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109 Cards in this Set
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McDonald's Criteria Sensitivity Specificity |
Criteria McDonald: Sens-47% Spec.- 91% PPV- 78% International Panel Criteria Sens-60%, Spec.-87%, PPV- 77% Magnims Sens- 97%, Spec.-60%, PPV-77% |
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Revised 1010 McDonald Criteria DIS > 1 T2 in at least 2/4 areas -Jxt cortical -infratentorial -periventricular -spinal cord |
DIT 1. Simultaneous presence of asymtpomatic Gd-enhancing and non-enhancing lesion @ anytime 2. New T2 and/or Gd-enhancing lesion on follow-up MRI with reference to baseline scan, irrespective of the timing of baseline MRI |
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Dissemination in time criteria |
1. New T2 lesion if it appears anytime compared with a reference scan done at least 30 days after onset of initial clinical event 2. Gd + lesion 3 months after initial clinical onset (not at the site corresponding to initial event) |
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Barkoff's MRI Criteria DIS |
3 out of 4 g T2 or 1 Gd 3 periventricular 1 or more Jx cortical 1 infrantentorial |
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NMO - JgG Ab Sensitivity ? Specificity ? |
Sensitivity 73% Specificity 91% |
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Most common presentations of MS |
Sensory 34% Weakness 22% Visual loss 13% Ataxia 11% Diplopia 8% Vertigo 4.3% Fatigue 2% Others Bowel/bladder Facial pain Dysarthria |
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Diagnostic Criteria for NMO 2006 |
1. Required Criteria - Transverse myelitis -Optic neuritis 2. Supportive (Need 2/3) -MR brain non diagnostic for MS -MR spinal cord = LETM > 3 segments -NMO Ig G seropositivity |
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PPMS Diagnostic Criteria |
1. 1 yr of disease progression PLUS 2/3 1) 1 brain T2 (DIS) 2) 2 or more cord DIS 3) + CSF |
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What is a + CSF in MS? |
Elevated Ig G index 2 or more OG bands |
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MS Age of onset F:M ratio |
30 yrs 2-3:1 |
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Pediatric MS Criteria MR Criteria for DIS 3 or more of the following > 9 wm lesions, > 1 lesion that enhances on Gd T1-W > 3 PV > 1 Jxt > 1 infratentorial or Abnormal CSF ( OCB or ↑IgG index) plus > 2 lesions on MRI (at lease one of which is in brain) |
MR Criteria for DIT > 1 new T2 or Gd enhancing lesion 3 or more months after the initial demyelinating event |
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Glatiramer acetate - polypeptide mixture of glutamic acid, alanine and tyrosine |
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Transverse myelitis and risk of MS Criteria for TS 1. Motor, sensory, autonomic attributable to sp. cord 2. Nadir 4h-21d 3. Bilateral Sx 4. Clear sensory level 5. Exlude compressive lesions 6. Prove inflammation (+CSF, gad-enh MRI lesion) |
Over 10 yrs 10% if N MRI 80% if abn. MRI Good prognosis ( or low risk) - complete TM - symmetric motor/sensory - spinal cord swelling - longitudinal cord lesions - No of MR brain lesions |
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MS By age 50, 28% need a cane By age 60, 50% need a cane Men's disease progresses 38% faster than women's disease |
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ADEM HISTOPATHOLOGY |
* Perivenular SLEEVES of demyelination * More macrophages rather than lymphocytes *pervascular hemorrhage may be seen * lymphocytes seen in meninges * Unlike MS, all lesioins are of the same age |
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Fatigue in MS Rx |
1. R/O thyroid, depression, sleep disorder 2. Amantadine 3. Modafinil 4. 4-AP (dalfampridine) 5. Stimulants (methylhenidate) 6. SSRI |
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Bladder - storage deficit symptoms |
Frequency Urge incontinence Urgency Nocturia Enuresis |
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Bladder emptying deficit Symptoms |
Hesitancy Double voiding Poor force of stream Bladder insensitivity |
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Bladder overactivity in MS - Rx |
Oxybutynin (Ditropan) Tolterodine (Detrol) Solifenacin, Darifenacin DDAVP Prazocin, Terazocin Tamsulosin ( ~ adrenergic antagonists) |
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Spasticity in MS Rx |
1. Exercise 2. Baclofen 3. Tizanidine 4. Benzos 5. Gabapentin 6. Dantrolene 7. Botox |
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PPMS - 5 DDx |
1. HSP 2. Adrenomyeloneuropathy 3. Primary lateral sclerosis 4. NMO 5. B12 deficiency (SCID) |
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Paroxysmal symptoms in MS |
Trigeminal Neuralgia Pain, paresthesias Weakness, seizures dysarthria, ataxia, pruritis Hemifacial spasm, dystonia |
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Paroxysmal symptoms in MS - Rx |
AED's mostly CBZ Gabapentin Pregabalin TCA |
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Weakness in MS Rx |
1. Physio/rehab 2. 4- AP - acts on damaged myelin and ↑ saltatory conduction of impulses and overcomes conduction block especially when temperative ↑ |
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NMO HYSTOPATHOLOGY |
* Inflammatory demyelination * Necrosis, cavitation seen *Eosinophils, neutrophis are seen in active inflamm. infiltrates *Penetrating spinal vessels are thickend + hyalinized *Rim and rosette pattern of Immunoglobulin/complement deposition *Aquaporin-4 innune reactivity depleted |
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NMO pearl 1st attack of NMO and the presence of NMO-IgG predicts a high risk of future relapses |
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NMO - IgG Ab Senstivity ? Specificity ? |
Sensitivity 73% Specificity 91% |
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NMO spectrum of disorders Endocrinopathies-NMO - Coma - encephalopathy - cerebral syndromes linked to focal or MF subcortical WML - PRES |
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NMO pearl Brainstem Sx such as nausea, vomiting, hicciups seen in up to 40-45% of pediatric patients (area postrema, NTS involvement) |
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NMO relapse rate |
> 90% follow a relapsing course 60% relapse within 1 yr 90% within 3 yrs |
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NMO Pearl Monophasic NMO more likely to be seronegative with les frequency and severity of relapses |
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MS What % of RRMS will become SPMS |
50% of RRMS will become SPMS within 10-20 yrs 75% by 25 yrs |
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Relapse rate in MS |
Median 1 per year for 1st 5 yrs then declines with time |
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Epidemiology of MS - Genetic - Environmental |
1. Genetic - polymorphism in the DR gene (DRB1*1501) allele Twin studies (MZ 30% vs DZ 36%) Fraternal twins same risk as 1st degree relatives with MS 2. Environmental (infection, VitD, smoking) |
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MS Disease type at onset |
85% relapsing 15% 1° progressive
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Top 10 paroxysmal symptoms in MS |
- Lhermitte - Chorea -Dystonia - Dysarthria - Hemifacial spasm - Pain (TN) - pruritis - Radicular pain - Segmental myoclonus - Seizures |
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Diagnostic Criterai DIT (2005 Criteria) |
1. New Tz lesion after a reference scn at least 30 days post CIS 2. Asymptomatic Gad lesion 3 months post CIS |
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Natural Hz and CIS Brex study 20 yr CIS FU 40% mild disability 40% major disability (cane) 20% in between |
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Variant forms of MS - NMO - Benign MS - CIS - clinically absent MS - Tumefactive MS - Fulminant MS (Marburg, Balo Schilder) - ADEM |
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Barkhof's Criteria DIS (2005 Criteria) |
Need 3/4 - gT2 or > 1 Gad lesion - > 1 Jxt cortical - > 1 infratentoral - > 3 PV lesion |
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Natural Hz of MS Worst Prognostic factors |
Frequent attacks Poor recovery from attacks Motor or cerebellar attacks Male gender Older age of onset Progressive course Smoking |
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MS Genetic risks |
1. Lifetime risk 0.1 - 0.2% 2. Both parents have MS then risk = 30% 3. Monozygotic twins = 30%, Dizygotic twins = 5% 4. Cousin 2-3% |
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MS Genetic risk |
5. Half sibling, aunt/uncle, nephew/neice = 2-3% 6. Sibling 5% 7. Sibling + 1 affected parent 15% 8 Sibling + 2 parents affected 25%
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Effect of MS on pregnancy |
MS does not affect the pregnancy state - No increase in fetal defects or in spontaneous abortion occurs. |
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Risk factors for post partum relapse in MS |
1. Higher EDSS score at pregnancy onset 2. Higher relapse rate in the year pre-pregnancy 3. Relapse during pregnancy 4. Replapse during previous pregnancy
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Effect of pregnancy on MS |
↓ relapses especially in the 3rd trimester approaching ~ 70 % reduction |
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Postpartum period and MS risk |
- ↑ relapses in the 1st trimester post partum - Have the same baseline pre-pregnancy risk rate by post partum month 6
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↓ relapses in pregnancy Mechanism? |
Estriol (↑ in 3rd trimester) Calcitriol (↑ in 3rd trimester) |
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Goals of Rx in MS |
1. Prevent relapses 2. Prevent disability 3. Reduce lesion burden on MRI |
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Optic Neuritis features that predict progression to MS in patients without MR brain lesions |
- Female gender - Retrobulbar ON - Lack of atypical features |
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AFFIRM Study |
Natalizumab reduces relapse rate by 67% and disability by 42% cover 2 yrs
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DMDs in MS 1st line 2nd line |
1st line - interforon beta 1a (rebif, avonex) interferon beta 1b (betaseron) Copaxone (glat.acetate) 2nd line - Natalizumab |
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Dalfampridine in MS |
Improves weakness Improves fatigue ↑ walking speed
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DMD's in pregnancy |
Interferons ( Class C ) Copaxone ( Class B ) |
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Other DMDs in MS |
Mitoxantrone Cyclophosphamide Fingolimod Cladribine, Alemtuzumab Laquinimod Teriflunomide
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MS Epidemiology Age @ onset 29-32 yrs PPMS 35-39 yrs F:M = 2:1 Common in Northern Europeans Migration - before age 15 risk same as the new area > 15 yrs risk same as birth place |
Genetics - overall risk in 1° relative 5% - Risk is high for siblings - Sibling risk is 3-5% ( 30=50 times the background risk for same population) - Twin studies dizygotic 3-5% monozygotic 20% |
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Aquaproin - 4 Function? |
- Antigenic target of NMO-IgG - found on astrocyte foot process ( not found on neurons/oligodend) - Expressed in high conc. spinal cord, optic N, brainstem, hypothalamus, PV regoins, area postremia, supraoptic N - water transport protein |
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Signature MRI lesions in NMO seen in which locations? |
Thalamus Hypothalamus Brainstem - regions of high aquaporin 4 density |
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NMO Rx |
1. Immunocsuppression Azathoprine, Cellcept, Mitox cyclophosphamide 2. B cell therapies PLEX, IVIG, Rituximab, Chlorambucil |
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Mechanism of Immunoregulation Intrinsic Apoptosis of Tcells, anergy, TH1 to TH2 shift Extrinsic Natural killer Tcells, CD4+ T regulatory CD8+ suppressor |
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Uhthoff's phenomenon - Pathophysiology |
Sx worsen with increased body temp ? due to drop below the safety threshold for conduction |
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Lhermitte's phenomenon -Pathophysiology |
Mechanical stimulation of demyelinated axons generate denovo action protentials in the axons causing electic shock like sensations on flexing the neck - ephaptic transmission |
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Name 4 categories of demyelinating disorder - Give 1 eg for each mnemonic vascular TIA T-oxic I -nfectious A-utoimmun |
1. Immune or inflmmatory - MS, ADME AHL 2. Viral - PML 3. Toxic - CPM, marchiafava-bignami solvent vapor abuse leukoencephalopathy necrotizing leukoenceph post chemo radiation induced demyelination 4. Chronic progressive subcortical demyelination (Binswanger) and leukoaraiosis |
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MS - active plague Path features |
White yellow or pink indistinct borders Perivenular distribution 1. Perivascular lymphocytes ( CD8 t-cells) macrphases, reactive astrocytes myelin depris within macrophages - 2. Oligodendroglia reduced in glague centre and ↑ in edge 3. Immunehisto ↑ cytokines in plagues |
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Fingolimod MOA SE: HSV/VZV infection Cardiac-bradycardia Macular edema Skin Cancer |
Sphingosine 1 - phosphate receptor modulator - inhibits lymphocyte exit from lymphoid tissue therefore prevents auto Rx T-cells entering CNS |
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IFN - B side effects |
1. flu-like symtpoms 2. ↑ LFT 3. Hemtologic 4. Injection site Rx 5. Thyroid dysfunction 6. Worsening of headache 7. Worsening of depressoin 8. Worsening of spasticity 9. Depression /suicide 10. Neutralizing Ab 11. Hormonal (menstrual irregularities) |
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What are shadow plagues in MS? |
Areas of partial demyelination and remyelination |
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Evidence that Vit D is implicated in MS |
1. Nurse health study - protective effect in women taking Vit D 400 IU/d compared to those taking no extra Vit D higher levels of Vit D @ baseline assoc with lower risk developing MS 2. Mortality statistic from 24 states inverse assoc between sunlight exposure and risk of death from MS 3. Children born May have 10% ↑ risk of MS than born in November (10% less) |
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1. Prodome illness/vaccination 2. MRI signs of demyelination 3. Acute presentation of neurologic symptoms |
ADEM TRIAD |
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Natalizumab MOA |
Blocks binding of VLA - 4 expresses on white cells to VCAM 1 on vascular endothelium - thus prevents autoreactive T-cells from crossing BBB |
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Natalizumab MOA ~ 4 B1 integrin also known as VLA 4 |
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Pain syndromes associated with MS Name 5 |
1. Pseudoradicular pain 2. Lhermittes' sign 3. Paroxysmal spasms 4. Trigeminal neuralgia 5. Migraine |
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Paroxysmal Symptoms in MS - Rx Rx Carbamazepine Oxcarbazapine Gabapentin |
1. Trigeminal neuralgia 2. Paresthesias 3. Tonic Spasms 4. Dysrthria 5. Ataxia 6. Vertigo 7. Lhermitte's sign 8. Dystonia 9. Hemfacial spasm |
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Natalizumab - Mechanism of action |
Inhibition of ~ 4 integrin molecule - This prevents trafficking of T-cells from blood into CNS by blocking adhesion to VCAM (vascular cell adhesion molecule) |
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CIS and early MS prognosis Good -optic neuritis - isolated sensory Sx - long interval to 2nd relapse - no disability after 5 yrs - normal MRI brain Poor - Multifocal CIS - efferent systems affected - high relapse rate in the 1st 2-5 yrs - sign. disability > 5 yrs - Abnormal MRI |
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Paroxysmal Symptoms in MS - Mechanism |
Ephaptic transmission across demyelinated tracts |
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Migration and MS risk (implies that MS risk is dictated early in life ~ pubescence or before < ~ age 15 and any environmental factor thought to initiate disease is encountered in childhood) |
Migration before age 15 - acquire the risk of MS of the population in that new country. Migration after age 15 - acquire MS risk of the population in the coutry of birth |
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Genetics and MS |
*HLA - DRB 1 gene on Chr6 HLA class II DR2 haplotype, DR4 haplotype in northern european descent ↑ risk of MS * HLA DRB 1 * 1501 allele |
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MS - theories of pathogenesis |
1. Environmental factors ( HHV6, EBV, Chlamydia) 2. Vit D hypothesis 3. Immunogenetics ( HLA DR2 and DR4) 4. Autoimmunity (CD4, CD8, B cells found with inflamm cells in MS plagues) 5. TH 17 T0-cells produce IL-17, TNFX IL6 →implicated in damage 6. Blood Braun Barrier and Chemokines |
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EDSS Scale Components |
Vision Brainstem Corticospinal Sensory Cerebellar Cognitive Bowel/Bladder |
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Risk of Ms in ONTT 5, 10, 15 year risks? |
5yrs 10yrs 15yrs All corners% 30 40 50 N0 MRI lesion% 15 20 25 + MRI% 40 56 75 |
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Category of drugs(s) contraindicated in MS |
TNF ~inhibitors (infliximab, etanercept, adalimumab) TNF ~ involved in pro-inflammatory pathways |
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PPMS Criteria (2005) |
1 yr of disease progression and 2/3 + brain MR (g Ts or > 4 T2 with + VEP) + spinal MR (2 or more cord lesions) + CSF |
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Copaxone - mechanism of action |
1. Bystander suppression 2. blocks AP (antigen presentation) 3. Regulation of immune response by CD8 T cells 4. Promotes BDNF production 5. Promotes TH2 suppressor cells
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DMT's used in MS Interferon beta 1a Interferon beta 1 b Glatiramer acetate Mitoxantrone Natallzumab |
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Side effects of Mitoxantrone |
1. Acute leukemia (~0.5%) 3. Myelosuppression 4. Alopecia 5. Bluish discoloration of sclera and urine |
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Mitoxantrone Anti-neoplastic/ anthracenedione compound that intercalates with DNA and modulates the immune system- antiproloertive effect on T-cells and suppression of humoral immunity |
Dose 12 mg/m2 q 3 months lifetime max 140 mg/m2 |
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Interferon beta 1a Avonex 30 mg IM once a week Rebif 44 mg SC 3 times a week Interferon beta 1b betaseron 8 miu sc q other day |
Mechanism TH 1→ TH2 shift Downregulation of AP Inhibition of MMP Enhanances suppressor t-cell activity |
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Differentiation of TH0 cells to TH1, TH2 and TH17 |
insert diagram here |
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Mitoxantrone - MOA |
DNA intercalating agent and topolsomerases inhibior - Inhibits DNA synthesis and repair |
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TH17 cells IL 17 IL 6 TNF ~ (pro-inflammatory) |
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Glatiramer acetate MOA |
1. Blocks antigen presentation 2. Bystande suppression 3. BDNF production 4. Regulation of immune response by CD8 T-cells 5. Neuroprotection + remyelination
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IFN - B MOA |
TH1 →TH2shift MMP inhibition Anti proliferatie effect antiviral IFN antagonism Blocks T cell activation apoptosis of autoreactive Tcells |
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Interferon side effects |
1. Flu like symptoms 2. CBC, LFT abnormalities 3. Worsening headaches 4. Worsening of depression 5. Injection site necrosis with SC injections |
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Copaxone SE |
1. Injection site redness, swelling or itching 2. Lipoatrophy @ injection site 3. Immediate post injection panic Rx - chest tightness, tachycardia, SOB, anxiety |
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HLA allele associated with ↑ susceptibility to MS |
HLA - DRBI * 1501 |
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Natalizumab - dose |
300 mg IV infusion over 1 hr q 4 weeks
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MRI features in MS Ovoid > 3 mm PV area (Dawson's fingers) CC involvement Juxtacortical, subcortical - U fibers Brainstem (MCP) Cervical > thoracic spine Cortical + deep WM Atrophy |
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ADEM prognosis |
~ 80 % recover in the first 6 months
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ADEM lesions on MRI |
Large Symmetric "fluffy" Edema, mass effect Deep gray matter affected |
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OCB's seen only in < 10 % of ADEM patients |
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Oligoclonal bands in CSF * No ocb in ADEM (< 10%) |
1. Infections - SSPE, Viral Encephalitis, HIV, Lyme 2. Autoimmune/inflammatory - SLE, NMO, MS, ADEM, GBS 3. Degenerative - Adrenoleukodystrophy, CADASYV |
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MRI lesions in MS - Characteristics |
1. WM lesions 2. lesions > 3 mm 3. cc involvement 4. Perpendicular to ventricles (Dawson's fingers) 5. Ovoid shape 6. Gd enhancing 7. Short (< 3 segment) spinal lesions |
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MS Epidemiology F:M = 2-3:1 Prevalence 1:500 to 1:1000 Alberta 1:300 |
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Name 3 myelin stains |
Luxol fast blue Solochrome and Eosin Sudan Black and Oil red O |
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Myelin Name 3 differences between Central + peripheral myelin |
CENTRAL Oligodendroglial 30-50 axons myelinated by single oligodend cell PLP, MBP (80%) MAG PERIPHERAL Schwann cells Only 1 axon myelinated by 1 schwan cell Po(>50%) MBP, MAG *No PLP Neural crest dervived |
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What are Creutzdeldt astrocytes? Significance? |
Reactive astrocytes with multiple small neclei (micronuclei) Commonly seen in demyelinating disorders (MS)
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MS plaque - What do you see acutely? |
- Intensely cellular - Inflamm lymphocytes, monocytes, astrocytes and macrophages - macrophages show foamy cytoplasm - Oligogendriglial cells proliferate in acute plague -Astrocytes reactive, enlarged eosinophilic cycto |
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MS - Chronic plaque features |
- Well defined, sharp margins - Less cellular, oligodendrocyte loss astrogliosis - Creutzfeld astrocyte - May show axonal loss |
