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SPP2 CNS > MS > Flashcards

MS Flashcards

1
Q

hindbrain components

A

medulla, pons, cerebellum

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2
Q

medulla

A

*autonomic functions: respiration, cardiac function, vasomotor responses
part of the brain stem

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3
Q

pons

A

relays signals from the forebrain to the cerebellum

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4
Q

cerebellum

A

governs motor coordination for producing smooth movements

***undergoes neurodegeneration in spinocerebellar ataxis

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5
Q

midbrain

A

substantia nigra
pars compacta: provides input to basal ganglia, supplies dopamine to the stratum, *undergoes neurodegeneration in parkinson’s

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6
Q

forebrain components

A

cortex: processing/interpreting information
basal ganglia: voluntary motor control
limbic system: emotions and memory
diencephalon: thalmus (relay station), hypothalmus (emotions, hormonal control)

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7
Q

cortex

A

involved in decision making and higher level functions
decisions are made in cortico-thalmic loops
often damage cannot be treated with drugs, except schizophrenia*

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8
Q

efferent

A

neuron tracks transmit signals from the cortex to the periphery

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9
Q

afferent

A

neuron tracks transmit from the periphery to cortex

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10
Q

meninges

A

layers of membranes collectively referred to as meninges
cerebrospinal fluid fills space between arachnoid and pia layers
*pathogenesis: meningitis, meningeal hemorrhage, meningioma

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11
Q

blood in the brain

A

enters the brain via the carotid artery

*pathogenesis: ischemia stroke, hemorrhagic stroke, migraine headache

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12
Q

neurons and glial cells

A

astrocytes: provide neurons with growth factors, antioxidants; remove extra glutamate; *support the blood brain barrier
oligodendrocytes: *produce myelin sheath that insulates axons
microglia: provide growth factors; clears debris; role in neuroinflammation

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13
Q

blood brain barrier

A

*stabilized by tight junctions in the endothelial cell layer of blood vessels in the brain
drugs must pass through cells, often by having low molecular weights

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14
Q

neurons

A

neurotransmission is triggered by electrical depolarization of the neuron by an influx of Na+ to change the polarity of the membrane

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15
Q

action potentials

A

excitatory neurons: increase frequency of action potentials
inhibitory NT: prevent action potentials
single magnitude no matter amount of NT
EPSPs (excitatory postsynaptic potential): act on ionotropic receptor allowing Na ions to cross membrane
IPSP (inhibitory postsynaptic potential): induce hyperpolarization by allowing Cl- ions to cross membrane *can decrease the magnitude of a subsequent EPSP

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16
Q

amino acid neurotransmitters

A

GABA: *major inhibitory NT in the brain, depresses excitability by *increasing the flux of Cl- ions, drugs acting with GABA are generally depressants: sedative hypnotics, anticonvulsants, anxiolytics

glycine: inhibitory *NT released by interneurons in the spinal cord
glutamate: major excitatory NT in the brain, allows Ca influx into the neuron

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17
Q

non-amino acid NTs

A

acetylcholine, dopamine, norepinephrine, serotonin,

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18
Q

acetylcholine

A

works on both muscarinic and nicotinic receptors

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19
Q

dopamine as a NT

A

*excessive dopaminergic signaling may be involved in schizophrenia, *loss of DA neurons in the SN is responsible for PD, drugs: anitpsychotics, dopamine receptor agonists for PD

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20
Q

norepinephrine

A

target adrenergic receptors, *NET inhibitors are used to treat depression

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21
Q

serotonin

A

systems involved in sleep, vigilance, mood, and sexual function
5-HT2A antagonists: atypical antipsychotics
5-HT1D agonists for migraine
SERT uptake inhibitor for depression
5-HT2A agonists: hallucinogens

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22
Q

MS

A

immune-mediated disorder involving destruction of the myelin sheath that surrounds neuronal axons

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23
Q

MS common symptoms*

A

visual problems, numbness/tingling, fatigue/motor weakness, difficulty walking, spasticity

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24
Q

MS less common symptoms

A

tremor/seizures, itching, speech and swallowing issues, breathing problems, headache, hearing loss

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25
Q

MS etiology

A
  • Viral or bacterial infections: may increase the risk of MS by activating autoreactive immune cells leading to an autoimmune response in genetically susceptible individuals* (i.e. not everyone who gets infections increases their risk), EBV may be involved in developing MS due to sequence similarities between EBV and self-peptides (*molecular mimicry), EBV is NOT thought to be a direct cause of MS, Individuals with a particular HLA have an increased risk of developing MS when they also have anti-EBNA antibodies (illustrates gene-environment interactions)
  • Genes Related to MS encode: HLA- DR15/16, IL-2α, and IL-7α receptors
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26
Q

forms of MS

A
  • Relapsing-Remitting (85% of cases)
  • Secondary Progressive MS
  • Primary Progressive MS (15% of cases)
  • Clinically Isolated Syndrome
  • Marburg variant: Aggressive variant involving a high degree of inflammation
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27
Q

relapsing remitting

A

RRMS

  • Initial symptoms disappear, but less remission with each relapse
  • Most cases of RRMS eventually enter a phase of secondary progressive MS
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28
Q

secondary progressive

A

SPMS

  • Characterized by less inflammation that RRMS
  • Involves more neurological decline and CNS damage
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29
Q

primary progressive

A

PPMS

  • Resembles SPMS at the initial stage of the disease
  • Mean age is later than RRMS
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30
Q

clinically isolated syndrome

A

CIS (MS)

  • Initial episode of neurologic symptoms lasting over 24 hours
  • Most cases progress to MS
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31
Q

marburg variant of MS

A

Aggressive variant involving a high degree of inflammation

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32
Q

amutoimmune phase of MS

A
  • Antigens are presented to B and T cells in the lymph nodes
  • B and T cells migrate to CNS sites where they re-encounter and are activated by their target ligands
  • Activated B and T cells the carry out immune functions in the CNS
33
Q

degenerative phase of MS

A

-CNS damaged triggered by autoimmune phase cause further release of antigens to prime more immune cells in the periphery

34
Q

autoimmune response in MS

A
  • Dendritic cells* that present CNS antigens activate T cell responses in peripheral lymph nodes -> ability to bind α-4 integrin = penetration into BBB
  • B cells -> plasma cells and release antibodies to target self-antigens (i.e. proteins on neurons)
  • ***CD8 with MHC-1 on oligodendrocytes/neurons
  • ***CD4 with MHC2 on microglia
  • T-cell activation = damage of myelin sheath: Cytokines released: IFN-γ, TNF-α, perforin, granzyme = oligodendrocyte death
  • *Antibodies trigger complement = pore formation and cell damage
  • Macrophages release toxic agents (reactive oxygen and nitrogen species, glutamate) and harm the myelin sheath via phagocytosis
35
Q

zones of demyelination

A
  • Propagation of action potential is slowed down
  • *Redistribution of Na channels and accumulate in intermodal regions
  • Disrupt conductive properties of the axon and in neurodegeneration
36
Q

neuron/oligodendrocyte damage

A
  • CD8: MHC1 interaction = cytokine/granule release
  • Glutamate release = NMDA receptor activation
  • Antibody-Antigen interactions = complement activation
  • Release of cytokines = inflammation, neurodegeneration
37
Q

neuron/oligodendrocyte repair

A
  • Cytokines are supposed to help neuroprotection
  • *Neurotrophin release by glial cells and CD4 T cells = neuroprotection
  • Migration of neuronal stem cells and oligodendrocyte progenitor cells = replacement of damaged neurons and oligodendrocytes: Typically fails in MS
  • *Remyelination: Demyelination = *activation of microglia and astrocytes; Activated microglia and astrocytes release *pro-migratory factors to recruit OPCs and stimulate proliferation; OPCs *differentiate into oligodendrocytes (this step fails in MS**)
38
Q

visualization of lesions in MS

A

-Observed by gadolinium-enhanced MRI may grow or recede depending on disease progression

39
Q

guillain-barre syndrome

A
  • Acute inflammatory neuropathy
  • *Autoimmune attack on peripheral nerves by circulating antibodies = demyelination
  • Peripheral neurons not in CNS
40
Q

astrosliosis

A

propagation of astroytes, resulting in the irreversible formation of gliotic plaques or scars

41
Q

treatment of acute attacks in MS

A

corticosteroids

42
Q

disease modifying therapies in MS

A

reduce relapse rates, may slow the progression of disability (used to treat relapsing rather than progressive)

  • First-line: Interferons, glatiramer, fingolimod
  • Second-line: Natalizumab, Mitoxantrone
  • New drugs: Teriflunoamide, Dimethyl Fumarate
43
Q

acute MS attacks

A

-*Corticosteroids upregulate anti-inflammatory genes, down-regulating pro-inflammatory genes, and alleviating edema in demyelinated areas

44
Q

interferon B1a and B1b

A

disease modifying therapy

  • **Actions: inhibition of autoreactive lymphocytes; inhibition of BBB penetration by decreased matrix metalloproteinase
  • Clinical Features: Relatively favorable safety profile, delay conversion of CIS -> MS, *efficacy reduced by neutralizing antibodies
45
Q

glatiramer acetate

A

disease modifying therapy

  • Action: Modulation of APC = inhibition of autoreactive lymphocytes (T cells and DCs)
  • Clinical Features: Relatively favorable safety profile, delay conversion of CIS -> MS
46
Q

fingolimod

A

disease modifying therapy

  • Actions: **Stimulation of oligodendrocyte survival, **remyelination; interfere with lymphocyte movement out of lymphoid organs
  • Clinical Features: first oral drug, side effects include cardiotoxicity and fatal viral encephalitis
47
Q

Natalizumab

A

disease modifying therapy

  • Actions: ***Monoclonal antibody specific for α4 integrin targeted at BBB
  • *α-4 integrin + β1 integrin = VLA-4 that generally binds to VCAM on CNS; this is inhibited by Natalizumab
  • Clinical Features: key side effect of PML, and induces the development of *neutralizing antibodies -> allergic reactions
48
Q

mitoxantrone

A
  • disease modifying therapies
  • Action: anthrocenedione with ***cytotoxic activity by *reducing lymphocyte numbers by causing DNA strand breaks via intercalation and delaying DNA repair via inhibition of topioisomerase
  • Clinical Features: first cytotoxic drug licensed for SPMS; key side effects include cardiotoxicity and malignancies; can be used as induction therapy
49
Q

teriflunomide

A
  • new drug
  • Action: cytotoxic agent* that inhibits dihydroorotate dehydrogenase to inhibit pyrimidine synthesis
  • inhibits proliferation of peripheral ltmphocytes (activated T and B cells)*
  • Clinical Features: reduces relapse rates, MRI endpoints; primary risks are hepatotoxicity and teratogenicity* (Teriflunomide and Teratogenicity)
50
Q

dimethyl fumarate

A

new drug

  • ***Actions: Nrf2-mediated cellular antioxidant responses, and anti-inflammatory pathways, May promote remyelination, Suppresses activated T and dendritic cells
  • Clinical Features: moderate side effects
51
Q

Nrf2 antioxidant pathway

A
  • Nrf2 is generally targeted for destruction; when cells is subjected to oxidative stress Nrf2 accumulates and activates antioxidant response elements
  • Genes from AREs are: glutathione biosynthesis and detoxification (GST)
  • Nrf2 antioxidant response pathway** induces GSH through astrocyte-neuron communication; GSH released by astrocytes reacts with ROS and RNS, GSH is also broken down into amino acid subunits and is taken up by neurons and reassembled into GSH
52
Q

new antibody MS therapies

A
  • Alemtuzumab: targets CD52 (early phase of MS)
  • Rituximab: targets CD20; repositioned* from NHL and RA; stops RRMS and effective for some PPMS*
  • Daclizumab: targets CD25
53
Q

firategrast

A

treats MS

  • Action: ***small molecule that targets α4 integrin to prevent movement into BBB
  • Clinical Features: reduces number of Gd lesions but little effect on relapse
54
Q

amiloride

A

treats MS

  • Action: targets/antagonizes ***ASIC-1 that is responsible for entry of neurotoxic levels of Ca => direct neuroprotective effects
  • Clinical Features: Often used in cardiovascular patients (repositioned drug)
55
Q

Laquinimod

A

MS

-Action: immunomodulatory effects and may upregulate BDNF leading to direct neuroprotective effects

56
Q

LINGO-1 antagonist

A

MS

*interferes with LINGO-1 a protein that negatively regulated OPC differentiation into oligodendrocytes

57
Q

cladribine

A
  • Action: Taken up in cells by purine nucleoside transporters, Cells with *high ratio of deoxycytidine kinase: deoxynucleotidase (selective for lymphocytes, monocytes) phosphorylate cladribine, Phosphorylated cladribine = damages DNA and interferes with DNA metabolism = **resulting in lymphocyte depletion (cytotoxic)
  • Clinical Feature: initially licensed to treat hairy cell leukemia
58
Q

MS goals of therapy

A

start early on drug therapy, treat acute attacks aggressively, begin DMTs at CIS if possible, focus on treating symptoms to increase QOL

59
Q

MS treatment of acute attacks

A
  • High-dose corticosteroids (methylprednisolone IV 500-1000 mg daily 3-7 days)
  • Second line: Adrenocorticotropic hormone or plasma exchange
60
Q

DMTs in MS

A

-First Line: Interferon β1a, Interferon β1b, Glatiramer acetate, Fingolimod
-Second Line: Natalizumab, Mitoxantrone
-Unknown/New: Teriflunomide, Dimethyl Fumarate
treatment resistant: Alemtuzumab
under study: cladribine, laquinimod

61
Q

interferons and flu like syndrome

A
  • Flu like reactions occur in 50% of patients
  • Most patients will see these symptoms decrease over time with continued injection
  • Reduce by administering at night, OTC pain reliever before, gradual dose titration
62
Q

injection site/post-injection reactions

A
  • Injection site reactions for interferons and glatiramer acetate
  • Must rotate injection sites
  • Post-injection reactions: facial flushing, chest tightness, dyspnea, palpitations, tachycardia, anxiety
63
Q

interferon B1a in MS

A

dose: 30 mcg IM once weekly or 22 or 44 mcg SQ three times weekly (brands)
AE: depression, flu-like symptoms, injection site reactions, psychosis, hepatotoxicity, worsening of preexisting CHF, thyroid dysfunction, seizures, cases of thrombotic microangiopathy
monitoring parameters: electrolytes, CBC, LFTs, thyroid, LVEF, depression, psychiatric symptoms, hepatic decompensation in cirrhosis

64
Q

interferon B1b in MS

A

dose: 250 mcg SQ QOD
AE: depression, flu-like symptoms, injection site reactions, psychosis, hepatotoxicity, worsening of preexisting CHF, thyroid dysfunction, seizures, cases of thrombotic microangiopathy
monitoring parameters: electrolytes, CBC, LFTs, thyroid, LVEF, depression, psychiatric symptoms, hepatic decompensation in cirrhosis, more injection site reactions

65
Q

glatramir acetate in MS

A

20 mg SQ QD
AE: Injection site reactions, infection, hypersensitivity, chest
tightness, flushing, urticaria, rash
monitoring: Pregnancy Category B, MRI, tissue necrosis, post- injection reaction

66
Q

fingolimod in MS

A

0.5 mg PO QD
1ST DOSE MUST BE AT DOCTOR
AE: Lymphocytopenia, macular retinal edema, AV block, bradycardia, headache, back pain, cough, nasopharyngitis, hepatotoxicity, decreased lung function, hypertension, infections (may be serious); 1 case of definite progressive multifocal leukoencephalopathy and 1 possible case reported in August 2015 in patients not previously treated with immunosuppressants
monitoring: Pregnancy Category C, Long t1/2 – 9 – 10 days; concentrations may remain up to 2 months post- discontinuation, No relapse or corticosteroid within 30
days of initiation, Contraindicated in recent heart attack/stroke 2nd or 3rd degree AV block, QT interval prolongation, decompensated CHF, Do not start in patients with active infection, Avoid live attenuated vaccines during treatment and for 2 months after stopping drug REMS – bradycardia/AV block – stay in clinic 6 hours post-dose CBC, EKG, varicella zoster antibody, blood pressure, eye exam, LFTs

67
Q

teriflunomide

A

dose: 7 or 14* mg PO QD
AE: Stevens-Johnson syndrome, liver failure, neutropenia, respiratory infection, activation of
tuberculosis, alopecia, neuropathy
monitoring: Pregnancy Category X, Pregnancy contraindicated while taking drug and for 2 years after stopping or until accelerated
elimination procedure complete (cholestyramine/charcoal), Do not start in patients with active infection, Screen for TB, Avoid live
vaccines, Active metabolite of
leflunomide CBC, LFTs, blood pressure, pregnancy, TB test

68
Q

dimethyl fumarate in MS

A

240 mg DR twice daily
AE: flushing, rash, pruritis, diarrhea, inc LFTs, lymphocytopenia, infections (1 case of PML)
monitoring: Withhold drug if serious infection occurs, Taking with food decreases incidence of flushing CBC, LFTs

69
Q

natalizumab in MS

A

300 mg IV every 4 weeks
AE: PML, depression
monitoring: Monotherapy only, Must test for JVC antibodies before starting, 14-day washout of interferon or glatiramer; 6- month washout of mitoxantrone, Risk of IRIS (immune reconstitution
inflammatory syndrome) after discontinuation due to PML – treat with highdose corticosteroids REMS – Limited availability through TOUCH Prescribing Program

70
Q

Mitoxantrone

A

12 mg/m2 IV every 3 months
AE: Bone marrow suppression, neutropenia, cardiotoxicity (decreased LVEF, irreversible CHF, cardio- myopathy, acute leukemia
monitoring: Pregnancy Category D, Pregnancy test prior to
each infusion, Lifetime dose should not exceed 140 mg/m2, LVEF, CBC, EKG, LFTs

71
Q

alemtuzumab in MS

A

Available only by REMS with pharmacy, patient, physician, facility registered, and only with availability of emergency services
dose (recognize): IV infusion over 4 hours 1st course: 12 mg/day x 5 consecutive days 2nd course: 12 mg/day x 3 consecutive days given 12 months after 1st course, premedicate with corticosteroid
AE: Immune thrombocytopenia, anti-glomerular basement membrane disease, lifethreatening infusion
reactions (anaphylaxis), cytokine release syndrome, increased risk of malignancies (thyroid CA, lymphoproliferative disorder, melanomas), glomerular nephropathies; N/V/D, headache, rash, UTI, fatigue/ general pain, insomnia, dizziness, paresthesias, flushing, viral infections; idiopathic
thrombocytopenic purpura Contraindicated in HIV due to prolonged reduced CD4 counts
monitoring: Pregnancy Category C, Patient MUST stay in clinic for 2 hours post-infusion to monitor for infusion reaction (may occur up to
24 hours post-dose), CBC w/differential, SCr, urinalysis with urine cell counts (continue for 48 months after last dose), baseline/yearly skin exams, TSH baseline and every 3 months (continue for 48 months after last
dose), Delay dosing in patients with active infection until infection is fully controlled, Do NOT give live virus vaccines

72
Q

symptoms associated with MS

A

bladder dysfunction (use antcholenergics), bowel dysfunction (use bulk forming or stool softener), cognitive dysfunction, depression, fatigue, gait impairment, neurogenic pain, spasticity, sexual dysfunction

73
Q

PML in MS

A
  • Rare caused by reactivation of dormant JCV*
  • Can be mistaken for a MS relapse
  • Use of natalizumab is associated with PML (black box)
74
Q

cardiac effects in MS tx

A
  • Fingolimod is associated with dose-dependent reduction in heart rate; so patients should remain supervised for 6 hours after the initial dose
  • Those with CV risk factors should be monitored for 24 hours with EKG
  • Those with existing bradycardia or heart block w/o pacemaker should not receive fingolimod
  • Mitoxantrone is associated with cardiomyopathy
75
Q

pseudobulbar affect

A
  • Dextromethorphan suppreses release of excitatory NTs and it an antagonist at NMDA receptors; it is a P450 2D6 substrate** that is metabolized to dextrorphan that does penetrate CNS
  • Paired with quinidine (2D6 inhibitor**) that blocks conversion to dextrorphan, allowing dextromethorphan to reach CNS
76
Q

autoimmune/malignancy AE

A

Alemtuzumab: Immune thrombocytopenia, anti-glomerular basement membrane disease, Increase risk of malignancies (MUST have baseline and yearly skin exams and TSH baseline)

77
Q

gait abnormalities in MS

A

-Dalfampridine* blocks K+ channels and prevents repolarization to prolong action potentials and nerve impulse transmissions in demyelinated axons which may improve walking speed*

78
Q

pregnancy in MS

A
  • Teriflunomide is Category X- known teratogen; pregnancy must be avoided for up to 2 years after stopping drug or accelerated elimination
  • Mitoxantrone is Category D- use of contraceptives is required during therapy
  • Fingolimod should be discontinued at least 2 months before conception
  • Glatiramer is Category B; all others Category C

SPP2 CNS (4 decks)

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