious encephalomyelitis
headache lethagy and coma if diffuse brain involvement
80% complete recovery
Pathology- perivenous demyelination with axonal preservation, polymorphonuclear leukocytes PMNs early and lymphocytes later
Pathogenesis- immune response to pathogen associated antigens cross reacts to myelin ags that results in myelin damage
neuromyelitis optica, devic disease
relapsing synchronous bilaterl optic neuritis and spinal cord lesions, W>M, asians and af am >caucasians
Median age of onset is 39
path- necrosis- not just demyelination with inflammatory cells , Aquaporins (AQP4)- membrane water channels that help maintain astrocytic foot processes (autoantibodies induce complement- dependent cytotoxicity, leukocyte infiltration, cytokine release, and BBB breakdown), lead to oligodendrocyte death, myelin loss
AQP4 specific igG antibodies detectable in 60-90% of NMO pts
Central pontine myelinolysis (osmotic demyelination syndrome)
Monophasic process- loss of myelin with relative preservation of the axons and neurons in basis pontis–> limb weakness (quadriplegia), gaze / speech abn, dysphagia, hypotension, may affect extrapontine sites
Most commonly associated with too rapid correction of hyponatremia, associted with alcoholic liver damage, post liver transplant, chronic malcourishment/debilitation extensive skin burns
MS common problems
Optic neuritis is very common
Will not affect the peripheral nerves
Periventricular, juxtacortical, cortical infratentorial, sp cd invovlement are the most common
Autoimmunity in MS
Autoimmunity is a failure of an organism to recognize its own tissues as self which can lead to an immune response against its own cells and tissues
It is not known what triggers the onset of MS Genetic factors MHC, Environmental factors
B cell and T cell with blood brain disorder
Ms pathology
MS is believed to be driven by autoreactive CD4 T cells with specificity for antigens expressed by oligodendrocytes which comprise myelin, Myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP)
It is generally believed that myelin specific T cells get activated in the periphery then cross the BBB, where they are reactivated and initiates destruction, activation and expansion of autoreactive CD4T cells, breakdown of the BBB, infiltration of immune cells into the CNS, De myelination and remyelination, axonal and neuronal degeneration
T cells in MS
Strongest genetic risk facotr of development of MS is the MHC class 2 DR2 DRb1 1501 During activation differentiate into effector T cells
Th1 signiture cytokine is IFNy, Th17 cytokin is IL17A
B cells in MS
ectopic germinal centers
AStocytes that mess with BBB
Microglia damage and repair
Axonal loss and progression
axons actually die along with the demyelination
Presenting symptoms
Sensory symptoms- numbness/tingling, weakness, visual loss, ataxia, diplopia, vertigo bladder and bowel
A clinical attack has to be 50 days apart
eEG cant use
MS risk factors
HLA Drb1*1501, vit D deficiency, viral infections EBV, smoking
Rare in black africans and asians
Dq 6
Environmental facotrs
Vitamin D- 1,25 dihydroxyvitD (calcitriul is protective on vit D
Smoking increases
Viral infections- herpetic- EBV
Internuclear opthalmoplegia
Decrease sensation in the face to fine touch, Internuclear opthalmolegia
Optic neuritis
acute or subacute onset of monocular visual blurring or loss, central blind spot
Pain with eye movement (90% of pts)
Loss of color vision
May have poor visual acuity but at least worse than baseline
Afferent pupillaty defect
initial symptom of MS in 13 %
Common
Relative apparent pupillary Defect (the other pupil doesnt constrict
sensory symptoms of MS
dysthesias/pain
Lhermittes phenomenon- Electric sensation passing down the back and limbs upon flexion of the neck
Brainstem symptoms of MS
Nystagmus, diplopia (intranuclear opthalmoplegia) facial weakness, vertigo, dysphagia, trigemina neuralgia
Nausea and vomiting (intractable), hiccupping< rare in MS but very often seen in neuromyelitis optica
motor symptoms of MS
Upper motor neuron- spasticity, hyperreflexia, atrophy uncommon,
Spastic parapresis is common in primary progressive MS
Fatigue in MS
Very common, (rule out thyroid)
CSF in MS
White blood cells may be elevated (<50) with a lymphocytic predominance, protein may be high but usually <100
Oligoclonal bands (OCBs)- 85-95% of pts with clinically definite MS (CDMS) will have OCB in the csf, positive OCB are bands that are found in th eCSF but not identified in the corresponding serum
PTs with a clinically isolated syndrome and positive OCBs have a higher rate of conversion to CDMS (25% v 9% at 3 years) hence the inclusion in 2017 criteria for DIT
OCBs can also be seen in infections such as, subacute sclerosing panencephalitis, viral encephalitis, Lyme disease and syphilis, or other inflammatory conditions (sarcoiid) thus it is important to rule out MS mimickers, can also be seen in 7% of normal individuals
ms treatment
Acute exacerbations- Steroids (typically) methylprednisolone (one gram IV) daily for 3-5 days, steroids only help speed the rate of recovery, they dont change how much a patient recovers, if very sever, can do plasma exchange
Immunomodulatory therapy or disease modifying therapy (DMT for long term
Symptom management
Healthy living abstain from smoking
Clinically isolated syndrome
first neurologic episode lasting>24 hrs caused by inflammatory or demyelinating lesion of the CNS, can be unifocal or multifocal symptoms
Patients with MR showing >2 lesions are likely to progress to those with normal MRI
Multiple studies demonstate that treating CIS delays the prgression to clinically definite MS
Radiologically isolated syndrome
White spots periventricular, juxtacortical infratentorial, spinal cord is seen on mri but before any symptoms
Prodrome
balos concentric sclerosisq
rare variant of ms in asians
tumefactive demyelination
constant headache and cant see quite right
usually cortical involvement
looks like a neoplasm
steroids
marburg variant
extremely severe ms
usually results in death
ADEM
pediatric, usually monophasic after an infection/vaccine
poly focal, encephalopathy
perivascular, lymphocytes and macrophages, T cell mediated
axonal sparing
steroids
neuromyelitis optica
optic neuritis inNMO usually bilateral and severe, sp cd , symptoms for days
CSFwith
pmns and oligoclonal bands
IGG against aquaforins
