Motor neuron disease Notes
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NOTES NOTES MOTOR NEURON DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of degenerative motor neuron diseases ▫ Progressive muscle weakness, disability CAUSES ▪ Mainly genetic SIGNS & SYMPTOMS ▪ Muscle weakness, fatigue → disability DIAGNOSIS OTHER DIAGNOSTICS ▪ History, physical examination (upper, lower motor neuron signs) ▪ Muscle biopsy ▪ Electromyography (EMG) TREATMENT MEDICATIONS ▪ Emerging disease-modifying agents (limited efﬁcacy) OTHER INTERVENTIONS ▪ Primarily supportive care AMYOTROPHIC LATERAL SCLEROSIS (ALS) osms.it/amyotrophic-lateral-sclerosis PATHOLOGY & CAUSES ▪ Progressive, degenerative motor neuron disease; upper, lower motor neuron signs ▫ AKA Lou Gehrig’s disease ▪ Genetic associations in familial ALS provide insight to pathogenesis ▪ Protein aggregation → neuronal injury, death → retrograde neuronal degeneration → gliosis ▪ Superoxide dismutase 1 (SOD1): antioxidant protein encoded on 632 OSMOSIS.ORG chromosome 9; 20% of familial ALS ▫ Gain-of-function mutation → misfolding → protein aggregation → direct neuronal injury, unfolded protein response → death ▫ Interference with organelle autophagy, proteasome function ▫ Interference with axonal transport, mitochondrial function ▫ Further protein sequestration within protein aggregate ▪ C9orf72: protein of unknown signiﬁcance; 40% of familial ALS
Chapter 82 Motor Neuron Disease ▫ Hexanucleotide repeat expansion → long 5’ end of RNA transcript → abnormal transcription, novel protein production → aggregation ▫ Unknown speciﬁc pathogenesis ▫ Accumulated, novel proteins; dead neurons ▪ TDP-43, FUS: RNA-binding genes ▫ Abnormal RNA processing → abnormal protein accumulation → neuronal injury ▫ Pathway not completely known ▪ Inﬂammatory response ▫ Cerebral inﬂammatory response primarily mediated by microglia, astrocytes ▫ Natural killer, peripheral T-cells, monocytes inﬁltrate, contribute to inﬂammation ▫ Microglial response → nitric oxide, oxygen radical, cytokine, glutamate release → motor neuron cell death ▫ SOD1 mutations especially susceptible to pathologic inﬂammatory response TYPES Progressive motor atrophy ▪ Predominant lower motor neuron degeneration Primary lateral sclerosis ▪ Predominant upper motor neuron degeneration COMPLICATIONS ▪ Frontotemporal lobar dementia (FTLD) ▫ Disinhibition, compulsivity, loss of empathy ▫ Pseudobulbar affect (PBA): common; inappropriate, labile, expressive emotions (e.g. crying, yawning) ▪ Neuromuscular respiratory failure ▪ Dysphagia → pneumonia SIGNS & SYMPTOMS ▪ Early symptoms ▫ Asymmetric hand weakness → dropping of objects (e.g. glasses of water) ▫ Cramping of upper extremities (common) ▫ Dysarthria, dysphagia, dysphonia develop later ▪ Atrophy → ↓ strength → ↓ muscle bulk, abnormal tone → fasciculations ▫ Weakness → inability to ambulate → wheelchair use ▪ Late symptoms ▫ Respiratory weakness → dyspnea → respiratory infection ▫ Recurrent bouts of cough, fever, chill → pneumonia DIAGNOSIS Progressive bulbar palsy (AKA bulbar ALS) ▪ Affected cranial nerves → abnormal deglutition, phonation → ventilator support required ▪ Poor prognosis ▫ Mortality rate > 50% at two years LAB RESULTS CAUSES ▪ El Escorial criteria (all three required) ▫ Evidence of lower motor neuron (LMN) disease by clinical/electrophysiologic/ neuropathic examination ▫ Evidence of upper motor neuron (UMN) disease by clinical examination ▫ Progressive spread of signs/symptoms within/outside of body region, as determined by history/examination ▪ Family history ▪ May be sporadic ▪ Familial (5–10%) ▫ Multiple genes (e.g. SOD1) RISK FACTORS ▪ Family history, age, cigarette smoking ▪ ↑ creatinine kinase (due to muscle atrophy) ▪ Heavy-metal levels, lyme disease ▫ Negative OTHER DIAGNOSTICS OSMOSIS.ORG 633
▪ Neurological ▫ Upper, lower motor neuron signs ▪ Psychiatric ▫ Mental status examination → apathy, disinhibition, PBA in FTLD individuals EMG ▪ Helps differentiate from other neuromuscular junction diseases ▪ Acute denervation ▫ Fibrillations of muscle ﬁbers → active denervation → improper neuronal discharge → small-amplitude baseline variance ▪ Chronic denervation ▫ Large amplitude, long duration, complex motor potentials ▫ Denervation injury → ↑ muscle ﬁber recruitment, ↓ neuronal innervation OTHER INTERVENTIONS ▪ Nothing curative, management of symptom progression, severity ▪ Symptom management ▫ Multidisciplinary approach: neurologists, physical therapists, speech therapists, dietitians ▫ Respiratory management: ↓ aspiration event → ↓ rate of progression to tracheostomy, ventilator-dependence ▫ Respiratory evaluation every three months after diagnosis TREATMENT MEDICATIONS Disease-modifying agents ▪ New to market, mild/modest beneﬁt ▪ Riluzole ▫ Indicated for mild-moderate disease of < ﬁve year duration ▫ Mechanism of action: ↓ any excitotoxic interplay by glutamate in neuronal toxicity → ↓ rate of neuron degeneration, symptom progression ▪ Edaravone ▫ Mechanism of action: free-radical scavenger → ↓ oxidative stress → ↓ rate of neuronal death, symptom progression ▪ Symptom management ▫ Muscle spasms: quinine ▫ Muscle spasticity: muscle relaxants 634 OSMOSIS.ORG Figure 82.1 Amyotrophic lateral sclerosis is also known as Lou Gehrig’s disease. Gehrig played for the Yankee’s and died of ALS at the age of 37.
Chapter 82 Motor Neuron Disease SPINAL MUSCULAR ATROPHY osms.it/spinal-muscular-atrophy PATHOLOGY & CAUSES ▪ Genetically-mediated degenerative neurologic disease of childhood ▫ Lower motor neuron weakness, muscular atrophy ▪ Survival of motor neuron-1 (SMN1) lossof-function mutation → ↓ motor neuron survival → loss of alpha motor neurons (even in utero) → degeneration of anterior horn cells → denervated skeletal muscle → hypotonia, muscle atrophy CAUSES SMN1 loss-of-function mutation ▪ Autosomal recessive ▪ Encoded on chromosome 5q ▪ Multiple physiologic roles ▫ Spliceosome assembly: ↓ nuclear expression of SMN1 in spinal muscular atrophy (SMA) ▫ Inhibition of caspase system: ↓ SMN1 expression → disinhibition of caspase → ↑ caspase expression → cellular apoptosis ▫ Unclear role in alpha motor neuron (patho)physiology SMN2 pseudogene point mutation ▪ Encodes similar protein as SMN1 ▫ Difference: exon 7 (c.840C>T) ▫ ↑ susceptibility for protein degradation → ↓ functional protein at baseline ▪ SMN1 deﬁcient → SMN2 responsible for SMN protein production → poor production of viable protein → motor neuron cell death ▫ Copy number variation correlates with clinical presentation RISK FACTORS ▪ Family history COMPLICATIONS ▪ Sleep disturbance ▪ Cardiac arrhythmias (esp. SMA 1, 2, 3) ▪ Restrictive respiratory disease (esp. SMA 0,1) ▫ Diaphragmatic involvement → respiratory collapse ▪ Dysphagia → aspiration → pneumonia ▪ Poor ambulation → delayed gastric emptying → gastrointestinal (GI) reﬂux, constipation OSMOSIS.ORG 635
SIGNS & SYMPTOMS ▪ Lower motor neuron signs ▫ Proximal limb severity (more common than distal), ↓ muscle strength, tone; ↓/absent DTRs, muscle atrophy, fasciculations DIAGNOSIS OTHER DIAGNOSTICS ▪ Neurological ▫ Fasciculations; ↓ muscle strength, tone; DTRs ▪ Muscle testing ▫ EMG ▫ Abnormal spontaneous activity, ﬁbrillations, positive sharp waves ▪ Muscle biopsy ▫ Large zones of severely atrophic myoﬁbers ▫ Remaining innervated ﬁbers → unchanged/hypertrophied size Figure 82.2 A muscle biopsy demonstrating neurogenic atrophy as would be seen in motor neurone diseases like spinal muscular atrophy. Denervated muscle ﬁber bundles are small and atrophied whilst those that remain innervated retain their normal size. 636 OSMOSIS.ORG TREATMENT MEDICATIONS Experimental disease-modifying therapy ▪ Nusinersen ▫ Antisense oligonucleotide → binds SMN2 mRNA → ↓ exon 7 splicing → ↑ levels of functional SMN protein ▫ Limited effectiveness OTHER INTERVENTIONS ▪ Pulmonary ▫ Secretion management → ↓ aspiration events → ↓ pneumonia ▫ Ventilator support (SMA 0,1) ▪ Nutrition, GI ▫ Manage food consistency → ↓ aspiration ▫ Gastrostomy tube placement in SMA 1 ▫ Encourage ambulation → ↓ gastric emptying time → ↓ constipation, GI reﬂux ▪ Orthopedic, musculoskeletal ▫ Physical therapy ▫ Spinal bracing → ↓ scoliosis → ↓ incidence of restrictive lung disease
Chapter 82 Motor Neuron Disease OSMOSIS.ORG 637
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This Osmosis High-Yield Note provides an overview of Motor neuron disease essentials. All Osmosis Notes are clearly laid-out and contain striking images, tables, and diagrams to help visual learners understand complex topics quickly and efficiently. Find more information about Motor neuron disease by visiting the associated Learn Page.