1. Approach to the Patient with Weakness

2. What are clinical features that might lead you to believe that weakness is peripheral? Why is it important to localize within the peripheral nervous system?

3. Localization within the Peripheral Nervous system Cell Body Peripheral Nerve/ Axon Neuromuscular Junction Muscle

4. Weakness in Motor Neuron Disease DistributionVariable but asymmetric at onset Muscle ToneHypotonic/Flaccid* Sensory LossNo ReflexesHyporeflexic* Other FeaturesAtrophy, fasciculations, cramping * Amyotrophic lateral sclerosis (ALS) and some related disorders affect both the motor neuron AND the corticospinal tracts, so patients have BOTH upper and lower motor neuron signs. In addition to the above features, these patients may have spasticity and hyperreflexia.

5. Examples of Motor Neuron Disease Congenital – Spinal Muscular Atrophy (SMA) - Types 1(most severe)-4(adult onset) Autosomal recessive: Survival motor neuron (SMN) gene (5q13) Amyotrophic Lateral Sclerosis – Neurodegenerative disease affecting motor neurons of the anterior horn (LMN signs) and the motor cortex (UMN signs) – Sporadic (90-95%) and hereditary (5-10%) Most common genetic form is autosomal dominant – Most common genes: C9ORF72 (9p21) and Superoxide dismutase (SOD) 1 (21q22) Infectious – Poliovirus - Enterovirus eradicated in the U.S. Other enteroviruses can cause similar disease - Enterovirus 70 and 71 – West Nile - Mosquito borne flavivirus Post Radiation - Years after para-aortic radiation

6. Weakness in Peripheral Nerve Disease DistributionDistal > Proximal Muscle ToneHypotonic Sensory LossYes ReflexesHyporeflexic Other FeaturesDistal atrophy over time, paresthesias/pain

7. Examples of Peripheral Nerve Disease Axonal – Systemic illness DM, uremia, cirrhosis, SLE, amyloidosis – Toxic EtOH, heavy metals Meds - Chemo (platinum, taxanes) – Nutrition B12, folate, B6 – Infection HIV, Herpes, leprosy Demyelinating – Hereditary Forms of Charcot-Marie Tooth – Guillian-Barre (AIDP) Preceding illness – e.g. Campylobactor Ascending weakness No reflexes – CIDP - Chronic form – Infectious – CMV, Lyme, Cryoglobulinemia, HIV, Diptheria Trauma - Especially entrapment neuropathy

8. Weakness in Neuromuscular Junction Disease DistributionProximal>Distal, Bulbar Muscle ToneNormal Sensory LossNo ReflexesNormal to hypo, may facilitate with repeat testing Other FeaturesFatigability

9. Examples of Neuromuscular Junction Disease Myasthenia Gravis – Postsynaptic autoimmune disease Antibodies to ACh receptors or MuSK – Sometimes associated with thymoma Lambert-Eaton Myasthenic Syndrome (LEMS) – Presynaptic autoimmune disease Antibodies to voltage gated calcium channels – Often associated with small cell lung cancer Botulism Toxic – Organophosphates, curare, black widow venom, some snake venom, aquatic neurotoxins (cone snail, stone fish)

10. Weakness in Muscle Disease DistributionProximal > Distal Muscle ToneNormal Sensory LossNo ReflexesNormal Other FeaturesSometimes myalgia

11. Examples of Muscle Disease Hereditary – Duchenne/Becker muscular dystrophy X-linked - Dystrophin gene Duchenne (more severe) - reading frame disrupted, Becker (less severe) - reading frame preserved – Mitochondrial disease Inflammatory – Dermatomyositis Skin change - Gottron’s papules, heliotrope Higher incidence of malignancy – Polymyositis Critical Illness Myopathy Toxic – Statins, glucocorticoids

12. Peripheral Nervous System Weakness Motor NeuronPeripheral Nerve Neuromuscular Junction Muscle DistributionVariableTypically Distal Proximal, BulbarProximal Muscle Tone  Sensory LossNoYesNo Reflexes   If demyelinating or severe axonal large fiber  May be facilitated with repeat testing  May be down if very weak Other Features Fasciculations, cramping ParesthesiasFatiguabilitySometimes myalgia