Case 6: Ron Chen Pt 2

Excitable Cells: Resting Potential

Membrane potential at rest

• -70 to -90 mV

Maintained by diffusion potentials

• Leaky K+ Channels: K+ move out

• Na+/K+ ATPase:

  • Transport 3 Na+ out

  • Transport 2 K+ in

• Voltage-Gated Na+ Channels: Closed at rest

  • Keep Na+ extracellular

Excitable Cells: Post-Synaptic Potential

Receive signal from pre-synaptic neuron

Pre-synaptic signal = Release NTs into synaptic cleft = Bind receptors on post-synaptic membrane = Propagate signal

• Excitatory post-synaptic potential (EPSP)

• Inhibitory post-synaptic potential (IPSP)

Excitable Cells: EPSP

Depolarizing potential

1. Post-synaptic receptors open = Cations enter

2. Summation = Post-synaptic neuron reach threshold potential = AP firing

NTs: ACh, NMDA, dopamine, glutamate

Ex: NMJ, nicotinic synapses, NMDA synapses

Excitable Cells: IPSP

Hyperpolarizing/depolarizing potential

1. Post-synaptic receptors open = Anions enter

2. Summation = Post-synaptic neuron move away from threshold potential = Decrease AP firing

NTs: GABA, glycine, dopamine, serotonin

Ex: GABAergic synapses, glycine synapses

Excitable Cells: Action Potentials

Threshold potential = Voltage-gated Na+ channels open = Na+ in = Depolarize membrane

APs: Myelinated Neurons

Saltatory conduction

Generation: Non-myelinated membrane areas (Nodes of Ranvier) ≥ Threshold potential

Propagation: Fast

• Note of Ranvier depolarization = Open voltage-dependent Na+ channels at next node of Ranvier = Depolarization skips/jumps along cell membrane → AP

APs: Unmyelinated Neurons

Continuous conduction

Generation: Any membrane area ≥ threshold potential

Propagation: Slow

• Membrane depolarization = Open voltage-dependent Na+ channels in adjacent areas = Depolarization migrate along cell membrane → AP

APs: Refractory Period

Na+ channels close = Membrane hyperpolarization = Prevent signal backpropagation

Polyneuropathy: Description

Peripheral nerve damage

Length-Dependent: Affect neurons with longer axons first

Types:

• Axonal: Pathology in neuron axons

• Schwann Cells/Myelin Sheath: Pathology affecting Schwann cells/myelin sheath

Polyneuropathy: Epidemiology

Risk factors…

• DM

• Alcohol use disorder

• Chemotherapy

• Nutritional deficiencies

• Obesity

• Autoimmune disorders

Polyneuropathy: Etiology

Axonal:

• DM

• Alcohol use disorder

• Leprosy

• Borreliosis

• HIV

• GBS

• Chemotherapy

  • Cisplatin

  • Doxorubicin

Myelin:

• Chronic inflammatory demyelinating polyneuropathy

• Hereditary motor + sensory neuropathies (HMSN)

  • Charco-Marie-Tooth Disease: Defect in axon/myelin sheath protein function/structure

• GBS

• Toxins

  • Diphtheria

  • Amiodarone

Other Causes:

• Idiopathic

• Toxins

  • Heavy metals (lead, arsenic)

• Inflammatory

  • Vasculitis

  • Connective tissue disorders

• Infectious

  • Herpes

Polyneuropathy: Axonal Pathophysiology

Axon degeneration = Axon/soma injury = Axon + myelin sheath degeneration distal to injury (Wallerian degeneration)

Neurons with longer axons targeted first

• Greater metabolic needs = Decrease metabolic trafficking down axon = Difficulty repair from injury

• Distal → Proximal symptoms

Polyneuropathy: Schwann Cell + Myelin Sheath Pathophysiology

Abnormal Schwann cell function = Segmental demyelination

Generalized muscle weakness

• Distal > proximal

Polyneuropathy: Connective Tissue + Vascular Pathophysiology

Inflammation = Increase capillary permeability = Edema

Polyneuropathy: Clinical Presentation

Symmetrical distal sensory loss

• Glove-and-stocking pattern

Neuropathic pain

• Burning-Foot syndrome: Burning pain, paresthesias, hyperhydrosis

Paresthesias

Motor weakness

• Muscle atrophy (stork legs)

Sensory ataxia

• Loss of sensation (proprioception)

• Affect postural reflexes

Decreased deep tendon reflexes

Polyneuropathy: Investigations

Blood tests

Nerve conduction studies

EMG

Biopsy

Genetic testing

Polyneuropathy Investigations: Blood Tests

CBC

• Anemia

CMP

• Electrolytes

• Serum glucose (DM)

• Vit B12 (low)

• TSH (thyroid disease)

Heavy metal

• Lead

Ethanol level

Serology

• Hep B/C

• HIV

• Lyme disease

Polyneuropathy Investigations: Nerve Conduction Studies

Myelin: Decreased impulse conduction velocity + normal response amplitude

Axonal: Normal impulse conduction velocity + decreased response amplitude

Polyneuropathy Investigations: EMG

Spontaneous electrical activity (fibrillation potentials)

Decreased interference pattern (decreased electrical activity density)

Polyneuropathy Investigations: Biopsy

Not routine

Sural nerve: Sensory nerve in leg

Skin

Polyneuropathy: Treatment

Treat underlying cause

Nonpharmacological

Pharmacological

Polyneuropathy Treatment: Nonpharmacological

Symptom management

Refer patients to…

• Podiatry: Foot care

• Physical therapy: Exercises

• Occupational therapy: Home assessment + modification

Polyneuropathy Treatments: Pharmacological

First-Line:

• Tricyclic antidepressants (TCAs)

• SNRIs

• Gabapentinoids

Topical analgesic: Adjuvant for pain

Tramadol: Treatment failure

Polyneuropathy Treatment: TCAs

MOA: Inhibit norepinephrine + serotonin (less) reuptake in synaptic cleft = Increase inhibbitory pathways in spinal cord = Decrease pain transmission

Ex: Amitriptyline

Polyneuropathy Treatment: SNRIs

MOA: Same as TCAs

Ex: Duloxetine

Polyneuropathy Treatment: Gabapentinoids

MOA: Bind voltage-gated Ca2+ channels = Decrease excitatory NT (glutamate) release = Inhibit pain signal transduction

Polyneuropathy Treatment: Tramadol

MOA:

• Weak opioid agonist

• Inhibit serotonin + norepinephrine reuptake

Polyneuropathy: Complications

Impaired balance = Increase fall risk

Charcot Joint: Neuropathic arthropathy

• Bone + joint destruction in foot + ankle