Module 2 - MS Flashcards
Describe the gross pathology of MS:
Translucent plaques, often periventricular, optic nerve, substantia nigra, pons, pyramidal tracts, cerebellar white matter, nuclei, peduncles. Widening of sulci because of grey matter demyelination.
Define MS:
A chronic inflammatory multifocal, demyelinating disease of the central nervous system of unknown cause, resulting in loss of myelin, and oligodendroglial and axonal pathology.
What is the epidemiology of MS?
2:1 women:men
White, Nordic
120,000 cases in UK (after Denmark and Sweden, Mackenzie 2013)
Life expectancy reduced by 7-14 years but disease duration <50 years and 31% remain in active employment after 15 years (89% controls) and 33% in relationship (53% controls) Pfleger 2010
What are the risk factors for MS?
Distinct latitudinal variation globally (except Norway, because vitamin D? More time outside and eat more fish and cod-liver oil supplements in North coastal towns)
Instead of latitude it could be UVB intensity.
Vitamin D: further studies show that people who don’t take vitamin D are more likely to get MS (Munger 2004), 41% risk reduction for every 50nmol/l of 25 (OH) D serum level (Munger 2006), people with MS may be more likely to get attacks if low serum vitamin D level (Simpson 2010), but not everyone with low vitamin D gets MS…
Kurtzke showed that less than 15yo migrants acquired frequency of new country
More MS in May births, least in November births (less vitamin D in utero is good?) and more MS attacks in Spring and Summer (because had long period of less vitamin D?)
Epstein-Barr virus - Faroe Islands had no MS until WWII, then 4 epidemics (Kurtzke 1975), same geographical locations as mononucleosis (more rich women at high latitude, Ascherio and Munger 2007), risk MS increases 2-3 times with mononucleosis Handel 2010), Sero-negativity OR=0.18, sero-positivity OR=13 but only 5-10% population is sero-negative (Ascherio 2007), MS risk and disease severity correlates with anti-EBNA titers (Ascherio and Munger 2010) (Infects B cells)
1st degree relatives 10-25 times more likely to get MS, 25-30% monozygotic twins, 20-60% genetic risk from HLA-DRB1*15 (Coles 2002) up to 33% risk genes shared with T1DM, RA, coeliac disease
Hormones: Same incidence for men and women and now women has doubled (Koch-Henriksen 2010), relapse frequency decreases during pregnancy and increases most in 3 months after pregnancy (clinically, often don’t breast feed because back on drugs asap) Confavreux 1998
What are the different types of MS?
Relapse-Remitting: A relapse = acute episode lasting more than 24 hours, presenting with neurological symptoms in patients otherwise free from concomitant illness. Can recover completely, especially when young (Poser 1983). Remission can occur over weeks, even after 12 months and is due to the remyelination after a relapse. Onset at 30yo, 70% at least 5 years relapse-free period, relapse rate decreases over time because of regression to the mean phenomenon.
Primary progressive: 40yo at onset
Secondary progressive: 25 years after onset RR MS, 40yo at onset.
Progression = insidious onset, relentless, steady accumulation of irreversible disability for at least 1 year (retrospective assessment) (Lublin 1996)
What symptoms can present in relapses?
Optic neuritis* (monocular vision loss, retro-bulbar optic neuritis in 2/3 or optic neuritis with papillitis 1/3)
Spinal cord lesion (limb weakness* with spasticity and hyperreflexia), paraesthesia, pain or sensory loss* in limbs or trunk, Lhermitte’s sign, urinary urgency and incontinence, sexual dysfunction)
Brainstem lesion (diplopia, paraesthesia, pain or numbness of face, vertigo, nystagmus, dysarthria)
Cerebellar lesion (incoordination of limbs, ataxic gait)
Cerebral lesion (impairment of concentration or memory, hemiparesis, hemisensory loss*, visual field defect, seizures, psychiatric disturbances)
Severe fatigue
What is required for the diagnosis of MS?
Dissemination in time and space of CNS lesions with no alternative diagnosis.
Can use McDonald’s diagnostic criteria. Mainly clinical, with examinations. If examinations can’t prove two lesions in different anatomical locations, then use: T2 MRI (with lesions typically eriventricular, subcortical, infratentorial or in the spinal cord), CSF showing increased productionof Igs, looking for oligoclonal bands in CSF only (normal/slight increase in WBCs of 10-20, higher suspect something else) Andersen et al 1994 showed CSF positive in >95% clinically definite MS, or electrophysiology showing visual evoked potentials of over 95ms, even in those with no visual symptoms.
MRI lesions are usually clinically silent (5-10x more frequent than clinical attacks). GAD shows active lesions for 2-6 weeks because inflammation breaks down BBB and allows in GAD.
What are some differential diagnoses of MS?
Acute Disseminated EncephaloMyelitis (ADEM) - prodromal infection and then acute monophasic course (no dissemination in time). Males>Females, 10yo at onset. Motor deficit, ON bilaterally, encephalopathy and seizures. MRI shows less frequent periventricular/callosal involvement and infrequently oligoclonal bands. Neuromyelitis Optica (NMO) - acute monophasic course, relapsing, >2:1 females:males, 35yo at onset, myelitis and ON bilaterally. On MRI, spinal cord lesion extending at least 3 vertebral segments. Infrequently oligoclonal bands and IgG binding to AQP4 in blood tests (76% sensitivity but 94% specificity).
What is the prognosis in MS?
Really variable. Benign - little disability after 15 years; malignant - severe disability after 5 years (Lublin 1996). Can use the Expanded Disability Status Scale (EDSS) 6 = cane, 7 = wheelchair, 8-9 = bed bound, 10 = dead.
50% require assistance to walk after 18 years.
Bad prognostic factors: male, >40 years at onset, cerebellar and pyramidal involvement, frequent early attacks and rapid development of fixed disability.
Good prognostic factors: young onset, female, optic neuritis or sensory symptoms at onset, low frequency early attacks, complete symptom remission, long first inter-attack interval.
What are some of the clinico-pathological correlations in MS?
- inflammatory foci without demyelination - acute relapses
- primary demyelination - acute & chronic
- grey matter demyelination - progressive
- axonal loss in lesions - progressive symptoms
- grey matter neuronal and axonal loss - progressive motor, sensory and cognitive
- diffuse white matter changes - fatigue?
- diffuse grey matter changes - motor, sensory and
cognitive symptoms.
Fatigue?
What is the role of CD4+ cells in MS?
CD4+ cells (mainly found perivascularly and parenchyma of white and grey matter, probably initiate lesions) which activate the microglia. Activated by DCs via CD40L and CD28 on CD4+ and CD40, CD80, CD86 (which correlates with axonal damage).
A particular type of CD4+ cell, Th1 (expressing CCr5 and CXCR3, TF of Tbet), is differentiated via IL-12 (from dendritic cells) and then Th1 produces IFNgamma and TNF* which correlates with MS disease activity. EAE mice were worse after IFNgamma. IL-12, IFNgamma and TNF deficient mice get more severe EAE. Transfer of Th17 gives worse EAE than Th1.
Th17 (expressing CCR6 and CCR4, TF of RORgammat) (require IL-23 (KO mice for IL-23 don’t get MS)) and produce IL-17 (transcripts found in post mortem brains, especially of chronic), GM-CSF, IL-22.
IFNgamma induces MHC class II (associated with HLA-DRB11501) expression on CD4+ -> cytokine release which attract and activate M1 macrophages and microglia which remove (?) MOG and MBP1.
Th2 (TF GATA3) produces IL-4, IL-5, IL-13 which are anti-inflammatory. *=associated SNP from IMSGC 2011
CD4+, CD25+, Treg (from thymus, induced in periphery by tolerogenic presentation of antigens) cells are impaired in MS as well and they inhibit activation myelin-specific T cells. CD25 (component IL-2 receptor) mutation in GWAS causes problems with Treg homeostasis. FoxP3 is their transcription factor and those secrete IL-10 and TGFbeta. IPEX mutation of FoxP3 leads to no Treg which still causes bad MS.
Tertiary lymphoid follicles are usually found deep in the sulci where there is less CSF flow so it’s a more protected microenvironment and favours retention and homing of immune cell (Serafini 2004) These structures are also found in RA, Sjogren, diabetes, thyroiditis
Meningeal inflammation -> disruption glia limitans and more grey matter inflammation.
Describe how the axonal loss occurs in MS:
Release of cytotoxic cytokines (TNF, lymphotoxin-alpha, Fas ligand) and free radicals (Nitric oxide (NO), peroxynitrite (OON-), hydroxyl radicals (OH-)) by peripheral immune cells and activated microglia, leading to oligodendrocyte death (they express NMDA and AMPA receptors).These free radicals reversibly block action potentials. They also damage mitochondria causing energy deficiency and apoptosis.
Glutamate release by microglia leads to excitotoxicity to oligodendrocytes.
Macrophages actively remove myelin and astrocytes form processes around the bare axons.
B cells produce anti-myelin antibodies and complement. Antibodies to neurofascin186.
Reduction in NAA (lipogenic enzyme) correlates with disease severity.
Disorganisation of axonal fascicles and reduction in axonal density is seen in areas of demyelination.
Caspase expressing neurons in grey matter.
A shift from TNFR2 neuroprotective signalling to TNFR1 pro-apoptotic signalling with increasing meningeal inflammation - In MS cortical GM TNFR1 is expressed on oligodendrocytes and pyramidal neurons; TNFR2 is expressed primarily by astrocytes in the GM and by microglia and astrocytes in the WM
What are the different stages of MS plaques?
Acute active: macrophages throughout the
lesion with synchronous myelin destruction.
• Chronic active: numerous macrophages at
expanding plaque edge; centre contains few
cells.
• Chronic inactive: hypocellular plaques with no
macrophages and no ongoing demyelination.
• Shadow Plaque: represent remyelinated lesions
with thin myelin sheaths.
• Destructive plaques: destruction of axons,
oligos, astros and myelin loss - Marburg type MS
and Devic’s disease.
Why is grey matter demyelination becoming more important? What are the different stages of leucocortical lesions?
Fisniku 2008: grey matter demyelination correlates better with disease progression.
1: part of grey matter and part of white matter
2: some grey matter
3: subpial lesion
4: extends entire width of grey matter
What is required for a tertiary lymphoid structure?
- CD20+ B-cells; (Majority of B-cells appear to be CD27+ antigen experienced)
- Ki67+ B-cells;
- Ig+ plasma cells
(parafollicular); - CD35+ FDCs
(reticular network); - CXCL13+ FDCs;
- CD4+ & CD8+ Tcells. Calabrese 2015
What is one hypothesis for calcium mediated death in axons that have lost their myelin sheaths?
Trapp and Stys 2009: Chronically demyelinated axons degenerate due to ionic imbalance and calcium influx
In normal myelinated axons, action potentials are propagated through the opening of Na⁺ channels at the node. Na+ also enters through Na⁺/Ca2⁺ exchangers, which passively trade Na⁺ entry for Ca2+ removal. Na⁺ entry is rebalanced by removal through internodal Na⁺/K⁺ ATPase, which uses ATP produced by axonal mitochondria to pump Na⁺ out in exchange for K⁺.
Na⁺ channels are diffusively distributed along
demyelinated axons resulting in increased Na⁺
influx during impulse transmission and increased
ATP demand for operating Na⁺/K⁺ ATPase pumps.
Alterations in ATP production reduce Na⁺/K⁺ exchange capacity and increase axonal accumulation of Na+.
Increased axonal Na⁺ reverses the Na⁺/Ca2⁺ exchanger, and increases axonal Ca2⁺
Increased Ca2+ activates proteolytic enzymes, leading to damage of axoplasmic
contents (F) and eventually to axonal death.
