MS Flashcards
1
Q
hindbrain components
A
medulla, pons, cerebellum
2
Q
medulla
A
*autonomic functions: respiration, cardiac function, vasomotor responses
part of the brain stem
3
Q
pons
A
relays signals from the forebrain to the cerebellum
4
Q
cerebellum
A
governs motor coordination for producing smooth movements
***undergoes neurodegeneration in spinocerebellar ataxis
5
Q
midbrain
A
substantia nigra
pars compacta: provides input to basal ganglia, supplies dopamine to the stratum, *undergoes neurodegeneration in parkinson’s
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)
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*
8
Q
efferent
A
neuron tracks transmit signals from the cortex to the periphery
9
Q
afferent
A
neuron tracks transmit from the periphery to cortex
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
11
Q
blood in the brain
A
enters the brain via the carotid artery
*pathogenesis: ischemia stroke, hemorrhagic stroke, migraine headache
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
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
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
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
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
17
Q
non-amino acid NTs
A
acetylcholine, dopamine, norepinephrine, serotonin,
18
Q
acetylcholine
A
works on both muscarinic and nicotinic receptors
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
20
Q
norepinephrine
A
target adrenergic receptors, *NET inhibitors are used to treat depression
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
22
Q
MS
A
immune-mediated disorder involving destruction of the myelin sheath that surrounds neuronal axons
23
Q
MS common symptoms*
A
visual problems, numbness/tingling, fatigue/motor weakness, difficulty walking, spasticity
24
Q
MS less common symptoms
A
tremor/seizures, itching, speech and swallowing issues, breathing problems, headache, hearing loss
25
MS etiology
* 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
26
forms of MS
- 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
27
relapsing remitting
RRMS
- Initial symptoms disappear, but less remission with each relapse
- Most cases of RRMS eventually enter a phase of secondary progressive MS
28
secondary progressive
SPMS
- Characterized by less inflammation that RRMS
- Involves more neurological decline and CNS damage
29
primary progressive
PPMS
- Resembles SPMS at the initial stage of the disease
- Mean age is later than RRMS
30
clinically isolated syndrome
CIS (MS)
- Initial episode of neurologic symptoms lasting over 24 hours
- Most cases progress to MS
31
marburg variant of MS
Aggressive variant involving a high degree of inflammation
32
amutoimmune phase of MS
- 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
degenerative phase of MS
-CNS damaged triggered by autoimmune phase cause further release of antigens to prime more immune cells in the periphery
34
autoimmune response in MS
- 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
zones of demyelination
- 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
neuron/oligodendrocyte damage
- CD8: MHC1 interaction = cytokine/granule release
- Glutamate release = NMDA receptor activation
- Antibody-Antigen interactions = complement activation
- Release of cytokines = inflammation, neurodegeneration
37
neuron/oligodendrocyte repair
- 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
visualization of lesions in MS
-Observed by gadolinium-enhanced MRI may grow or recede depending on disease progression
39
guillain-barre syndrome
- Acute inflammatory neuropathy
- *Autoimmune attack on peripheral nerves by circulating antibodies = demyelination
- Peripheral neurons not in CNS
40
astrosliosis
propagation of astroytes, resulting in the irreversible formation of gliotic plaques or scars
41
treatment of acute attacks in MS
corticosteroids
42
disease modifying therapies in MS
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
acute MS attacks
-*Corticosteroids upregulate anti-inflammatory genes, down-regulating pro-inflammatory genes, and alleviating edema in demyelinated areas
44
interferon B1a and B1b
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
glatiramer acetate
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
fingolimod
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
Natalizumab
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
mitoxantrone
- 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
teriflunomide
- 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
dimethyl fumarate
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
Nrf2 antioxidant pathway
- 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
new antibody MS therapies
- 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
firategrast
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
amiloride
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
Laquinimod
MS
| -Action: immunomodulatory effects and may upregulate BDNF leading to direct neuroprotective effects
56
LINGO-1 antagonist
MS
| *interferes with LINGO-1 a protein that negatively regulated OPC differentiation into oligodendrocytes
57
cladribine
- 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
MS goals of therapy
start early on drug therapy, treat acute attacks aggressively, begin DMTs at CIS if possible, focus on treating symptoms to increase QOL
59
MS treatment of acute attacks
- High-dose corticosteroids (methylprednisolone IV 500-1000 mg daily 3-7 days)
- Second line: Adrenocorticotropic hormone or plasma exchange
60
DMTs in MS
-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
interferons and flu like syndrome
- 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
injection site/post-injection reactions
- Injection site reactions for interferons and glatiramer acetate
- Must rotate injection sites
- Post-injection reactions: facial flushing, chest tightness, dyspnea, palpitations, tachycardia, anxiety
63
interferon B1a in MS
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
interferon B1b in MS
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
glatramir acetate in MS
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
fingolimod in MS
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
teriflunomide
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
dimethyl fumarate in MS
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
natalizumab in MS
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
Mitoxantrone
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
alemtuzumab in MS
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
symptoms associated with MS
bladder dysfunction (use antcholenergics), bowel dysfunction (use bulk forming or stool softener), cognitive dysfunction, depression, fatigue, gait impairment, neurogenic pain, spasticity, sexual dysfunction
73
PML in MS
- Rare caused by reactivation of dormant JCV*
- Can be mistaken for a MS relapse
- Use of natalizumab is associated with PML (black box)
74
cardiac effects in MS tx
- 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
pseudobulbar affect
- 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
autoimmune/malignancy AE
Alemtuzumab: Immune thrombocytopenia, anti-glomerular basement membrane disease, Increase risk of malignancies (MUST have baseline and yearly skin exams and TSH baseline)
77
gait abnormalities in MS
-Dalfampridine* blocks K+ channels and prevents repolarization to prolong action potentials and nerve impulse transmissions in demyelinated axons which may improve walking speed*
78
pregnancy in MS
- 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
