Pathophysiology

MS is a progressive neuroinflammatory disease in which neurons are demyelinated in response to an autoimmune reaction. The reaction is thought to be initiated or enhanced by viral infections, particularly by EBV; however EBV is not considered to be the direct cause of MS (i.e. pts can develop MS w/o EBV, but EBV can act as a “catalyst” in susceptible pts). There is also some association between MS and certain HLA phenotypes, IL-2α receptor phenotypes, and IL-7α phenotypes.

Autoimmune Responses in MS

• Dendritic cells present Myeline Basic Protein and other antigens to lymphocytes
• α4-integrin allows for leukocyte migration into the CNS

Demyelination and Neuronal Conduction

The regions of axon under myelin often contain primarily K channels. After demyelination, Na channels infiltrate the region, and this migration and the accompanying dysregulation of the channels may explain the loss of proper conduction in demyelinated axons.

Remyelination

Glial cells and CD4 T-cells release neurotrophin which promotes the migration of Oligodendrocyte Progenitor Cells and neuronal stem cells to the lesion. These cells then attempt to repair the inflammatory damage. If astrocytes invade the area first, astrogliosis (scaring) of the area can occur instead. In MS there is often a lack of OPCs or OPCs fail to differentiate.

MS Classification

Relapsing-Remitting MS (RRMS)

The most common form of MS. Symptomatic phases and relapsing phases occur in a cyclical manner. These relapses are accompanied by spikes in inflammatory markers; however neurodegeneration is constantly occurring (not just during the inflammatory phases). During the remitting phases the patient will return to or near to baseline. These phases can last for weeks or months.

Secondary Progressive MS (SPMS)

Eventually almost all RRMS will progress to SPMS. This is a non-inflammatory phase of the disease where neurodegenration continues with no remission.

Primary Progressive MS (PPMS)

PPMS is essentially MS which begins as SPMS. The patient has continuous neurodegeneration which does not improve, but has no relapses or their associated inflammatory markers.

Progressive Relapsing MS (PRMS)

Acute relapses and steadily worsening condition from the onset of the disease. There is no remission between relapses.

Clinically Isolated Syndromes

An initial episode of Neurological SSx lasting for more than 24hrs. Most commonly this condition will progress to MS.

Marburg Variant MS

An aggressive form of MS presenting initially with a large number of lesions and high amounts of inflammation which often resembles a brain tumor.

Dx

• Must have at least 2 demyelination related episodes
• May use the Expanded Disability Stats Scale (EDSS)
  • 0-10 (0: Normal Exam, 10: Death from MS)
  • Average score of 4 in RRMS w/i 7yrs of Dx

SSX

Common

• Visual problems; e.g. monocular blindness (optic nerve), double vision
• Numbness, tingling (often an early symptom)
• Fatigue, motor weakness (corticospinal tract)
• Difficulty walking, gait problems, falls; ataxia (cerebellum)
• Pain (sensory pathways)
• Spasticity (stiffness, involuntary muscle spasms)
• Dizziness, vertigo (vestibular pathways)
• Sexual dysfunction
• Bladder problems, constipation
• Emotional or cognitive changes; depression

Uncommon

• Tremor
• Szs
• Itching (pruritis), feeling of pins and needles
• Speech and swallowing issues
• Breathing problems (chest muscles affected by nerve damage)
• HA Hearing loss

Predictors of Quicker Progression

• Short time between relapses
• Progressive from Dx
• Older age at onset
• Abnormal baseline MRI

Relapse Management

High Dose Steroids

• Inpatient: Methylprednisolone 500-1000mg (yes mg) IV QD x3-7d (w/ or w/o PO taper over 1-3d)
  • Most pts are admitted
  • Pts w/ optic neuritis should be admitted and given IV methylprednisolone
• Outpatient: Prednisone PO 1250mg (yes 1250mg) QOD x5doses w/o taper

Other Options

• ACTH
• Plasma Exchange

Chronic Management

See “Disease Modifying Therapies in MS” by Dr. Ott for dosing, comprehensive SEs and monitoring parameters.

RRMS

First Line

• Interferon β1a (Avon, Rebif)
  • Can cause flu-like SSx
    • Pretreat w/ OTC pain killer
    • Give before bed so pt sleeps through worst SSx
    • Low BMI females experience most
  • Pain / inflammation at injection site
• Interferon β1b (Betaseron, Extavia)
  • Can cause flu-like SSx
    • Pretreat w/ OTC pain killer
    • Give before bed so pt sleeps through worst SSx
    • Low BMI females experience most
  • Pain / inflammation at injection site
• Glatiramer Acetate (Copaxone)
  • MOA: Modulation of antigen-presenting cells by mimicry of Myelin Basic Protein
  • Lipoatrophy at injection site
  • Pain / inflammation at injection site
• Fingolimod (Gilenya)
  • MOA: Stimulates oligodendrocyte survival and interferes with lymphocyte movement out of lymphoid organs via Sphingosine-1-Phosphate Receptor Agonism
  • Dose-Dependant Reduction in HR
  • 1st or 2nd Degree Heart Block
  • Should remain in clinic 6hr after initial dose w/ CV monitoring (BP & HR)
    • CV Risk factors => 24hr EKG
  • Avoid in preexisting bradycardia or heart block w/o pacemaker
  • PML Risk in Pts with JCV Igs, must test for JCV Igs before initiating therapy
• Teriflunomide (Aubagio, may be second line)
  • MOA: Cytotoxic via inhibition of dihydroorotate dehydrogenase (used in de novo pyrimidine synthesis). Inhibits lymphocyte proliferation.
• Dimethyl Fumarate (Tecfidera, may be second line)
  • MOA: Prodrug metabolized by esterase’s which activated Nrf2-mediated cellular antioxidant response. Suppresses T cells and dendritic cells. May promote remyelination.
  • Nrf2: Nrf2 is constantly ubuquinated by Keap1, destroying it. During times of oxidative stress, Keap1 is damaged, allowing Nrf2 to enter the nuclear and activate genes controlled by the Antioxidant Response Element. This increases glutathione synthesis and Glutathione-S-Transferase synthesis. This GSH can be release by astrocytes to break down extracellular oxidative stressors, or broken down and reassembled in neurons to detoxify intracellular stressors.
  • PML Risk in Pts with JCV Igs, must test for JCV Igs before initiating therapy
• Daclizumab (Zinbryta, may be second line)
  • CI in Hx of Autoimmune hepatitis or hepatic impairment (LFTs ≥2x ULN)
  • Avoid Live Vaccines up to 4mo after therapy
  • TB test prior to initiation

Second Line

• Natalizumab (Tysabri)
  • MOA: MAB against α4-integrin, prevents binding with β1-integrin to form VLA-1 which combines with VCAM-1 to allow leukocyte infiltration of the CNS
  • PML Risk in Pts with JCV Igs, must test for JCV Igs before initiating therapy
  • Immunocompromised pts, pts with active viral hepatitis, active malignancy, or inability to have an MRI cannot take natalizumab
• Mitoxantrone (Novantrone)
  • MOA: Cytotoxic agent via DNA breaks (via DNA intercalation) and delay of DNA repair via inhibition of Topoisomerase-II. Inhibits lymphocyte proliferation
  • Cardiomyopathy
  • rLVEF
  • Irreversible CHF
  • Baseline and yearly LVEF

Treatment Resistant

• Alemtuzumab (Mentrada)
  • Anaphylaxis risk, must monitor for 2hr post infusion
  • Can cause thrombocytopenia
  • Increased risk of thyroid cancer, lymphoproliferative disorders, and melanoma
    • Baseline TSH and q3mo to 48mo past final dose
    • Baseline and yearly skin exams
  • Do not give if there is an active infection
  • Do not give live-attenuated or live vaccines
  • CI in HIV

PPMS

• Ocrelizumab (Ocrevus)
  • CI in Hep B, must screen before 1st dose
  • Can be used in RRMS, but place in therapy is currently unknown
    • Does Decrease relapse rate in RRMS
  • Do not give if there is an active infection
  • Do not give live-attenuated or live vaccines
  • Increased risk of cancer
  • Infusion reaction common, premedicate with GCs/antihistamine/antipyretic

Symptomatic Management

See “Symptoms Associated with MS and Treatment Options” by Dr. Ott for comprehensive SSx of MS and their management.

Pseudobulbar Affect

Characterized by inappropriate episodes of crying, laughing, or both unrelated to current mood. Treat with Neudexta (Dextromethorphan/Quinidine). Dextromethorphan agonizes σ-1receptors, suppressing neurotransmitter release, as well as antagonizing NMDA receptors. Quinidine inhibits CYP2D6 increasing blood levels of dextromethorphan.

Gait Abnormalities

Dalfampridine (Ampyra) blocks K channels, prolonging action potentials and conduction speed in demyelinated neurons. SEs of ER formulation include UTIs, insomnia, dizziness, HA, nausea. IR formulation can cause Szs (CI in Hx of Szs).

Pregnancy and MS

• Teriflunomide is Cat X (wait 2yrs after D/C or accelerate w/ cholestyramine)
• Mitoxantrone is Cat D (Contraception & pregnancy test required before every dose)
• Fingolimod (D/C 2mo before conception)
• Glatiramer is Cat B
• All others Cat C
• Relapse rates decrease during pregnancy, then increase for 3mo post-partum
• Do not breastfeed if on MS therapy
• Ocrelizumab may cause fetal harm

Medical Marijuana

• Only decreases subjective spasticity scores, not objective
• Cannabis extract decreases central pain
• THC probably decreases painful spasms
• Useless for tremor, bladder dysfunction

Guillain-Barré Syndrome

GBS behaves very similarly to MS, but occurs in the peripheral nervous system instead of the CNS. It is often preceded by GI or respiratory infections, and can lead to paralysis in a matter of days. Patients are usually treated with supportive care (ventilation) and plasmapheresis.