By the end of this lecture you will be able to: 1. Describe the pathophysiology of motor neurone disease and multiple sclerosis 2. Describe available treatments for these disorders • Mechanisms of action • Main unwanted effects
❌
Motor neurone disease is ❌ of motor neurons. The most affected group is ❌. Motor neurons - Upper ones originate in brain, lower ones originate in spinal cord. MND affects ❌ upper and lower. Also know as: • ❌ Disease • Charcot's Disease (in Europe). • Amyotrophic Lateral ❌ (in US)
Which of these is NOT a presentation of MND?
Stumbling
Dropping, difficulty holding things
Hoarse voice/slurred speech
Muscle cramps
Dysphagia
Fatigue
Behavioural/emotional changes
Severe cognitive difficulties
What causes MND? Most cases ❌... • ❌ infection • ❌ mediated damage • Premature motor neuron ❌ • Loss of ❌ ❌% hereditary (❌ mutation).
Pathophysiology? • TDP-43 ❌ dysfunction • Excessive ❌ activation • Intracellular ❌ • Mitochondrial damage • ❌ cell death • Oxidative stress (❌)
Tx for motor neurone disease: 1. Riluzole Slows progression, prolongs median survival time by ❌ Multiple effects on ❌ neurotransmission. Presynapic: inhibits ❌ - inhibits ❌ channels Postsynaptic: prevents ❌ - non competitive ❌ Rreceptors Contraindicated: hepatic impairment Caution: ❌ (fever, sore-throat, malaise)
2. Endaravone (not available in NZ). First FDA approved MND therapy in ❌ years. Free ❌ scavenger.
Which of these is not a common unwanted effect of riluzole?
Nausea and vomiting
Lethargy
Dizziness
Diarrhoea
Multiple Sclerosis is an ❌ disorder that affects nerve ❌. There are multiple areas of ❌ in the brain, and spinal cord. Inflammation causes relapse. ❌ cause: Optic neuritis, weakness, spasticity, ataxia, ❌ dysfunction.
Epidemiology: - Affects 1 in 1000 - ❌ adults (average age 37 years old) - ❌ three times more than men • ❌ • People in ❌ climates
Pathology of MS: Trigger = ❌ immune response. Primed ❌ lymphocytes cross ❌. Upregulation of ❌ causes ❌,
Inflammation - ❌ autoimmune response involving INF-g, IL-17, TNF-b.
❌ cell mediated ❌ - ❌ myelin destruction
❌ - Destroy myelin ❌, damage ❌dendrocytes. Demyelination leads to ❌ damage
Drug treatment for MS: Reduction of symptoms. 15% of patients have ❌ progressive MS, 85% ❌ MS (❌ progressive MS). • Modulating immune response early reduces ❌
Fingolimob • Oral ❌ (reversible ❌) • Agonist of ❌ R • Then internalisation prevents ❌ egress, reduced ❌ to lesions Immunomodulator - ❌ risk UEs: Headache, migraine, ❌ Caution: patients with ❌ risk – transient bradycardia, heart block.
Teriflunomide • Immunomodulator, anti-inflammatory • Selective, ❌ inhibition of dihydro-orotate dehydrogenase • Key ❌ in de novo ❌ synthesis • Reduced ❌ of activated T and B cells (without cell death) Contraindicated: ❌ disorders, severe ❌ Caution: >65 years, significant ❌ consumption
Dimethyl fumarate • Immunomodulatory • Anti-❌ • Anti-❌ • MMF upregulates nuclear factor (erythroidlike)2 (Nrf2) pathways • Activated by oxidative-stress Unwanted effects: ❌, GI - ❌
❌ - humanized monoclonal antibody • Selective for ❌ • Prevents ❌ with R • Cant cross ❌ Unwanted effects (❌ related): flushing, rigors, fatigue, fever, arthralgia, sore throat…❌ reactions (1%)
Interferons Reduce immune response (directed @ ❌) to reduce ❌ of relapses Unwanted effects: • ❌ symptoms common • ❌ @ injection site
Glatiramer acetate - Used when interferon effectiveness reduced. • Synthetic ❌ Unwanted effects: • ❌ • Post injection reaction: shortness of ❌, ❌ tightness, flushing (15-30 mins)
Ocrelizumab - Not funded, under consultation ❌ monoclonal that targets ❌ Unwanted effects: - ❌ related reactions - ❌ - Oral herpes reactivation, neoplasms
