-
Multiple sclerosis (MS) definition
- neurodegenerative disease of the central nervous system (CNS)
- - demyelinating disease
- - most common cause of chronic neurological disability in young adults
- -affected areas of brain and spinal cord
- -characteristic plaques or sclerosed areas
-
high risk for MS (5)
- 1. 15-45 years
- 2. females (ratio 2:1)
- 3. caucasians
- 4. northern latitudes (higher)
- 5. family members with MS
-
etiology of MS
- unknown - no cure***
- could be:
- biological: increased HLA, mutations in IL-2, IL-7 receptor genes, race, gender
- environmental: location - high latitudes, smoking cigarettes, vitamin D, viral/bacterial infections (EBV)
-
REMEMBER etiology 15 and MS
- 1. genetically susceptible 15 yo in high-risk area ≥2 years exposed to crucial environmental agent = at risk
- 2. migrates low to high < 15 yo = at risk
- 3. migrates high to low > 15 yo = retains HIGH risk (vs lower if moved before 15).
-
pathophysiology: inflammation
infiltrate consisting of T and B lymphocytes, macrophages, antibodies, and complement
-
pathophysiology: demyelination
stripping of the myelin sheath surrounding CNS axons
-
pathophysiology: axonal injury and transaction
- damage to axons are irreversible when severed
- neurodegeneration
- gliotic sclerosis
-
pathophysiology: autoimmune process directed against myelin and oligodendrocytes
- T-cell entry into the CNS attract activated Th17 cells
- actual mediator of myelin and axonal destruction has not been established
- - combo of macrophages, antibodies, destructive cytokines, and reactive oxygen intermediates
- number of T-regulatory (Treg) cells (suppressor activity) is reduced
-
clinical presentation: primary
visual complaints, gait problems, paresthesias (pins and needles), pain, spasticity, weakness, ataxia, speech difficulty, psychology changes, cognitive changes, fatigue, bowel/bladder dysfunction, sexual dysfunction, optioc neuritis
-
clinical presentation: secondary
recurrent urinary tract infections, urinary calculi, muscle contractures, respiratory infections, poor nutrition
-
clinical presentation: tertiary
financial, personal, social, vocational, and/or emotional problems
-
Clinically isolated symptom (CIS)
- 85% have first attacks that can last ≥24 hrs
- attacks may present separate from another symptom for 30 days, followed by remission
-
Radiologically isolated symptom (RIS)
patients who present atypically for MS but MRI results suggest MS
-
Classification of MS (4)
- 1. relapsing-remitting (RRMS)
- 2. secondary-progressive (SPMS)
- 3. primary-progressive (PPMS)
- 4. progressive-relapsing (PRMS)
-
definition: characterized symptoms that develop over a period of a few hours to a few days, followed by recovery and stale course between relapses
Classification of MS: relapsing-remitting (RRMS)
-
definition: characterized by gradual neurological deterioration with or without superimposed relapses and minor remissions
Classification of MS: secondary-progressive (SPMS)
-
definition: characterized by continual disease progression from onset with no superimposed relapses or remissions
Classification of MS: primary-progressive (PPMS)
-
definition: characterized by gradual neurological deterioration from the onset of symptoms and subsequent superimposed relapses
Classification of MS: progressive-relapsing (PRMS)
-
Exacerbation factors (10)
unpredictable, infections, heat (fever), sleep deprivation, stress, malnutrition, anemia, organ dysfunction, exertion, childbirth
-
clinical rating scale
expanded disability status scale (EDSS)
-
t/f MS is differential diagnosis (of exclusion)
- T.
- ≥ 2 episodes of neurologic disturbance reflecting distinct sites of damage in the CNS that cannot be explained by another mechanism
-
____ criteria for diagnosis for MS
- Mcdonald Criteria
- - Brain magnetic resonance imaging (MRI)
- - Cerebrospinal fluid (CSF)
- - Visual-evoked potential (VEP) studies
- - with physical exam + history
- - no specific labs
-
diagnosis: MRI
- images of brain and spine
- est. dx and px
- - plaques, atrophy, lesions
- single demyelination attack and ≥3 T2-weighted lesions: 90% likelihood of developing a second attach (clinically definite MS) over 15 years
- Similar individuals with normal brain MRIs: 19% likelihood of developing MS over 15 years
-
diagnosis: CSF
- oligoclonal banding
- -level increased in CSF
- -level normal in serum
- -atypical clinical scenarios
- -possible MS diagnosis: > 50x106/mL (50x109/L) mononuclear cells in the CSF usually indicates a diagnosis other than MS
-
diagnosis: VEP
- detect clinically silent areas
- - slowed conductance of visual, brainstem, and somatosensory
- << sensory and specificity
- blood studies
- - antimyelin antibodies
- -help define px
- -rule out differentials
-
Prognosis: good
- long interval between 1st and 2nd attack
- no residual neurologic deficits from the 1st attack
- relatively benign 2- and especially 5-year course of MS
- early onset <40 years
- absence of cerebrospinal oligoclonal IgG bands
- normal or low MRI scan disease burden at the time of diagnosis
-
Prognosis: bad
- frequent attacks
- disabling early attacks
- prolonged or permanent residual disability
- 5-year history of active MS
- early involvement of cerebellar pathways
- later onset >40 years
- presence of CSF oligoclonal IgG bands
- high MRI disease burden at diagnosis
-
5 goals of treatment for MS
- 1. decrease severity, intensity, and duration of exacerbations
- 2. enhance recovery from exacerbations
- 3. prevent relapses and the onset of progressive disease
- 4. provide symptomatic relief from complications
- 5. maintain the patient's quality of life (disease-modifying therapies - DMTs, treatment of acute exacerbations, symptomatic therapy)
-
goals of THERAPY for MS
- early therapy is most effective
- -relapsing - Avonex, Betaseon (or Extavia), Copaxone, Rebif (ABC-R) therapy immediately after the diagnosis
-
9 medications for MS
- AABCEGNRT
- Avonex (interferon beta-1a)
- Aubagio (teriflunomide)
- Betaseron (interferon beta-1b)
- Copaxone (glatiramer acetate)
- Extavia (interferon beta-1b)
- Gilenya (fingolimod)
- Novantrone (mitoxantrone)
- Rebif (interferon beta-1a)
- Tysabri (natalizumab)
-
MOA: suppresses the autoimmune destruction of myelin; slows accumulation of disability and decreases the frequency of clinical exacerbations
hint: interferon B-1a
- Avonex: IM weekly, RRMS, category C
- Rebif: SC TIW, RRMS, category C
- (room temp up to 30 days)
-
MOA: suppresses T-cell proliferation through immunoregulatory activity, reduces pro-inflammatory mediators, and decreases BBB permeability
hint: interferon B-1b
- Betaseron: SC QOD, RRMS, category C
- Extavia: SC QOD, RRMS, category C
-
Adverse reactions for Interferons in MS
- common:
- injection site pain, redness and swelling, flu-life symptoms last for 24 hours
- infrequent:
- dyspnea, tachycardia, depression, liver-thyroid, abnormalities, leukopenia
-
monitoring parameters for interferons in MS (3)
- 1. CBC with PLT
- 2. LFTs
- 3. TFTs
- baseline, every 3 months for a year, then every 6 months thereafter
-
MOA: active metabolite of leflunomide. Inhibits a mitochondrial enzyme, thus interfering with DNA synthesis --> reduced lymphocyte activation
Aubagio (teriflunomide): oral QD, RRMS, category X
-
BLACK BOX WARNING: hepatotoxicity and teratogenicity
drug for MS
- Aubagio (teriflunomide)
- recommended: transaminase and bilirubin obtained PRIOR to treatment (up to 6 months) for the first 6 months
-
AE for Aubagio (teriflunomide)
- short term:
- abnormal LFT(5%) - reversible, alopecia, diarrhea, influenza, nausea, paresthesias
- long term:
- no specific issues have been seen in patients with MS
- Major:
- Stevens Johnsons Syndrome (SJS), increase BP, fetal malformations, elevated serum hepatic transaminases (BBW)
-
MOA: blocks myelin-specific autoimmune responses and likely serves as a "decoy" that blocks myelin-damaging T-cells
Copaxone (Glatiramer acetate): SC QD, RRMS, category B
-
AE for Copaxone (Glatiramer acetate)
- mild pain/pruritis (10%)
- Chest tightness/dyspnea (10-15%, transient)
- flushing
- no lab monitoring needed
- (room temp up to 1 week)
-
MOA: partial agonist at the sphingosine-1-phosphate receptor 1
-internal sequester lymphocytes in the lymphoid tissue
- reduces the infiltration of T-lymphocytes and macrophages into the CNS
-bind to SP-1 receptor in the CNS to promote remyelination
Gilenya (fingolimod): oral QD, relapsing form, category C
-
AE for Gilenya (fingolimod)
- general:
- h/a, migraine, back pain, diarrhea
- major:
- first dose bradycardia, infections, macular edema, decrease in forced expiratory volume over 1 second, LFT elevation, BP elevation, lymphoma (rare - reversible 2-4 weeks after d/c)
-
monitoring parameters for Gilenya (fingolimod) (5)
- CBC, LFTs, ophthalmologic examinations, pulse and BP, ECG
- *patient should be observed for 6 hours after first dose
- *ECG is mandatory prior to first dose and after the 6 hours observation period
-
MOA: anthrocenedione chemotherapeutic agent (inhibiting DNA and RNA synthesis)
Novantrone (mitoxantrone): IV Q3months (body surface area), monotherapy for SPMS, worsening RRMS, PRMS, max cumulative dose 140 mg/m2, category D, may cause blue discoloration
-
AE for Novantrone (mitoxantrone)
- cardiotoxicity: obtain left ventricular function (prior, before each does, after accumulated dosage of 100 mg/m2), if heart failure signs/symptoms develop)
- nausea, alopecia, menstrual disorder, amenorrhea, URI, UTI, leukopenia, hair thinning
- BBW: cardiotoxicity, secondary acute myelogenous leukemia
-
MOA: blocks alpha-4-integrin which inhibits the trafficking of immune cells into the CNS
Tysabri (natalizumab): IV Q4W in NaCl over 1 hour, relapsing form, category C
-
Touch Program for which MS drug
- Tysabri (natalizumab)
- -educate on risk of PML (progressive multifocal leukoencephalopathy)
- -provide medication guide
- -diagnose PML, if indicated
- -obtain signatures
- -makes copies and send report
- -evaluate at 3 months and 6 months, then every 6 months
- CHANGES: recommend blood and CSF screen at baseline and every 6 months to assess the presence of JC and BK virus DNA
-
treatment of acute exacerbations of MS
- mild acute exacerbations that do not produce functional decline may not require tx
- if functional ability is affected: IV high-dose corticosteroids
- -Methylprednisolone 500-1000 mg/d IV
- (duration 3-10 days, 3-5 days for signs of improvement)
-
AE for methylprednisolone in MS
- sleep disturbance, a metallic taste, GI upset, INC glucose
- long term use AE: acne, fungal infections, mood alteration, GI hemorrhage
-
symptomatic therapy: fatigue
- most COMMON complaint (disabling for some)
- commonly occurs mid-late afternoon (heat exposure, exertion, intercurrent infection, spasticity, weakness, and depression)
- TX:
- 1. amantadine hydrochloride: 100 mg BID
- 2. methylphenidate (Ritalin): and related
- 3. modafinil (Provigil): 100 mg BID
-
symptomatic therapy: impaired gait
- dalfampridine (AMPYRA):
- 10 mg PO BID, improve walking, not restricted on stage of MS
- safety profile: urinary tract infections, insomnia, dizziness, h/a, nausea, weakness
- contraindications: history of seizures or moderate-severe kidney disease
-
symptomatic therapy: spasticity - jerking (6)
- legs >> arms
- 1. baclofen: 10 mg TID titrated up to 40-80 mg/d
- 2. tizanidine (Zanaflex): titrate over 2-4 weeks up to 2-36 mg/d (AE: sedation, dizziness, dry mouth)
- 3. diazepam (Valium): 2-10 mg/d (addiction/CNS depression)
- 4. clonazepam (Klonopin): 1-3 mg/d
- 5. dantrolene sodium (Dantrium): 100-400 mg/d
- 6. gabapentin (Neurontin): 1800-3600 mg/d
-
symptomatic therapy: neurologic bladder (7)
- 1. darifenacin (Enablex): 7.5-15 mg/d
- 2. fesosterodine (Toviaz): 4-8 mg/d
- 3. oxybutynin (Ditropan): 10-20 mg/d
- 4. solifenacin (Vesicare): 5-10 mg/d
- 5. tolterodine (Detrol): 2-4 mg/d
- 6. trospium (Sanctura): 40 mg/d
- 7. dicyclomine hydrochloride (Bentyl): 30-80 mg/d
-
symptomatic therapy: neurogenic bowel
- 1. conservative measures:
- timed bowel evacuation, dietary fiber, bulk-forming agents, biofeedback, physical activity, hydration
- 2. medical therapies:
- stool softeners, rectal stimulants, laxatives, enemas
- *common occurrence with increase use of narcotics and/or anticholinergic medications
-
symptomatic therapy: sexual dysfunction (3)
- sildenafil (Viagra): 4 hrs 1/2 life
- tadalafil (Cialis): longest half-life (17.5 hrs) and duration (24-36 hrs)
- vardenafil (Levitra): more CYP2C, 4 hrs 1/2 life
- all rapid bioavailability, CYP3A4
-
MOA: reduces inflammation caused by the MS immune response and protects nerves against injury
hint: emerging therapy
- Tecfidera: oral 2-3x daily
- AE: flushing and hot flashes, GI-upset, diarrhea, nausa, abdominal pain, h/a
-
MOA: humanized monoclonal antibodies, targeting CD 20 (ex: depletion of B-cells and reduction in antigen presentation) (3)
- 1. rituximab
- 2. ocrelizumab
- 3. ofatumumab
- IV infusions
- AE: impaired antibody response, infections, PML
-
second line therapy for side effects (2)
|
|
