Part 1 — Synapses: what they are + why they matter (Intro)

1️⃣ Big picture: why synapses exist

• Axons + skeletal muscle conduct in an all-or-none way (action potentials).
• Neurons don’t directly “continue” an action potential into the next cell.

Instead, signals pass cell-to-cell at synapses.

• Synapse = junction where a part of presynaptic cell ends on a postsynaptic cell:
• Presynaptic terminal can end on postsynaptic dendrites, soma, or axon, and sometimes on muscle or gland cells.

2️⃣ Two major types of synapses

A) Chemical synapse (most common)

• Synaptic cleft present between cells.
• Presynaptic impulse → releases a chemical mediator (neurotransmitter).
• Neurotransmitter diffuses across cleft → binds receptors on postsynaptic membrane.
• Receptor activation triggers events that open or close ion channels in postsynaptic membrane.

B) Electrical synapse

• Pre + post membranes come very close.
• Gap junctions connect them → low-resistance ion bridge.
• Ions pass easily → very fast electrical coupling.

C) Conjoint synapses (rare)

• Transmission has both electrical + chemical components.

3️⃣ Key concept: synaptic transmission is NOT “simple AP relay”

• Each synaptic input can be:
• Excitatory
• Inhibitory
• In a postsynaptic neuron, the final output depends on summation of all EPSPs and IPSPs.
• This complexity allows:
• Grading
• Fine adjustment
• Flexible control of neural activity needed for normal function.
• Because most synapses are chemical, the chapter mainly focuses on chemical transmission unless stated otherwise.

4️⃣ Special cases: nerve → muscle vs autonomic targets

• Neuromuscular junction (NMJ):
• Highly specialized
• Stereotyped, consistent transmission process.
• Autonomic → smooth/cardiac muscle contacts:
• Less specialized
• More diffuse transmission.

Part 2 — Synaptic transmission: functional anatomy (where synapses sit)

1️⃣ Presynaptic endings: typical shapes + locations

• Presynaptic fibers often enlarge into:
• Terminal boutons / synaptic knobs
• In cerebral + cerebellar cortex:
• Endings commonly on dendrites
• Often on dendritic spines (tiny dendritic projections/knobs)
• Other wiring patterns:
• Basket/net around soma (e.g., cerebellar basket cells)
• Intertwine with dendrites (e.g., climbing fibers in cerebellum)
• End directly on dendrites (e.g., apical dendrites of pyramidal cells)
• End on axons: axoaxonal endings

2️⃣ The scale of CNS connectivity (numbers you must keep)

• Average neuron forms > 2000 synaptic endings.
• Human CNS has about 10¹¹ neurons.
• Therefore total synapses ≈ 2 × 10¹⁴.
• Synapses are dynamic:
• Can increase/decrease in number and complexity with use + experience.

3️⃣ Where synapses land: dendrites vs soma (important proportions)

• Cerebral cortex:
• 98% synapses on dendrites
• 2% on cell bodies
• Spinal cord (typical spinal neuron):
• ~8000 endings on dendrites
• ~2000 endings on cell body
• Soma can look “encrusted” with endings.

Part 3 — Functions of synaptic elements (the hardware)

1️⃣ Synaptic cleft + postsynaptic density

• Synaptic cleft width: 20–40 nm
• Postsynaptic membrane has many neurotransmitter receptors.
• Often there’s a thickened region: postsynaptic density (PSD)
• PSD = ordered complex of:
• Specific receptors
• Binding proteins
• Enzymes
• Built/organized in response to postsynaptic effects.

2️⃣ What’s inside presynaptic terminal

• Many mitochondria
• Many membrane-enclosed vesicles containing neurotransmitters

3️⃣ Three synaptic vesicle types (match vesicle → transmitter class)

1. Small clear vesicles
• Contain: ACh, glycine, GABA, glutamate
2. Small dense-core vesicles
• Contain: catecholamines
3. Large dense-core vesicles
• Contain: neuropeptides

4️⃣ Vesicle production + transport (who makes what, where)

• Vesicles + vesicle wall proteins are synthesized in the neuronal cell body.
• Transported down axon to terminals by fast axoplasmic transport.
• Neuropeptides (large dense-core vesicles):
• Depend heavily on the cell body’s synthesis machinery.

5️⃣ Vesicle recycling vs “kiss-and-run”

A) Recycling (common for small clear + small dense-core)

• Vesicle fuses → releases transmitter via exocytosis
• Membrane retrieved via endocytosis
• Refilling occurs locally at ending
• Sometimes:
• Vesicles enter endosomes
• Bud off again and refill → cycle repeats

B) “Kiss-and-run” discharge (often)

• Vesicle opens a small transient pore
• Releases transmitter
• Pore reseals quickly
• Vesicle stays inside → endocytosis step is largely bypassed (short-circuited)

6️⃣ Where vesicles release: active zones + spatial arrangement

• Large dense-core vesicles
• Spread throughout terminal
• Release neuropeptides by exocytosis from many parts of terminal
• Small vesicles
• Cluster near synaptic cleft
• Fuse and release very rapidly at active zones
• Active zones
• Membrane thickening near cleft
• Packed with:
• Many proteins
• Rows of Ca²⁺ channels

7️⃣ Ca²⁺ timing + proximity (numbers + logic)

• Ca²⁺ enters presynaptic terminal and triggers exocytosis.
• Transmitter release begins within ~200 μs.
• Therefore:
• Voltage-gated Ca²⁺ channels must be extremely close to release sites at active zones.
• Also, transmitter must be released close to postsynaptic receptors to be effective.

8️⃣ Neurexins: how synapses align + possibly gain specificity

• Synapse alignment depends partly on neurexins (presynaptic membrane proteins)
• They bind neurexin receptors on postsynaptic membrane.
• Species detail:
• Many vertebrates: one gene → α isoform
• Mice + humans: 3 genes, produce α + β isoforms
• Each gene has 2 regulatory regions + extensive alternative splicing
• Result: >1000 different neurexins
• Implication:
• Neurexins may not only “hold synapse together”
• They may help produce synaptic specificity (who connects to whom).

9️⃣ Vesicle fusion machinery (general cell biology → specialized synapse)

• Exocytosis/endocytosis are general cellular processes; synapses are specialized versions.
• Key proteins in synaptic vesicle fusion:
• NSF (N-ethylmaleimide–sensitive fusion protein)
• SNAPs (soluble NSF attachment proteins)
• SNAREs (SNAP receptors)
• Core SNARE pairing:
• Synaptobrevin (on vesicle membrane)
• interacts with syntaxin + SNAPs (on presynaptic cell membrane)
• Regulators:
• GTPases coordinate a multiprotein complex including:
• Rab
• Sec1/Munc18-like proteins
• Functional principle:
• Synapses behave like a one-way gate (directionality is essential for orderly neural function).

🔟 Toxins that block transmitter release (mechanism)

• Several lethal toxins are zinc endopeptidases
• They cleave SNARE/fusion proteins, blocking neurotransmitter release.
• Key examples: Clostridium tetani and Clostridium botulinum (expanded later in clinical box).

Part 4 — Electrical events in postsynaptic neurons (EPSP vs IPSP)

1️⃣ How we study postsynaptic potentials (α-motor neuron experiment)

• Microelectrode advanced into ventral spinal cord.
• When electrode punctures membrane:
• a steady ~70 mV potential difference appears (inside relative to outside).
• Identify penetrated cell as α-motor neuron:
• Stimulate appropriate ventral root
• observe antidromic impulse conducted to soma and stops there
• If action potential appears after antidromic stimulation → confirms α-motor neuron.
• Stimulating a dorsal root afferent can study:
• excitatory and inhibitory events in α-motor neuron.

2️⃣ Synaptic delay (number + what it’s used for)

• After presynaptic impulse reaches terminals, postsynaptic response appears after a delay.
• Cause: time needed for:
• transmitter release
• transmitter action on postsynaptic receptors
• Consequence:
• Multi-synapse pathways conduct slower than pathways with few synapses.
• Minimum transmission time across one synapse ≈ 0.5 ms
• Clinical/physiology use:
• Measure delays to determine if reflex is:
• monosynaptic
• polysynaptic (>1 synapse)

3️⃣ EPSP (excitatory postsynaptic potential)

• Single sensory stimulus typically does not cause propagated AP in postsynaptic neuron.
• Instead produces graded (non-propagated) potential.
• EPSP characteristics (given example):
• begins about 0.5 ms after afferent impulse enters spinal cord
• peaks about 11.5 ms later
• declines exponentially
• Functional meaning:
• during EPSP → excitability increases
• Mechanism:
• excitatory transmitter opens Na⁺ or Ca²⁺ channels
• inward current causes local depolarization under synaptic knob
• current sink is tiny → doesn’t depolarize whole membrane
• produces a small EPSP “inscribed” locally
• Summation:
• EPSP from one knob is small
• multiple active knobs → EPSPs summate

4️⃣ IPSP (inhibitory postsynaptic potential)

• Some inputs produce hyperpolarizing responses (IPSP).
• IPSP characteristics:
• peaks about 11.5 ms after stimulus
• declines exponentially
• Functional meaning:
• during IPSP → excitability decreases
• Common mechanism (classic):
• transmitter opens Cl⁻ channels
• Cl⁻ moves down its gradient → negative charge enters cell
• membrane potential becomes more negative (hyperpolarizes)
• Why excitability drops:
• membrane potential moves away from firing threshold
• more excitation needed to reach threshold
• Evidence it’s Cl⁻ mediated:
• vary resting membrane potential
• at ECl, IPSP disappears
• at more negative potentials, IPSP can reverse (becomes positive) → reversal potential
• Other ways to generate IPSPs:
• opening K⁺ channels → K⁺ efflux
• closing Na⁺ or Ca²⁺ channels

5️⃣ Slow postsynaptic potentials (where + timing + mechanism)

• Found in:
• autonomic ganglia
• cardiac muscle
• smooth muscle
• cortical neurons
• Timing:
• latency 100–500 ms
• duration: several seconds
• Mechanisms:
• slow EPSP: usually ↓ K⁺ conductance
• slow IPSP: usually ↑ K⁺ conductance

6️⃣ Electrical transmission vs chemical (latency logic)

• Electrical synapses:
• presynaptic impulse → EPSP in postsynaptic cell with very short latency
• because of low-resistance bridge
• Conjoint synapses:
• may see both:
• a short-latency response (electrical)
• a long-latency response (chemical)

Part 5 — How a postsynaptic neuron decides to fire (integration + trigger zone)

1️⃣ Soma as an integrator

• Postsynaptic membrane potential fluctuates due to:
• excitatory depolarizations
• inhibitory hyperpolarizations
• Net potential = algebraic sum of all inputs.
• When depolarization reaches threshold, a propagated AP occurs.

2️⃣ Trigger zone in motor neurons: initial segment

• Lowest threshold region = initial segment
• axon area at and just beyond axon hillock
• unmyelinated
• It receives electrotonic effects from synaptic current sinks/sources.
• When it fires:
• AP propagates down axon
• and back into soma (retrograde)
• Proposed value of retrograde soma firing:
• “wipes the slate clean” for renewed integration of incoming signals.

Part 6 — Temporal & spatial summation (time constant + length constant)

1️⃣ Two passive properties control summation ability

A) Time constant

• Determines time course of synaptic potential decay.
• Longer time constant → EPSP lasts longer → more overlap with next EPSP.
• Temporal summation:
• If second EPSP arrives before first decays → they add.
• With enough additive depolarization → AP can occur.

B) Length constant

• Determines how much a depolarizing current decrements as it spreads passively.
• Long length constant:
• potentials spread further with less decay.
• Spatial summation:
• EPSPs arriving at different sites can still reach trigger zone with minimal loss and sum to trigger AP.

Part 7 — Dendrites: not just passive cables (modern view)

1️⃣ Old view

• Dendrites = passive extensions that provide surface area for synapses and allow electrotonic spread to initial segment.

2️⃣ Current view (important upgrades)

• Action potentials can be recorded in dendrites
• often initiated in initial segment and conducted back (retrograde)
• but some dendrites can initiate propagated APs
• Dendritic spines are malleable
• spines can appear, change shape, or disappear over minutes to hours
• Local protein synthesis in dendrites
• mRNA strands migrate into dendrites
• can associate with single ribosomes in spines
• locally produce proteins
• alters synaptic effect at that spine
• These dendritic spine changes are implicated in:
• motivation
• learning
• long-term memory

Part 8 — Inhibition & facilitation at synapses (post vs pre)

1️⃣ Two major CNS inhibition sites

• Postsynaptic inhibition
• Presynaptic inhibition

2️⃣ Direct vs indirect inhibition (concept)

• Direct inhibition = postsynaptic inhibition during an IPSP (not dependent on prior firing).
• Indirect inhibition = due to effects of prior postsynaptic firing, e.g.:
• refractory period after firing
• after-hyperpolarization reduces excitability
• in spinal neurons after repeated firing, after-hyperpolarization can be large and prolonged

3️⃣ Postsynaptic inhibition (classic spinal example)

• Inhibitory transmitter (e.g. glycine, GABA) released onto postsynaptic neuron → IPSP.
• Example: muscle spindle afferents
• Afferent fibers project directly to spinal motor neurons supplying the same muscle.
• Afferent impulses → EPSPs (and with summation, APs) in motor neurons of that muscle.
• Simultaneously, motor neurons of antagonist muscle receive IPSP via an inhibitory interneuron.
• Result = reciprocal innervation:
• agonist excited
• antagonist inhibited

4️⃣ Presynaptic inhibition (axoaxonal control of excitatory endings)

• Mediated by neurons whose terminals synapse on excitatory endings → axoaxonal synapses.
• Three described mechanisms:
1. Activation increases Cl⁻ conductance in excitatory ending → reduces action potential size reaching terminal

→ less Ca²⁺ entry → less transmitter release

2. Opens voltage-gated K⁺ channels → K⁺ efflux → decreases Ca²⁺ influx
3. Direct inhibition of transmitter release independent of Ca²⁺ influx (evidence supports)

Key transmitter for presynaptic inhibition: GABA

• GABA_A receptors:
• increase Cl⁻ conductance
• GABA_B receptors:
• via G-protein → increase K⁺ conductance
• Clinical drug:
• Baclofen (GABA_B agonist) treats spasticity in:
• spinal cord injury
• multiple sclerosis
• especially effective when intrathecal via implanted pump
• Other transmitters can also produce presynaptic inhibition via G-protein effects on Ca²⁺ and K⁺ channels.

5️⃣ Presynaptic facilitation (the opposite direction)

• Occurs when action potential is prolonged
• Ca²⁺ channels stay open longer → more Ca²⁺ entry → more transmitter release
• Detailed model: serotonin in Aplysia
• serotonin at axoaxonal ending → ↑ cAMP
• phosphorylation closes a group of K⁺ channels
• repolarization slows → AP duration increases → facilitation

Part 9 — Organization of inhibitory systems (feedback + feed-forward + pain gating)

1️⃣ Negative feedback inhibition (Renshaw cell example)

• Spinal motor neuron sends recurrent collateral to inhibitory interneuron.
• Interneuron synapses back on motor neuron (and other motor neurons).
• This inhibitory neuron often called Renshaw cell.
• Motor neuron firing activates interneuron → releases glycine → reduces/stops motor neuron discharge.
• Similar recurrent inhibition exists in:
• cerebral cortex
• limbic system
• Presynaptic inhibition from descending pathways in dorsal horn may help gate pain transmission.

2️⃣ Feed-forward inhibition (cerebellum)

• Basket cells produce IPSPs in Purkinje cells.
• Basket cells and Purkinje cells are both excited by same parallel fiber input.
• Effect: limits duration of excitation from a given afferent volley.

Part 10 — Neuromuscular transmission (NMJ) (structure → sequence → quantal release)

1️⃣ Neuromuscular junction anatomy

• As motor axon approaches muscle fiber:
• loses myelin sheath
• divides into multiple terminal boutons
• Terminal contains many small clear vesicles with acetylcholine (ACh).
• Endings sit in junctional folds within the motor endplate (thickened muscle membrane).
• Cleft between nerve and muscle resembles synaptic cleft.
• Whole structure = neuromuscular junction
• Key wiring rule:
• Only one nerve fiber ends on each endplate
• No convergence from multiple inputs

2️⃣ Sequence of transmission events (NMJ physiology)

1. Motor nerve AP arrives → presynaptic terminal permeability to Ca²⁺ increases
2. Ca²⁺ enters terminal → triggers exocytosis of ACh vesicles
3. ACh diffuses to nicotinic (NM) receptors concentrated at tops of junctional folds
4. Receptor activation increases Na⁺ and K⁺ conductance
5. Na⁺ influx dominates → depolarizing endplate potential (EPP)
6. EPP creates local current sink → depolarizes adjacent muscle membrane to threshold
7. Muscle AP generated on either side of endplate → propagates both directions
8. Muscle AP triggers contraction (from earlier muscle chapter)
9. ACh removed by acetylcholinesterase, abundant at NMJ

3️⃣ Safety factor + curare demonstration (numbers must be exact)

• Human endplate has about 15–40 million ACh receptors.
• Each nerve impulse releases ACh from ~60 vesicles.
• Each vesicle contains ~10,000 ACh molecules.
• This normally activates about 10× the NM receptors needed for a full EPP.
• So muscle AP is reliably produced, often obscuring the EPP.
• If you reduce safety factor (e.g., small dose curare, competitive NM antagonist):
• EPP becomes smaller
• may fail to reach threshold
• then EPP can be recorded locally and shows exponential decay away from endplate
• under these conditions, EPPs can show temporal summation

4️⃣ Quantal release (miniature EPPs)

• Even at rest, ACh released in small random quanta.
• Each quantum produces a miniature endplate potential (MEPP):
• ~0.5 mV amplitude
• Quantum size depends on ions:
• varies directly with Ca²⁺ concentration
• varies inversely with Mg²⁺ concentration
• With a nerve impulse:
• quanta released increase by several orders of magnitude
• produces large EPP above threshold
• Quantal transmitter release is not unique to NMJ:
• occurs at other cholinergic synapses
• also for other transmitters (noradrenergic, glutamatergic, etc.)
• Two important NMJ disorders introduced (expanded later):
• Myasthenia gravis
• Lambert–Eaton myasthenic syndrome

Part 11 — Autonomic endings in smooth & cardiac muscle (diffuse transmission)

1️⃣ Smooth muscle innervation pattern

• Postganglionic neurons branch extensively and contact many muscle cells.
• Some fibers:
• clear vesicles → cholinergic
• dense-core vesicles → norepinephrine (noradrenergic)
• No clear endplates / no specialized postsynaptic structures.
• Axons run along muscle membranes and may groove them.
• Varicosities:
• beaded enlargements along axon
• contain synaptic vesicles
• in noradrenergic neurons:
• ~5 μm apart
• up to 20,000 varicosities per neuron
• Transmitter likely released at each varicosity → many release sites along axon.
• Allows one neuron to activate many effector cells.
• This pattern is called synapse en passant:
• neuron makes contact then moves on to make similar contacts with other cells.

2️⃣ Cardiac autonomic endings

• Cholinergic + noradrenergic fibers end on:
• SA node
• AV node
• Bundle of His
• Noradrenergic fibers also innervate ventricular muscle.
• Exact nature of nodal endings not fully known.
• Ventricular noradrenergic contacts resemble smooth muscle pattern.

3️⃣ Junctional potentials (smooth muscle equivalents of EPP)

• If noradrenergic discharge is excitatory:
• stimulation produces excitatory junction potentials (EJPs)
• discrete partial depolarizations resembling small EPPs
• can summate with repeated stimuli
• Similar EJPs occur with excitatory cholinergic input.
• If noradrenergic input is inhibitory:
• stimulation produces inhibitory junction potentials (IJPs) (hyperpolarizing)
• Junctional potentials spread electrotonically.

Part 12 — Axonal injury, degeneration, regeneration, supersensitivity

1️⃣ Degeneration patterns after axon injury

• Orthograde degeneration (Wallerian degeneration)
• occurs distal to injury (from injury site → terminal)
• interrupts transmission
• distal membrane breaks down + myelin degenerates
• Proximal effects:
• can undergo retrograde degeneration
• neuron may die

2️⃣ Cell body reaction (chromatolysis)

• Cell body swells
• Nucleus shifts to eccentric position
• Rough ER fragments → chromatolytic reaction

3️⃣ Regeneration attempt

• Nerve regrows with multiple small branches along old path:
• regenerative sprouting
• Sometimes successful (especially at NMJ).
• Often limited because axons tangle in damaged tissue at disruption site.
• This difficulty can be reduced by neurotrophins.

4️⃣ Denervation hypersensitivity (supersensitivity)

Skeletal muscle

• After motor nerve cut + degenerates:
• muscle becomes extremely sensitive to ACh
• Normally NM receptors are localized near endplate.
• After denervation:
• marked proliferation of nicotinic receptors over a wide region around NMJ → hypersensitivity.

Autonomic junctions / smooth muscle

• Also shows denervation supersensitivity.
• Smooth muscle generally does not atrophy when denervated, but becomes hyperresponsive to the usual mediator.

Pharmacologic demonstration

• Example:
• prolonged reserpine use depletes norepinephrine stores → reduces exposure of target organ to NE.
• after stopping, smooth/cardiac muscle become supersensitive to subsequent NE release.

5️⃣ Why supersensitivity happens (multiple mechanisms)

• General rule:
• deficiency of messenger → up-regulation of its receptors
• Also:
• lack of reuptake of secreted neurotransmitters contributes.

Part 13 — Clinical Box 6–1: Botulinum & tetanus toxins (mechanism → clinical pattern)

1️⃣ Source + general mechanism

• Clostridia: gram-positive bacteria.
• C. tetani and C. botulinum produce extremely potent toxins.
• These toxins prevent neurotransmitter release by targeting vesicle fusion proteins (SNARE machinery).

2️⃣ Tetanus toxin (C. tetani)

• Binds irreversibly to presynaptic membrane at NMJ
• Travels by retrograde axonal transport to motor neuron cell body in spinal cord
• Then taken up by presynaptic inhibitory interneuron terminals
• In inhibitory terminals:
• attaches to gangliosides
• blocks release of glycine + GABA
• Net effect:
• loss of inhibition → motor neuron activity becomes markedly increased
• Clinical pattern:
• spastic paralysis
• “lockjaw” due to masseter spasm

3️⃣ Botulinum toxin (C. botulinum)

• Exposure routes:
• contaminated food ingestion
• infant GI colonization
• wound infection
• Family of 7 toxins, but A, B, E are main human toxins.
• Molecular targets:
• A and E cleave SNAP-25 (needed for vesicle fusion)
• B cleaves synaptobrevin (VAMP)
• Blocks ACh release at NMJ → flaccid paralysis
• Symptoms can include:
• ptosis, diplopia
• dysarthria, dysphonia
• dysphagia

4️⃣ Therapeutic highlights

• Tetanus toxoid vaccine prevents tetanus; widespread use (US mid-1940s onward) led to marked decline.
• Botulism:
• incidence low (~100 cases/year in US)
• fatality rate 5–10%
• antitoxin available
• ventilatory support if respiratory failure risk
• “Botox” (small local doses) useful for muscle hyperactivity conditions:
• e.g., injection into lower esophageal sphincter for achalasia
• injection into facial muscles to reduce wrinkles

Part 14 — Clinical Box 6–2: Myasthenia gravis (MG)

1️⃣ Core definition

• MG = autoimmune disease causing skeletal muscle weakness + easy fatigability.
• Caused by circulating antibodies against muscle-type nicotinic ACh receptors.

2️⃣ Epidemiology

• ~25–125 per 1 million worldwide
• Any age, but bimodal peaks:
• 20s (mainly women)
• 60s (mainly men)

3️⃣ Pathophysiology (exact steps)

• Antibodies:
• destroy some receptors
• cross-link others → triggers removal by endocytosis
• Normal physiology:
• with repetitive stimulation, quanta released per impulse naturally decline.
• In MG:
• with fewer functional receptors, transmission fails when quantal release is low
• → hallmark: fatigue with sustained/repeated activity

4️⃣ Clinical patterns

• Two main forms:
1. predominantly extraocular muscle involvement
2. generalized weakness
• Severe cases:
• can involve diaphragm → respiratory failure and death possible

5️⃣ Structural abnormality at NMJ

• sparse, shallow, abnormally wide or absent synaptic clefts
• postsynaptic membrane response to ACh reduced
• 70–90% decrease in receptor number per endplate in affected muscles

6️⃣ Associations + thymus role

• Higher tendency to have other autoimmune diseases:
• rheumatoid arthritis
• SLE
• polymyositis
• ~30% have a maternal relative with autoimmune disorder → genetic predisposition idea
• Thymus involvement:
• may supply helper T cells sensitized against thymic proteins cross-reacting with ACh receptor
• thymus often hyperplastic
• 10–15% have thymoma

7️⃣ Therapeutic highlights

• Improves after rest or with AChE inhibitors:
• neostigmine, pyridostigmine
• Immunosuppressants can help:
• prednisone, azathioprine, cyclosporine
• Thymectomy:
• indicated especially if thymoma suspected
• even without thymoma:
• remission in 35%
• symptom improvement in 45%

Part 15 — Clinical Box 6–3: Lambert–Eaton myasthenic syndrome (LEMS)

1️⃣ Core definition

• LEMS = muscle weakness due to autoimmune attack against voltage-gated Ca²⁺ channels in nerve endings at NMJ.
• → reduces Ca²⁺ influx → reduces ACh release.

2️⃣ Epidemiology

• ~1 per 100,000 (US)
• adult onset
• similar occurrence in men and women

3️⃣ Clinical pattern

• Primarily proximal lower limb weakness:
• waddling gait
• difficulty raising arms also noted

4️⃣ Key diagnostic physiology contrast vs MG

• Repetitive stimulation causes:
• Ca²⁺ accumulation in nerve terminal
• ↑ ACh release
• increased muscle strength (facilitation)
• In MG, repetitive stimulation typically worsens weakness.

5️⃣ Cancer association (important numbers + types)

• ~40% have cancer, especially small cell lung cancer
• Theory: antibodies made against cancer cross-react with Ca²⁺ channels
• Also associated with:
• lymphosarcoma
• malignant thymoma
• cancers of breast, stomach, colon, prostate, bladder, kidney, gallbladder
• Clinical signs often appear before cancer diagnosis.

6️⃣ Drug-induced similar syndrome

• Aminoglycosides can impair Ca²⁺ channel function → LEMS-like syndrome.

7️⃣ Therapeutic highlights

• Because of strong cancer link:
• first strategy = check for cancer and treat it if present
• Without cancer:
• immunotherapy options include prednisone, plasmapheresis, IVIG
• Aminopyridines improve strength:
• block presynaptic K⁺ channels
• promote activation of voltage-gated Ca²⁺ channels
• AChE inhibitors may be used but often don’t improve symptoms much.