NE10 Other neurological disorders

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 [blank_start]OK[blank_end]

Motor neurone disease is [blank_start]progressive degeneration[blank_end] of motor neurons. The most affected group is [blank_start]middle aged males[blank_end]. Motor neurons - Upper ones originate in brain, lower ones originate in spinal cord. MND affects [blank_start]both[blank_end] upper and lower. Also know as: • [blank_start]Lou Gehrig's[blank_end] Disease • Charcot's Disease (in Europe). • Amyotrophic Lateral [blank_start]Sclerosis[blank_end] (in US)

Which of these is NOT a presentation of MND?

What causes MND? Most cases [blank_start]sporadic[blank_end]... • [blank_start]Viral[blank_end] infection • [blank_start]Immune[blank_end] mediated damage • Premature motor neuron [blank_start]aging[blank_end] • Loss of [blank_start]growth factors[blank_end] [blank_start]5-10[blank_end]% hereditary ([blank_start]SOD[blank_end] mutation). Pathophysiology? • TDP-43 [blank_start]RNA splicing[blank_end] dysfunction • Excessive [blank_start]glutamate R[blank_end] activation • Intracellular [blank_start]Ca2+ overload[blank_end] • Mitochondrial damage • [blank_start]Excitotoxic[blank_end] cell death • Oxidative stress ([blank_start]free radicals[blank_end])

Tx for motor neurone disease: 1. Riluzole Slows progression, prolongs median survival time by [blank_start]2-3 months[blank_end] Multiple effects on [blank_start]glutamate[blank_end] neurotransmission. Presynapic: inhibits [blank_start]release[blank_end] - inhibits [blank_start]voltage gated Na+[blank_end] channels Postsynaptic: prevents [blank_start]action[blank_end] - non competitive [blank_start]blockade of NMDA[blank_end] Rreceptors Contraindicated: hepatic impairment Caution: [blank_start]neutropenia[blank_end] (fever, sore-throat, malaise) 2. Endaravone (not available in NZ). First FDA approved MND therapy in [blank_start]22[blank_end] years. Free [blank_start]radical[blank_end] scavenger.

Which of these is not a common unwanted effect of riluzole?

Multiple Sclerosis is an [blank_start]autoimmune[blank_end] disorder that affects nerve [blank_start]conduction[blank_end]. There are multiple areas of [blank_start]scarring[blank_end] in the brain, and spinal cord. Inflammation causes relapse. [blank_start]Demyelination and axon damage[blank_end] cause: Optic neuritis, weakness, spasticity, ataxia, [blank_start]bladder and bowel[blank_end] dysfunction. Epidemiology: - Affects 1 in 1000 - [blank_start]Young[blank_end] adults (average age 37 years old) - [blank_start]Women[blank_end] three times more than men • [blank_start]Caucasians[blank_end] • People in [blank_start]cooler[blank_end] climates

Pathology of MS: Trigger = [blank_start]peripheral[blank_end] immune response. Primed [blank_start]T and B[blank_end] lymphocytes cross [blank_start]BBB[blank_end]. Upregulation of [blank_start]integrins[blank_end] causes [blank_start]adhesion[blank_end], Inflammation - [blank_start]Th1 lymphocytic[blank_end] autoimmune response involving INF-g, IL-17, TNF-b. [blank_start]B[blank_end] cell mediated [blank_start]antibodies[blank_end] - [blank_start]Initiate[blank_end] myelin destruction [blank_start]Macrophages[blank_end] - Destroy myelin [blank_start]sheath[blank_end], damage [blank_start]oligo[blank_end]dendrocytes. Demyelination leads to [blank_start]axon[blank_end] damage

Drug treatment for MS: Reduction of symptoms. 15% of patients have [blank_start]primary[blank_end] progressive MS, 85% [blank_start]relapsing- remitting[blank_end] MS ([blank_start]secondary[blank_end] progressive MS). • Modulating immune response early reduces [blank_start]disability[blank_end]

Fingolimob • Oral [blank_start]prodrug[blank_end] (reversible [blank_start]phosphorylation[blank_end]) • Agonist of [blank_start]sphingosine-1-phosphate[blank_end] R • Then internalisation prevents [blank_start]lymphocyte[blank_end] egress, reduced [blank_start]migration[blank_end] to lesions Immunomodulator - [blank_start]infections[blank_end] risk UEs: Headache, migraine, [blank_start]dizziness, paraesthesia, depression[blank_end] Caution: patients with [blank_start]CV[blank_end] risk – transient bradycardia, heart block.

Teriflunomide • Immunomodulator, anti-inflammatory • Selective, [blank_start]irreversible[blank_end] inhibition of dihydro-orotate dehydrogenase • Key [blank_start]enzyme[blank_end] in de novo [blank_start]pyrimidine[blank_end] synthesis • Reduced [blank_start]proliferation[blank_end] of activated T and B cells (without cell death) Contraindicated: [blank_start]blood[blank_end] disorders, severe [blank_start]immunodeficiency[blank_end] Caution: >65 years, significant [blank_start]alcohol[blank_end] consumption

Dimethyl fumarate • Immunomodulatory • Anti-[blank_start]oxidative[blank_end] • Anti-[blank_start]inflammatory[blank_end] • MMF upregulates nuclear factor (erythroidlike)2 (Nrf2) pathways • Activated by oxidative-stress Unwanted effects: [blank_start]flushing, abdominal pain, rash, itching[blank_end], GI - [blank_start]diarrhoea, N&V[blank_end]

[blank_start]Natalizumab[blank_end] - humanized monoclonal antibody • Selective for [blank_start]a4 integrin[blank_end] • Prevents [blank_start]interaction[blank_end] with R • Cant cross [blank_start]BBB[blank_end] Unwanted effects ([blank_start]infusion[blank_end] related): flushing, rigors, fatigue, fever, arthralgia, sore throat…[blank_start]hypersensitivity[blank_end] reactions (1%)

Interferons Reduce immune response (directed @ [blank_start]myelin[blank_end]) to reduce [blank_start]frequency[blank_end] of relapses Unwanted effects: • [blank_start]Flu-like[blank_end] symptoms common • [blank_start]Ulceration[blank_end] @ injection site

Glatiramer acetate - Used when interferon effectiveness reduced. • Synthetic [blank_start]tetra peptide immunomodulator[blank_end] Unwanted effects: • [blank_start]Lipoatrophy[blank_end] • Post injection reaction: shortness of [blank_start]breath[blank_end], [blank_start]chest[blank_end] tightness, flushing (15-30 mins)

Ocrelizumab - Not funded, under consultation [blank_start]Humanised[blank_end] monoclonal that targets [blank_start]CD20+ B cells[blank_end] Unwanted effects: - [blank_start]Infusion[blank_end] related reactions - [blank_start]URTIs[blank_end] - Oral herpes reactivation, neoplasms