Specialty: Physiology

NCS & EMG Basics

NCS Basics

Motor vs Sensory NCS

Feature Motor NCS (CMAP) Sensory NCS (SNAP)
Recording site Muscle Sensory nerve (digit or nerve trunk)
Amplitude reflects Number of motor axons + muscle fibers Number of sensory axons
Normal amplitude >4-5 mV (varies by nerve) >10-20 μV (varies by nerve)
Key clinical use Motor axon loss, NMJ, myopathy Distinguishes pre- vs postganglionic lesions

Key NCS Parameters

Parameter What It Measures Abnormal In
Amplitude Number of functioning axons Axonal loss, conduction block
Conduction velocity (CV) Speed of fastest fibers (myelination) Demyelination (<70-75% LLN)
Distal latency (DL) Time from distal stim to response Distal demyelination (>130% ULN)
Duration Synchrony of fiber conduction Temporal dispersion (demyelination)
💎 Board Pearl

SNAP preserved in radiculopathy because the lesion is preganglionic (DRG intact). SNAP lost in plexopathy and peripheral neuropathy (postganglionic). This is key for localization!

Demyelinating vs Axonal Patterns

NCS Criteria

Feature Demyelinating Axonal
Conduction velocity <70-75% LLN Normal or mildly slow (>70% LLN)
Distal latency >130% ULN Normal or mildly prolonged
Amplitude May be preserved early; low late Low (proportional to axon loss)
Temporal dispersion Present (>30% duration increase) Absent
Conduction block Present (>50% amplitude drop) Absent
F-wave latency Prolonged or absent Normal or mildly prolonged
EMG fibrillations Less prominent (unless 2° axonal loss) Prominent

Clinical Examples

Demyelinating Axonal
GBS (AIDP) GBS (AMAN, AMSAN)
CIDP Diabetic polyneuropathy
CMT1 (hereditary) CMT2 (hereditary)
MMN Toxic neuropathies
Anti-MAG neuropathy Vasculitic neuropathy
💎 Board Pearl

Conduction block = weakness WITHOUT atrophy (axons intact but can’t conduct through demyelinated segment). Temporal dispersion indicates acquired (non-uniform) demyelination – not seen in hereditary demyelinating neuropathies like CMT1.

NCS Patterns by Location

Common Mononeuropathies – Entrapment Sites

Nerve Site NCS Findings Clinical
Median Carpal tunnel Prolonged DL; slow sensory CV across wrist; compare to ulnar Numbness digits 1-3; thenar weakness (severe)
Ulnar Elbow (cubital tunnel) CV slowing across elbow (>10 m/s drop); conduction block Numbness digits 4-5; intrinsic hand weakness
Ulnar Wrist (Guyon’s canal) Abnormal dorsal ulnar cutaneous spares (branches proximal) Similar to elbow but dorsum hand spared
Peroneal Fibular head Conduction block/slowing across fibular head; superficial peroneal SNAP normal Foot drop; lateral leg numbness
Radial Spiral groove Conduction block across spiral groove Wrist drop; Saturday night palsy
Tibial Tarsal tunnel Prolonged DL; low amplitude medial/lateral plantar Sole numbness/burning

Radiculopathy vs Plexopathy vs Neuropathy

Feature Radiculopathy Plexopathy Mononeuropathy
SNAP Normal (preganglionic) Abnormal Abnormal
CMAP Low (if severe axon loss) Low Low
EMG distribution Myotomal (multiple nerves, one root) Multiple nerves/roots, one plexus region Single nerve distribution
Paraspinals Abnormal Normal Normal
💎 Board Pearl

SNAP normal + paraspinals abnormal = radiculopathy. SNAP abnormal + paraspinals normal = plexopathy or peripheral nerve lesion. This is the most important distinction!

Special NCS Studies

Late Responses

Study Pathway Clinical Use Abnormal In
F-wave Motor nerve → anterior horn → back (antidromic-orthodromic) Tests proximal nerve segments, roots GBS (early), radiculopathy, proximal neuropathy
H-reflex Ia afferent → spinal cord → motor neuron (monosynaptic) Electrical ankle jerk; tests S1 root S1 radiculopathy, polyneuropathy

Repetitive Nerve Stimulation (RNS)

Finding Low-Frequency (2-3 Hz) Post-Exercise/High-Frequency Diagnosis
Decrement >10% Yes Repair of decrement Myasthenia gravis
Low baseline + increment >100% May decrement Large increment Lambert-Eaton
Low baseline + small increment May decrement 20-40% increment Botulism

Blink Reflex

  • Tests: Trigeminal (V1 afferent) and facial (VII efferent) nerves; brainstem
  • R1: Ipsilateral, oligosynaptic (pons)
  • R2: Bilateral, polysynaptic (lateral medulla)
  • Uses: Facial nerve lesions, trigeminal neuropathy, brainstem lesions, GBS

Single-Fiber EMG (SFEMG)

SFEMG is the most sensitive test for neuromuscular junction disorders. It measures the variability in timing between two muscle fibers within the same motor unit.

Parameter Definition Normal Abnormal In
Jitter Variation in interpotential interval (IPI) between two single-fiber APs <~40-55 μs (varies by muscle) MG (most sensitive test), LEMS, botulism, reinnervation, motor neuron disease
Blocking Intermittent failure of one fiber to fire (extreme jitter) Absent Severe NMJ dysfunction (MG, LEMS); correlates with clinical weakness
Fiber density Number of single fibers per motor unit within recording area 1.3-1.8 (varies by muscle/age) ↑ in reinnervation (neuropathy, motor neuron disease); reflects collateral sprouting
Feature SFEMG RNS
Sensitivity for MG 95-99% (most sensitive) ~75% generalized MG; ~50% ocular MG
What it measures Jitter between individual fibers Decrement of compound potential
Technical difficulty High (requires expertise) Moderate
Best muscle Orbicularis oculi, frontalis, EDC Proximal: trapezius, deltoid; distal: ADM
Specificity for MG Lower (abnormal in many NMJ/neurogenic conditions) Higher (decrement pattern more specific)
When to use When RNS normal but MG still suspected; ocular MG Initial screening; monitoring treatment

SFEMG Interpretation Pearls

  • Increased jitter with normal fiber density → NMJ disorder (MG, LEMS)
  • Increased jitter WITH increased fiber density → Neurogenic process with reinnervation (ALS, neuropathy)
  • Blocking on SFEMG → Correlates with weakness; more blocking = more severe NMJ dysfunction
  • Stimulated SFEMG (stimSFEMG): Uses nerve stimulation instead of voluntary activation. Easier to perform, more standardized. Good alternative when voluntary SFEMG not possible (children, uncooperative patients)
💎 Board Pearl

SFEMG is the MOST SENSITIVE test for myasthenia gravis (~99% sensitivity in generalized MG). However, it is NOT specific — increased jitter also occurs in motor neuron disease, reinnervation, and other NMJ disorders. Use RNS for specificity, SFEMG for sensitivity.

💎 Board Pearl

F-waves test the entire motor nerve including proximal segments – prolonged or absent early in GBS when distal NCS still normal. H-reflex = S1; absent H-reflex with normal ankle jerk suggests early/mild S1 radiculopathy.

EMG Spontaneous Activity

Types of Spontaneous Activity

Finding Description Sound Associated Conditions
Fibrillation potentials Spontaneous single muscle fiber discharge; biphasic/triphasic; regular “Rain on a tin roof” Denervation, inflammatory myopathy, muscular dystrophy, NMJ disorders
Positive sharp waves (PSWs) Initial positive deflection then negative; regular Dull “thud” Same as fibrillations
Fasciculation potentials Spontaneous motor unit discharge; irregular “Popcorn” ALS, radiculopathy, benign fasciculations, cramp-fasciculation syndrome
Myotonic discharges Waxing and waning frequency AND amplitude; triggered by needle movement “Dive bomber” Myotonic dystrophy, myotonia congenita, paramyotonia, hyperkalemic PP
Myokymic discharges Grouped, repetitive bursts of same MUP; semi-rhythmic “Marching soldiers” Radiation plexopathy, GBS, MS, facial myokymia (brainstem glioma)
Neuromyotonic discharges Very high frequency (150-300 Hz); decrementing; “pinging” “Ping” or musical Isaac’s syndrome (anti-VGKC/CASPR2), thymoma, post-radiation
Complex repetitive discharges (CRDs) Polyphasic; regular; abrupt start/stop; no waxing/waning “Jackhammer” or “motorcycle” Chronic denervation, chronic myopathy, radiculopathy
Cramp potentials High-frequency MUP discharge; irregular; painful Rumbling Cramps (ALS, metabolic, benign)
💎 Board Pearl

Myotonic discharge = waxing/waning (dive bomber). CRD = NO waxing/waning (jackhammer). Myokymia on EMG = consider radiation injury or GBS. Neuromyotonia = Isaac’s syndrome (continuous muscle fiber activity).

EMG in Denervation & Reinnervation

Timeline of EMG Changes After Nerve Injury

Time After Injury NCS Findings EMG Findings
Immediate (0-7 days) Conduction block at injury site; distal responses NORMAL Reduced recruitment only; NO fibrillations yet
Acute (7-10 days) Distal CMAP/SNAP drop (Wallerian degeneration complete) Reduced recruitment; fibs/PSWs starting (proximal muscles first)
Subacute (2-3 weeks) Low/absent distal responses Fibs/PSWs prominent in proximal muscles
Subacute (4-6 weeks) Low/absent distal responses Fibs/PSWs in distal muscles; maximal denervation
Early reinnervation (2-4 months) May see nascent CMAPs Nascent MUPs (small, polyphasic); fibs persist
Chronic reinnervation (6+ months) CMAP may improve Large, polyphasic MUPs; reduced recruitment; fibs decrease
Chronic stable (years) May be normal or low amplitude Giant MUPs; reduced recruitment; NO fibs (stable)

Key Points

  • Fibs appear at different times depending on distance from lesion:
    • Paraspinals: ~10 days
    • Proximal limb: 2-3 weeks
    • Distal limb: 4-6 weeks
  • Nascent MUPs = first sign of reinnervation (small, polyphasic, unstable)
  • Chronic neurogenic MUPs = large amplitude, long duration, polyphasic (collateral sprouting)
  • Reduced recruitment = fewer MUPs firing fast (neurogenic pattern)
💎 Board Pearl

Wait 3 weeks for optimal EMG after nerve injury – fibs take time to appear. Fibs WITHOUT large MUPs = acute/ongoing denervation. Fibs WITH large MUPs = chronic with ongoing denervation. Large MUPs WITHOUT fibs = chronic stable.

MUP Analysis & Recruitment

Myopathic vs Neurogenic MUPs

Feature Myopathic Neurogenic
Amplitude Low (small) High (large/giant)
Duration Short Long
Phases Increased polyphasia Increased polyphasia
Recruitment Early (many small units for weak effort) Reduced (few units firing fast)
Reason Fewer muscle fibers per motor unit Collateral sprouting → larger motor units

Recruitment Patterns

Pattern Description Seen In
Normal Ratio ~5:1 (firing rate : number of MUPs) Normal
Reduced (neurogenic) Few MUPs firing rapidly (>15-20 Hz before next recruited) Neuropathy, radiculopathy, ALS
Early (myopathic) Many MUPs at low firing rates; full interference with weak effort Myopathy
Poor activation Few MUPs at low firing rates; normal MUP morphology UMN lesion, pain, poor effort
💎 Board Pearl

Myopathic = SNAP (Small, short, polyphasic with early recruitment). Neurogenic = LARP (Large amplitude, long duration, reduced recruitment, polyphasic). Remember: “Sick muscle = small units, sick nerve = big units.”

Disease-Specific EMG Findings

Quick Recognition Table

Disease Key EMG/NCS Findings
ALS Widespread fibs + fasciculations + neurogenic MUPs; NORMAL sensory NCS; multiple regions (bulbar, cervical, thoracic, lumbar)
Myasthenia gravis Decrement on RNS; increased jitter on single-fiber EMG; normal routine NCS/EMG
Lambert-Eaton Low CMAP amplitude; >100% increment post-exercise; may have mild decrement at rest
GBS (AIDP) Prolonged/absent F-waves (early); conduction block; temporal dispersion; slow CV
CIDP Same as AIDP but symmetric and chronic; uniform demyelination
Multifocal motor neuropathy (MMN) Conduction block in motor nerves ONLY; normal sensory; asymmetric
Myotonic dystrophy Myotonic discharges (dive bomber); myopathic MUPs; fibs common
Polymyositis/Dermatomyositis Fibs/PSWs + myopathic MUPs (“irritable myopathy”); CRDs; normal NCS
Inclusion body myositis Mixed myopathic AND neurogenic features; fibs; long-duration MUPs
Steroid myopathy Myopathic MUPs; NO fibrillations; normal NCS
Critical illness myopathy Low CMAP with direct muscle stimulation; fibs; myopathic MUPs
Radiation plexopathy Myokymic discharges; axonal loss pattern
Isaac’s syndrome Neuromyotonic discharges; fasciculations; doublets/triplets
Carpal tunnel syndrome Prolonged median distal latency; slow sensory CV across wrist; compare to ulnar (normal)
💎 Board Pearl

ALS = motor only (normal sensory NCS is required). MMN = motor conduction block only. IBM = mixed pattern (unique!). Radiation plexopathy = myokymia (distinguishes from tumor infiltration which doesn’t have myokymia).

Summary Tables

Localization Quick Reference

Clinical Scenario SNAP Paraspinals Diagnosis
Weakness + sensory loss in one nerve Abnormal Normal Mononeuropathy
Weakness in myotome + sensory loss in dermatome Normal Abnormal Radiculopathy
Weakness/sensory loss spanning multiple nerves and roots Abnormal Normal Plexopathy
Length-dependent sensory > motor Abnormal (distal) Normal Polyneuropathy

Spontaneous Activity Quick Reference

Sound Finding Think Of
“Dive bomber” (waxing/waning) Myotonic discharge Myotonic dystrophy, myotonia congenita
“Marching soldiers” (grouped bursts) Myokymia Radiation injury, GBS
“Ping” (high-frequency, decrementing) Neuromyotonia Isaac’s syndrome
“Jackhammer” (no waxing/waning) CRD Chronic denervation/myopathy
“Rain on tin roof” Fibrillations Denervation, inflammatory myopathy

Key Clinical Pearls

High-Yield Points
  • SNAP normal = preganglionic (radiculopathy)
  • Conduction block = demyelinating
  • Low amplitude everywhere = axonal
  • Wait 3 weeks for EMG after nerve injury
  • Fibs appear proximal to distal (paraspinals first)
  • Myopathic = small, short, early recruitment
  • Neurogenic = large, long, reduced recruitment
  • F-waves abnormal early in GBS (before distal changes)
  • Myokymia = radiation plexopathy
  • ALS requires normal sensory NCS

Red Flags

Important Considerations
  • Fibs in first week: Pre-existing denervation or myopathy (not new injury)
  • Abnormal sensory NCS in suspected ALS: Reconsider diagnosis
  • Conduction block in sensory AND motor: Think CIDP/GBS, not MMN
  • Rapidly progressive with normal EMG: Consider NMJ disorder, myopathy, or too early after injury
  • Myokymia without radiation history: Consider GBS, MS, or brainstem lesion

Sleep

Sleep Architecture

Sleep Stages

Stage EEG Pattern Key Features % of Sleep
Wake Alpha (8-13 Hz) relaxed; Beta alert Alpha = posterior, eyes closed —
N1 Theta (4-7 Hz); vertex sharp waves Light sleep; easily aroused; slow eye movements 5%
N2 Sleep spindles (12-14 Hz) + K-complexes Majority of sleep; memory consolidation 45-55%
N3 (Slow Wave) Delta (<4 Hz); >20% of epoch Deep sleep; restorative; GH release; hardest to arouse 15-20%
REM Low voltage, mixed frequency; sawtooth waves Rapid eye movements; muscle atonia; dreaming 20-25%

Sleep Cycle Organization

  • Cycle duration: 90-120 minutes
  • Cycles per night: 4-6
  • First half of night: More N3 (slow wave sleep)
  • Second half of night: More REM sleep
  • REM latency: ~90 minutes (shortened in narcolepsy, depression)

Two-Process Model of Sleep Regulation

Process S (Homeostatic): Sleep pressure builds during waking hours. Mediated by adenosine accumulation. Caffeine blocks adenosine receptors. Determines NREM sleep intensity (delta power).

Process C (Circadian): SCN-driven ~24h rhythm independent of sleep debt. Controls timing of sleep propensity. Peaks of alertness in late morning and early evening (“forbidden zone for sleep”).

The interaction: Process S builds during wake, Process C gates when sleep can occur. Mismatch between the two processes leads to jet lag and shift work problems.

💎 Board Pearl

Sleep spindles + K-complexes = N2. Sleep spindles generated by thalamic reticular nucleus. K-complexes are cortical responses to stimuli. N2 is the most abundant stage (~50%).

Neuroanatomy of Sleep-Wake Regulation

Wake-Promoting Systems

Structure Neurotransmitter Notes
Locus coeruleus Norepinephrine Off during REM
Raphe nuclei Serotonin Off during REM
Tuberomammillary nucleus Histamine Antihistamines cause sedation
Basal forebrain Acetylcholine Also active in REM
Lateral hypothalamus Orexin/Hypocretin Stabilizes wake; lost in narcolepsy type 1

Sleep-Promoting Systems

Structure Neurotransmitter Function
VLPO GABA, Galanin Inhibits wake centers; “sleep switch”
Adenosine — Builds during wake; caffeine blocks receptors

REM Sleep Regulation

REM-on: PPT/LDT (ACh), sublaterodorsal nucleus

REM-off: Locus coeruleus (NE), raphe (5-HT)

REM atonia: Sublaterodorsal nucleus inhibits spinal motor neurons. Loss → REM sleep behavior disorder.

💎 Board Pearl

Orexin/hypocretin from lateral hypothalamus stabilizes wakefulness. Loss = narcolepsy type 1. CSF orexin <90 pg/mL is diagnostic. Orexin receptor antagonists (suvorexant) treat insomnia.

Circadian Rhythm

Suprachiasmatic Nucleus (SCN)

  • Location: Anterior hypothalamus, above optic chiasm
  • Function: Master circadian pacemaker
  • Input: Light via retinohypothalamic tract (melanopsin RGCs)
  • Output: Pineal gland (melatonin), temperature, cortisol
  • Intrinsic cycle: ~24.2 hours (needs daily light entrainment)

Melatonin

  • Source: Pineal gland
  • Regulation: Suppressed by light; peaks at night
  • Function: Signals darkness; promotes sleep onset
  • Clinical use: Circadian rhythm disorders, jet lag

Circadian Rhythm Disorders

Disorder Features Treatment
Delayed Sleep Phase Sleep onset 2+ hrs late; common in adolescents; “night owls” Morning bright light; evening melatonin
Advanced Sleep Phase Sleep onset/wake too early; common in elderly Evening bright light; morning melatonin
Non-24-Hour Free-running rhythm; common in blind Melatonin agonists (tasimelteon)
Shift Work Misalignment with work schedule Strategic light exposure; melatonin
💎 Board Pearl

Delayed = give melatonin in evening + morning light. Advanced = opposite. Non-24-hour rhythm is common in totally blind patients due to loss of light entrainment.

Sleep Disorders

Narcolepsy

Feature Type 1 (with Cataplexy) Type 2 (without Cataplexy)
Orexin/CSF Low (<110 pg/mL, usually <90) Normal
Cataplexy Present (emotion-triggered atonia) Absent
HLA association DQB1*06:02 (>90%) Less strong
MSLT criteria Mean sleep latency ≤8 min + ≥2 SOREMPs

Narcolepsy tetrad:

  1. Excessive daytime sleepiness (100%)
  2. Cataplexy (emotion-triggered weakness; type 1 only)
  3. Sleep paralysis (can’t move at sleep-wake transitions)
  4. Hypnagogic/hypnopompic hallucinations

Treatment:

  • EDS: Modafinil, armodafinil, solriamfetol, pitolisant; stimulants
  • Cataplexy: Sodium oxybate, antidepressants (SNRIs, TCAs)
💎 Board Pearl

Cataplexy is pathognomonic for narcolepsy type 1. Triggered by strong emotions (laughter, surprise). Consciousness preserved. CSF orexin <90 pg/mL is diagnostic even without MSLT.

Parasomnias

Feature NREM Parasomnias REM Parasomnias
Timing First third of night (N3 predominant) Last third of night (REM predominant)
Recall No memory of event Vivid dream recall
Eyes Open, glassy Closed
Examples Sleepwalking, sleep terrors, confusional arousals REM sleep behavior disorder, nightmare disorder
Age Children (usually outgrow) RBD: older adults (>50)

REM Sleep Behavior Disorder (RBD)

  • Pathophysiology: Loss of REM atonia → dream enactment
  • Clinical: Violent movements during dreams; may injure self/bed partner
  • PSG: REM without atonia (increased chin EMG tone during REM)
  • Association: Strongly linked to α-synucleinopathies (Parkinson’s, DLB, MSA)
  • Conversion: >80% develop parkinsonism within 10-15 years
  • Treatment: Melatonin (first line), clonazepam; bedroom safety
💎 Board Pearl

RBD is a prodrome of α-synucleinopathies. New RBD in elderly = high risk for PD, DLB, MSA. Can precede motor symptoms by years. Also seen with antidepressants (especially SSRIs, SNRIs).

Restless Legs Syndrome (RLS)

  • Criteria: Urge to move legs + worse at rest + better with movement + worse at night
  • Associations: Iron deficiency (check ferritin), uremia, pregnancy, neuropathy
  • Pathophysiology: Dopaminergic dysfunction; low brain iron
  • Treatment:
    • Iron supplementation if ferritin <75 ng/mL
    • Dopamine agonists (pramipexole, ropinirole) – watch for augmentation
    • Alpha-2-delta ligands (gabapentin, pregabalin) – now often first line
  • Augmentation: Symptoms occur earlier, spread to arms, worsen with dopamine agonists

Sleep Apnea

Feature Obstructive (OSA) Central (CSA)
Mechanism Upper airway collapse Loss of respiratory drive
Respiratory effort Present (paradoxical breathing) Absent
Associations Obesity, large neck, retrognathia Heart failure, opioids, brainstem lesions
Treatment CPAP, weight loss, oral appliance Treat underlying cause; ASV (not in HFrEF)

AHI (Apnea-Hypopnea Index):

  • 5-15: Mild
  • 15-30: Moderate
  • >30: Severe

Sleep Pharmacology

Drug Class Mechanism Examples Clinical Notes
Benzodiazepines GABA-A positive allosteric modulator Clonazepam, temazepam ↑ N2, ↓ N3 and REM; tolerance and dependence risk
Z-drugs Selective GABA-A (α1 subunit) Zolpidem, zaleplon, eszopiclone Less effect on sleep architecture than benzos; complex sleep behaviors
Melatonin agonists MT1/MT2 receptor agonists Ramelteon, tasimelteon Circadian rhythm disorders; Non-24-hr (tasimelteon)
Orexin antagonists (DORAs) Block orexin receptors Suvorexant, lemborexant Promotes sleep without GABA; lower abuse potential
Antihistamines H1 receptor blockade Diphenhydramine, doxepin (low dose) Sedation; low-dose doxepin FDA-approved for insomnia maintenance
Gabapentinoids α2δ calcium channel Gabapentin, pregabalin ↑ Slow wave sleep; useful in RLS, comorbid pain
Sodium oxybate GABA-B agonist Xyrem, Xywav Narcolepsy (consolidates sleep, ↑ N3, improves cataplexy); controlled substance
💎 Board Pearl

Z-drugs (zolpidem) target α1 subunit of GABA-A → sedation with less anxiolytic/muscle relaxant effect than benzos. Both suppress N3 (deep sleep). Sodium oxybate is unique in INCREASING N3.

Sleep in Neurological Disease

Condition Sleep Disturbance Key Points
Parkinson’s disease RBD, insomnia, EDS, sleep fragmentation RBD may precede motor symptoms by >10 years; nocturnal OFF symptoms; restless legs common
Alzheimer’s/Dementia Sundowning, circadian disruption, ↓ slow wave sleep Loss of cholinergic neurons affects sleep-wake cycling; ↓ melatonin production
Epilepsy Sleep deprivation triggers seizures; seizures disrupt sleep; NREM activates IEDs Some epilepsies are sleep-related (Rolandic, ESES, frontal lobe epilepsy); AEDs affect sleep architecture
Multiple Sclerosis Fatigue, RLS, OSA, insomnia Central fatigue from demyelination; hypothalamic lesions can cause narcolepsy-like symptoms
Stroke Central sleep apnea, insomnia, circadian disruption Brainstem strokes can cause central apnea; sleep disorders impair recovery
Fatal Familial Insomnia Progressive insomnia → autonomic dysfunction → death Prion disease affecting thalamus; no treatment; very rare but board-favorite
💎 Board Pearl

Fatal familial insomnia = prion disease of the thalamus (mediodorsal and anterior nuclei). Progressive total insomnia, dysautonomia, and death. Autosomal dominant mutation in PRNP gene.

Summary Tables

Sleep Stage Quick Reference

EEG Finding Stage
Alpha waves (posterior) Relaxed wake
Theta + vertex sharp waves N1
Sleep spindles + K-complexes N2
Delta waves (>20%) N3
Low voltage + sawtooth waves REM

Sleep Disorder Quick Recognition

Clinical Clue Diagnosis
EDS + cataplexy + low CSF orexin Narcolepsy type 1
Elderly + dream enactment + later develops PD REM sleep behavior disorder
Child + first third of night + no recall + eyes open NREM parasomnia (sleepwalking/terror)
Urge to move legs + worse at rest + better with movement Restless legs syndrome
Snoring + witnessed apneas + EDS + obesity Obstructive sleep apnea
Adolescent can’t fall asleep until 2 AM Delayed sleep phase disorder
Blind patient with free-running rhythm Non-24-hour sleep-wake disorder

Key Clinical Pearls

High-Yield Points
  • N2 = most abundant stage (45-55%); spindles + K-complexes
  • First half of night = more N3; second half = more REM
  • Orexin stabilizes wake; loss = narcolepsy type 1
  • Cataplexy = pathognomonic for narcolepsy type 1
  • RBD predicts α-synucleinopathy (PD, DLB, MSA)
  • RLS: check ferritin – treat if <75 ng/mL
  • NREM parasomnias = first third; REM = last third
  • MSLT: ≤8 min mean latency + ≥2 SOREMPs = narcolepsy

Red Flags

Important Considerations
  • New-onset RBD in elderly: Screen for parkinsonism; high conversion rate
  • RLS with low ferritin: Rule out GI blood loss
  • Severe OSA: Associated with HTN, arrhythmias, stroke risk
  • Sudden cataplexy onset in child: Consider secondary causes (hypothalamic lesion)
  • RLS augmentation: Consider switching from dopamine agonist to alpha-2-delta ligand

Neurotransmitters

Neurotransmitters – High-Yield Overview

Key idea: For boards, think in terms of: NT → major nucleus → main pathway → function → clinical + drugs.

Major Neurotransmitter Classes

Class Examples Key Features
Excitatory (fast) Glutamate, Aspartate Main CNS excitatory NT; ionotropic (AMPA, NMDA) & metabotropic receptors
Inhibitory (fast) GABA (CNS), Glycine (spinal cord) Main CNS & spinal inhibitory NTs; Cl⁻ or K⁺ mediated
Monoamines Dopamine, NE, Serotonin Slow modulators; small nuclei with diffuse projections; psychiatric & movement disorders
Cholinergic Acetylcholine (ACh) Cortex, hippocampus, neuromuscular junction, autonomic ganglia
Neuropeptides Substance P, Enkephalins, Endorphins, Orexin, CRH, etc. Co-transmitters; slow, modulatory; often G-protein coupled receptors

Receptor Types

  • Ionotropic (ligand-gated channels): Fast, millisecond scale
    • Glutamate: AMPA, NMDA, Kainate
    • GABAA, Glycine
    • Nicotinic ACh receptors
  • Metabotropic (G-protein coupled): Slower, modulatory
    • mGluRs, GABAB
    • Monoamine receptors (D, α, β, 5-HT)
    • Muscarinic ACh receptors
    • Most neuropeptide receptors
💎 Board Pearl

Most fast EPSPs = glutamate (AMPA); most fast IPSPs = GABAA (CNS) or glycine (spinal cord/brainstem). Monoamines & peptides modulate, but do not usually mediate the primary fast synaptic transmission.

Synapse Physiology (High-Yield Steps)

Chemical Synapse – Steps & Targets of Drugs/Toxins ▼
Step Physiology Key Drugs/Toxins
1. AP arrival Action potential → depolarization of presynaptic terminal Na⁺ channel blockers (phenytoin, carbamazepine, lidocaine)
2. Ca²⁺ influx Voltage-gated Ca²⁺ channels open → Ca²⁺ entry Ca²⁺ channel blockers (gabapentin, pregabalin; some anesthetics)
3. Vesicle fusion SNARE complex mediates vesicle fusion and exocytosis Botulinum toxin: cleaves SNAREs (↓ ACh release)
4. NT binding NT diffuses across cleft → binds receptors Receptor agonists/antagonists (benzos @ GABAA, ketamine @ NMDA, etc.)
5. Termination Reuptake, enzymatic breakdown, diffusion Reuptake inhibitors: SSRIs, SNRIs, TCAs (SERT/NET)
Enzyme inhibitors: MAOIs, COMT inhibitors, AChE inhibitors

Electrical synapses: Gap junctions; fast, bidirectional; found in some brainstem nuclei, hypothalamus, and early development.

💎 Board Pearl

Most clinically used CNS drugs act at the synapse, NOT at the axon: receptors, transporters, enzymes, or vesicle release machinery.

Glutamate – Main Excitatory Neurotransmitter

Receptors & Functions ▼
Receptor Type Key Features Clinical/Drugs
AMPA Ionotropic (Na⁺/K⁺) Fast EPSPs; majority of excitatory transmission Targeted indirectly by many anticonvulsants
NMDA Ionotropic (Ca²⁺/Na⁺) Voltage & ligand dependent (Mg²⁺ block); central to plasticity & excitotoxicity Antagonists: ketamine, PCP, memantine
Implicated in stroke, TBI, epilepsy
Kainate Ionotropic Less prominent; modulates excitability Experimental agonists used to induce seizures in models
mGluRs Metabotropic Pre- and postsynaptic modulation, slow effects Targets for experimental epilepsy/psychiatric drugs

Metabolism: Glutamate–glutamine cycle between neurons and astrocytes (astrocytes clear glutamate via EAAT transporters).

Clinical – Excitotoxicity & Disease ▼
  • Excitotoxicity: Excess glutamate → prolonged NMDA activation → Ca²⁺ overload → neuronal death
    • Seen in ischemic stroke, hypoxia, TBI, status epilepticus
  • Riluzole (ALS): ↓ glutamate release, modest survival benefit
  • Memantine (Alzheimer’s): NMDA antagonist, protects against excitotoxicity
  • Ketamine: NMDA antagonist; anesthetic & rapid-acting antidepressant
💎 Board Pearl

Ischemia → ↓ ATP → failed Na⁺/K⁺ pump → depolarization → massive glutamate release → NMDA-mediated Ca²⁺ influx → neuronal death. This cascade underlies many neuroprotective strategies.

GABA – Main Inhibitory Neurotransmitter (CNS)

Receptors, Metabolism & Drugs ▼
Receptor Type Effect Key Drugs
GABAA Ionotropic (Cl⁻ channel) Fast inhibition (hyperpolarization via Cl⁻ influx) Benzodiazepines, barbiturates, zolpidem
General anesthetics, alcohol (potentiation)
GABAB Metabotropic (G-protein) Opens K⁺ channels, ↓ Ca²⁺ → slow inhibition Baclofen: GABAB agonist (spasticity)

Metabolism: Synthesized from glutamate by glutamic acid decarboxylase (GAD); broken down by GABA transaminase.

Clinical: Vigabatrin irreversibly inhibits GABA transaminase → ↑ GABA (used in refractory epilepsy, infantile spasms).

Glycine & Spinal Inhibition ▼
  • Glycine: Main inhibitory NT in spinal cord and lower brainstem
  • Strychnine: Competitive glycine antagonist → severe muscle spasms, seizures
  • Tetanus toxin: Blocks release of glycine and GABA from inhibitory interneurons → disinhibition & spasticity
💎 Board Pearl

Tetanus = loss of inhibitory glycinergic & GABAergic interneurons → disinhibited motor neurons → generalized rigidity & spasms.

Monoamines – Dopamine, Norepinephrine, Serotonin

Major Monoamine Systems (Nucleus → Projection → Function → Disorders) ▼
NT Nucleus / Origin Main Pathways & Functions Clinical / Drugs
Dopamine Substantia nigra pars compacta (SNc)
VTA (mesolimbic/mesocortical)
Tuberoinfundibular (hypothalamus) 		Nigrostriatal: Movement
Mesolimbic: Reward, psychosis
Mesocortical: Motivation, cognition
Tuberoinfundibular: ↓ Prolactin 		↓ Nigrostriatal: Parkinson’s disease
↑ Mesolimbic: Schizophrenia (positive symptoms)
Antipsychotics = D2 antagonists; L-dopa, agonists for PD
Norepinephrine Locus coeruleus (pons) Diffuse projections to cortex, limbic system, spinal cord
Arousal, attention, stress response 		Implicated in depression, anxiety, ADHD
SNRIs, TCAs, stimulants ↑ NE (and DA)
Serotonin (5-HT) Raphe nuclei (midbrain → medulla) Mood, anxiety, sleep, pain modulation
Descending pain inhibition in spinal cord 		SSRIs, SNRIs, TCAs ↑ 5-HT
Triptans = 5-HT1B/1D agonists (migraine)
Risk of serotonin syndrome with polypharmacy

Metabolism: Monoamines broken down by MAO (A/B) and COMT. Metabolites include HVA (DA), VMA (NE/Epi), 5-HIAA (5-HT).

Dopamine Receptor Subtypes – Board-Relevant Detail ▼
Receptor Family Location Function Clinical
D1 D1-like (Gs → ↑ cAMP) Striatum (direct pathway), cortex Activates direct pathway → facilitates movement D1 agonists improve PD motor symptoms
D2 D2-like (Gi → ↓ cAMP) Striatum (indirect pathway), pituitary, VTA Inhibits indirect pathway → facilitates movement; inhibits prolactin Antipsychotics = D2 antagonists; D2 agonists = pramipexole, ropinirole
D3 D2-like Nucleus accumbens, VTA Reward, motivation Target for addiction research; pramipexole has D3 affinity
D4 D2-like Frontal cortex, amygdala Cognition, attention Clozapine has high D4 affinity
D5 D1-like Hippocampus, hypothalamus Memory modulation Less clinical relevance currently

Key concept: D1 (direct pathway, ‘go’) and D2 (indirect pathway, ‘stop’) work together in the basal ganglia. PD = loss of dopamine → underactive D1 direct pathway + overactive D2 indirect pathway → bradykinesia.

Serotonin (5-HT) Receptor Subtypes – Key Types ▼
Receptor Type Location Function Clinical Relevance
5-HT1A Gi-coupled Raphe nuclei (autoreceptor), hippocampus, cortex ↓ Serotonin release (presynaptic); anxiolytic (postsynaptic) Buspirone = 5-HT1A partial agonist (anxiety)
5-HT1B/1D Gi-coupled Cranial blood vessels, trigeminal neurons Vasoconstriction, ↓ CGRP release Triptans = 5-HT1B/1D agonists (migraine abortive)
5-HT2A Gq-coupled Cortex, platelets Cortical excitation, platelet aggregation Target of atypical antipsychotics (5-HT2A antagonism); hallucinogens are 5-HT2A agonists
5-HT2C Gq-coupled Hypothalamus, limbic Appetite, mood Weight gain with 5-HT2C antagonists (olanzapine, mirtazapine)
5-HT3 Ligand-gated ion channel Area postrema, vagus, GI Emesis, visceral pain Ondansetron = 5-HT3 antagonist (anti-emetic)
5-HT4 Gs-coupled GI tract, CNS GI motility, cognition GI prokinetics
Serotonin Syndrome
  • Cause: Excess serotonergic activity — usually from drug combinations (SSRI + MAOI, SSRI + triptan, SSRI + tramadol, SSRI + linezolid)
  • Triad: Mental status changes (agitation, confusion) + Autonomic instability (hyperthermia, tachycardia, diaphoresis) + Neuromuscular hyperactivity (clonus, hyperreflexia, rigidity)
  • Key finding: CLONUS (especially lower extremity) — distinguishes from NMS
  • Vs NMS: Serotonin syndrome = rapid onset, clonus, hyperreflexia. NMS = slow onset (days), lead-pipe rigidity, bradyreflexia
  • Treatment: Stop offending agent; cyproheptadine (5-HT2A antagonist); supportive care; benzodiazepines for agitation
💎 Board Pearl

Dopamine pathways: Nigrostriatal (movement), Mesolimbic (reward/psychosis), Mesocortical (negative symptoms), Tuberoinfundibular (prolactin). Side effect patterns of antipsychotics mirror these pathways (EPS, hyperprolactinemia, negative/cognitive symptoms).

Acetylcholine – Cortex, NMJ & Autonomics

CNS Cholinergic Systems ▼
Nucleus Projection Function Clinical
Nucleus basalis of Meynert Diffuse to neocortex Attention, arousal, cortical activation Degenerates in Alzheimer’s disease → basis for AChE inhibitors
Medial septal nucleus Hippocampus Memory, hippocampal theta rhythms Memory impairment with cholinergic dysfunction
Pontine cholinergic nuclei Thalamus, cortex REM sleep, arousal Sleep regulation; REM-related phenomena
Neuromuscular Junction & Autonomics (Quick Neuro Review) ▼
  • NMJ: ACh at nicotinic receptors → muscle contraction
    • Myasthenia gravis: Antibodies to postsynaptic nicotinic AChR
    • Lambert–Eaton: Antibodies to presynaptic Ca²⁺ channels → ↓ ACh release
  • Autonomics:
    • All preganglionic (symp + parasymp) use ACh (nicotinic)
    • Most parasympathetic postganglionic: ACh (muscarinic)
  • AChE inhibitors: Donepezil, rivastigmine (Alzheimer’s); pyridostigmine (MG)
  • Organophosphates: Irreversible AChE inhibitors → cholinergic crisis
💎 Board Pearl

Nucleus basalis of Meynert is the key cholinergic nucleus affected early in Alzheimer’s disease. AChE inhibitors (donepezil, rivastigmine) are designed to compensate for this loss.

Histamine – Wake Promotion & Neuroinflammation

Histaminergic System ▼
Feature Detail
Source Tuberomammillary nucleus (TMN) of posterior hypothalamus
Projections Diffuse to entire CNS (cortex, hippocampus, striatum, brainstem)
Primary function Wakefulness, arousal (part of ascending arousal system)
H1 receptors Gq-coupled; wakefulness; allergic responses. Blocked by first-gen antihistamines → sedation
H2 receptors Gs-coupled; gastric acid secretion; minor CNS role
H3 receptors Gi-coupled; presynaptic autoreceptor → ↓ histamine release. Also modulates DA, NE, ACh release
Pitolisant H3 inverse agonist → ↑ histamine release → promotes wakefulness. FDA-approved for narcolepsy and OSA-related EDS

Histamine neurons in TMN are active during wakefulness and silent during sleep — similar to NE (locus coeruleus) and 5-HT (raphe). Antihistamines cause sedation by blocking H1-mediated cortical activation.

💎 Board Pearl

Pitolisant (H3 inverse agonist) increases histamine release and is approved for narcolepsy. First-generation antihistamines (diphenhydramine) cause sedation via CNS H1 blockade. The tuberomammillary nucleus is the ONLY source of brain histamine.

Neuropeptides & Modulators

Key Neuropeptides – High Yield Only ▼
Peptide Function Clinical Relevance
Substance P Pain transmission (esp. in dorsal horn); neurogenic inflammation NK1 receptor antagonists (aprepitant) used as antiemetics
Endorphins/Enkephalins Endogenous opioids; pain modulation, reward Opioid receptors (μ, κ, δ) targeted by analgesics (morphine, fentanyl)
Orexin (hypocretin) Wakefulness, appetite Loss in narcolepsy type 1; orexin antagonists (suvorexant) for insomnia
CRH, ACTH, etc. Stress axis (hypothalamic–pituitary) Interact with mood, anxiety, neuroendocrine disorders
💎 Board Pearl

Narcolepsy type 1 = loss of orexin-producing neurons in lateral hypothalamus. This is a favorite board association.

Summary Tables & Quick Reference

Neurotransmitter Localization – Quick Board Table

Neurotransmitter Major Nucleus Main Targets Key Disorders
Glutamate Ubiquitous (most excitatory neurons) Entire CNS Stroke, epilepsy, neurodegeneration (excitotoxicity)
GABA Interneurons, cerebellum, basal ganglia CNS inhibition Epilepsy, anxiety, spasticity
Dopamine SNc, VTA Striatum, limbic system, cortex Parkinson’s, schizophrenia, addiction
Norepinephrine Locus coeruleus Diffuse cortical & spinal projections Depression, anxiety, ADHD
Serotonin (5-HT) Raphe nuclei Cortex, limbic, spinal cord Depression, anxiety, migraine, pain
ACh Nucleus basalis, septal nuclei, brainstem Cortex, hippocampus, NMJ Alzheimer’s, myasthenia gravis, organophosphate poisoning
💎 Board Pearl – One-Liners
  • Parkinson’s: ↓ dopamine (SNc → striatum)
  • Alzheimer’s: ↓ ACh (nucleus basalis)
  • Depression: ↓ NE and 5-HT
  • Schizophrenia: ↑ mesolimbic dopamine, ↓ mesocortical dopamine
  • Huntington’s: ↓ GABA & ACh in striatum, relative ↑ dopamine

Physiology of Muscles

Muscle Fiber Types

Type I vs Type II Fibers

Feature Type I (Slow Twitch) Type II (Fast Twitch)
Color Red (high myoglobin) White (low myoglobin)
Metabolism Oxidative (aerobic) Glycolytic (anaerobic)
Mitochondria Many Few
Fatigue resistance High (endurance) Low (quick fatigue)
Function Sustained activity, posture Rapid, powerful movements
ATPase staining Light at pH 9.4 Dark at pH 9.4

Clinical Relevance of Fiber Type

Fiber Type Affected Conditions
Type I atrophy Myotonic dystrophy type 1, congenital myopathies
Type II atrophy Disuse, steroids, cachexia, aging (sarcopenia)
Type I predominance Endurance athletes, central core disease
💎 Board Pearl

Type II fiber atrophy = steroid myopathy, disuse. These are the “expendable” fibers lost first in catabolic states. Type I fibers are preserved because they’re needed for posture and breathing.

Energy Metabolism & Metabolic Myopathies

ATP Sources in Muscle

Source Duration Clinical Defect
Phosphocreatine Seconds (immediate) Rare
Glycolysis/Glycogenolysis Minutes (short burst) Glycogen storage diseases
Fatty acid oxidation Hours (prolonged) Lipid storage myopathies
Oxidative phosphorylation Sustained Mitochondrial myopathies

Glycogen Storage Diseases

Disease Enzyme Defect Key Features Hallmark
McArdle’s (GSD V) Myophosphorylase Exercise intolerance, cramps, myoglobinuria “Second wind” phenomenon; no lactate rise on forearm test
Pompe’s (GSD II) Acid maltase (α-glucosidase) Proximal weakness, respiratory failure, cardiomyopathy (infantile) Diaphragm weakness out of proportion to limbs; ERT available
Tarui’s (GSD VII) Phosphofructokinase Similar to McArdle’s “Out of wind” phenomenon (worse with glucose); hemolysis
💎 Board Pearl

McArdle’s = second wind (feels better after 10-15 min as fatty acids kick in). Tarui’s = out of wind (glucose makes it worse by blocking fatty acid use). Both have no lactate rise on forearm exercise test.

Lipid Storage Myopathies

Disease Defect Key Features Hallmark
CPT II Deficiency Carnitine palmitoyltransferase II Recurrent myoglobinuria with prolonged exercise, fasting, cold, infection Most common cause of recurrent myoglobinuria in adults; normal strength between attacks
Primary Carnitine Deficiency Carnitine transporter (OCTN2) Cardiomyopathy, weakness, hypoglycemia Low serum carnitine; responds to carnitine supplementation

Mitochondrial Myopathies

Syndrome Key Features Hallmark
CPEO (Chronic Progressive External Ophthalmoplegia) Ptosis, ophthalmoplegia (no diplopia), proximal weakness Ptosis + ophthalmoplegia WITHOUT diplopia
KSS (Kearns-Sayre) CPEO + retinitis pigmentosa + cardiac conduction defects; onset <20 years Heart block – needs monitoring/pacemaker
MELAS Stroke-like episodes, seizures, lactic acidosis, myopathy Strokes not following vascular territories; often occipital
MERRF Myoclonus, epilepsy, ataxia, ragged red fibers Myoclonic epilepsy
💎 Board Pearl

Ragged red fibers on Gomori trichrome = mitochondrial myopathy. CPEO has no diplopia because both eyes move together (symmetric). Always screen KSS for heart block. MELAS strokes are non-vascular distribution.

Muscular Dystrophies

Major Muscular Dystrophies

Dystrophy Gene/Protein Inheritance Key Features Hallmark
Duchenne (DMD) Dystrophin (absent) X-linked Onset 2-5 yrs; calf pseudohypertrophy; cardiomyopathy; wheelchair by 12 Gowers’ sign; CK >10,000
Becker (BMD) Dystrophin (reduced/abnormal) X-linked Later onset; milder; ambulation into adulthood; cardiomyopathy can be severe Cardiomyopathy out of proportion to skeletal weakness
Myotonic Dystrophy Type 1 (DM1) DMPK (CTG repeat) AD Distal weakness, myotonia, cataracts, cardiac conduction defects, frontal balding, testicular atrophy Grip myotonia; “hatchet face”
Myotonic Dystrophy Type 2 (DM2/PROMM) CNBP (CCTG repeat) AD Proximal weakness, myotonia (milder), muscle pain, no congenital form Proximal > distal (opposite of DM1); muscle pain prominent
FSHD D4Z4 contraction (chr 4) AD Face, scapular, humeral weakness; scapular winging; asymmetric Can’t whistle, smile, or close eyes tightly; scapular winging
LGMD Multiple genes (>30 types) AD or AR Proximal limb-girdle weakness; variable age of onset Heterogeneous group; need genetic testing
Emery-Dreifuss Emerin or Lamin A/C X-linked or AD Humeroperoneal weakness; early contractures (elbow, Achilles, neck) Cardiac conduction defects (sudden death risk); contractures before weakness
Oculopharyngeal (OPMD) PABPN1 (GCG repeat) AD Onset >40 yrs; ptosis, dysphagia, proximal weakness Late-onset ptosis + dysphagia; French-Canadian or Hispanic ancestry
💎 Board Pearl

DM1 = distal, DM2 = proximal. DM1 has anticipation (worse in successive generations); congenital form has profound hypotonia. Always screen DM1 and Emery-Dreifuss for cardiac conduction disease. FSHD is very asymmetric.

Inflammatory Myopathies

Comparison of Inflammatory Myopathies

Feature Dermatomyositis (DM) Polymyositis (PM) Inclusion Body Myositis (IBM)
Age Any (children or adults) Adults >18 >50 years
Weakness pattern Proximal, symmetric Proximal, symmetric Distal (finger flexors) + proximal (quads); asymmetric
Skin findings Heliotrope rash, Gottron’s papules, shawl sign, mechanic’s hands None None
CK Elevated (10-50x) Elevated (10-50x) Normal or mildly elevated
Pathology Perifascicular atrophy; perivascular inflammation (B cells, CD4) Endomysial inflammation (CD8 T cells invading non-necrotic fibers) Rimmed vacuoles; CD8 T cells; congophilic inclusions
Cancer association Yes (screen!) Possible (less than DM) No
Treatment response Good (steroids, IVIG) Good (steroids) Poor (no effective treatment)
Dysphagia Can occur Can occur Common (60%)

Key Antibodies

Antibody Association
Anti-Jo-1 (and other anti-synthetases) Antisynthetase syndrome: myositis + ILD + arthritis + mechanic’s hands + Raynaud’s
Anti-Mi-2 Classic DM with good prognosis
Anti-MDA5 Amyopathic DM with rapidly progressive ILD
Anti-TIF1-γ (p155/140) DM with high cancer risk
Anti-NXP2 DM with calcinosis (children) or cancer (adults)
Anti-SRP Necrotizing myopathy; severe, cardiac involvement
Anti-HMGCR Statin-associated necrotizing myopathy (persists after stopping statin)
Anti-cN1A (Mup44) IBM (not specific but supportive)
💎 Board Pearl

IBM = elderly male + finger flexor + quad weakness + doesn’t respond to steroids. Pathology shows rimmed vacuoles. DM has perifascicular atrophy; PM has endomysial CD8 invasion. Anti-TIF1-γ = screen hard for cancer.

Toxic & Drug-Induced Myopathies

Common Drug-Induced Myopathies

Drug/Toxin Mechanism Clinical Features Key Points
Statins Toxic myopathy; or immune-mediated (anti-HMGCR) Myalgias, weakness, elevated CK, rhabdomyolysis (rare) Most resolve with discontinuation; anti-HMGCR requires immunotherapy
Corticosteroids Type II fiber atrophy Proximal weakness; normal CK; no myalgias Fluorinated steroids worse (dexamethasone, triamcinolone)
Colchicine Microtubule disruption Proximal weakness; may have neuropathy Risk increases with renal failure, CYP3A4 inhibitors
Chloroquine/Hydroxychloroquine Lysosomal dysfunction Proximal weakness; cardiomyopathy Curvilinear bodies on EM; may have neuropathy
Alcohol Direct toxicity Acute: rhabdomyolysis; Chronic: proximal weakness Most common toxic myopathy; Type II fiber atrophy
Zidovudine (AZT) Mitochondrial toxicity Proximal weakness; ragged red fibers Reversible with discontinuation
Immune checkpoint inhibitors Autoimmune Myositis, myasthenia, myocarditis Can be severe; may overlap with MG
💎 Board Pearl

Steroid myopathy = normal CK. Distinguish from underlying inflammatory myopathy flare (elevated CK). Statin myopathy usually resolves, but anti-HMGCR necrotizing myopathy persists and needs immunosuppression.

EMG Patterns in Muscle Disease

Myopathic vs Neurogenic Patterns

Feature Myopathic Neurogenic
MUP amplitude Low (small) High (large)
MUP duration Short Long
Recruitment Early (many small units for weak effort) Reduced (few units firing fast)
Polyphasia Increased Increased
Fibrillations May be present (inflammatory, necrotic myopathies) Present (denervation)

Specific EMG Findings by Disease

Disease Characteristic EMG Finding
Myotonic dystrophy Myotonic discharges (“dive bomber” sound); waxing-waning frequency and amplitude
Inflammatory myopathies (DM, PM) Fibrillations, PSWs + myopathic MUPs; “irritable myopathy”
IBM Mixed myopathic AND neurogenic features
Muscular dystrophies Myopathic MUPs; fibs/PSWs in actively necrotic dystrophies
Steroid myopathy Myopathic MUPs; NO fibrillations (no membrane irritability)
Critical illness myopathy Low CMAP amplitudes; fibs; myopathic MUPs; reduced muscle membrane excitability
💎 Board Pearl

Myopathic = small, short, polyphasic MUPs with early recruitment. Fibrillations in myopathy indicate membrane instability (inflammation, necrosis, DM1). IBM is unique: mixed pattern due to its dual pathology (inflammation + degeneration).

Summary Tables & Quick Reference

Metabolic Myopathy Presentation Patterns

Presentation Think Of
Exercise intolerance with “second wind” McArdle’s disease
Recurrent myoglobinuria with prolonged exercise/fasting CPT II deficiency
Proximal weakness + respiratory failure (adult) Pompe’s disease (late-onset)
Ptosis + ophthalmoplegia without diplopia Mitochondrial myopathy (CPEO)
Stroke-like episodes + seizures + lactic acidosis MELAS

Dystrophy Quick Recognition

Clinical Clue Diagnosis
Boy + calf pseudohypertrophy + Gowers’ sign DMD
Distal weakness + grip myotonia + cataracts + frontal balding DM1
Can’t whistle + scapular winging + asymmetric FSHD
Early contractures + cardiac conduction defects Emery-Dreifuss
Late-onset ptosis + dysphagia OPMD

Inflammatory Myopathy Quick Recognition

Clinical Clue Diagnosis
Heliotrope rash + Gottron’s papules + proximal weakness Dermatomyositis
Elderly + finger flexor weakness + quad weakness + doesn’t respond to steroids IBM
Myositis + ILD + mechanic’s hands + arthritis Antisynthetase syndrome (anti-Jo-1)
Persistent weakness after stopping statin Anti-HMGCR necrotizing myopathy

Red Flags

Urgent Situations
  • Rapidly progressive weakness + respiratory decline: Check FVC urgently; may need ICU
  • Myoglobinuria (dark urine): Rhabdomyolysis risk; aggressive hydration, monitor renal function
  • New dermatomyositis in adult: Screen for malignancy (especially with anti-TIF1-γ)
  • Cardiac symptoms in muscular dystrophy: DMD/BMD, DM1, Emery-Dreifuss all have cardiac risk
  • Dysphagia in myopathy: Aspiration risk; may need modified diet or feeding tube
  • Late-onset Pompe’s with respiratory symptoms: Diaphragm weakness; start ERT

Key Clinical Pearls

High-Yield Points
  • Type II fiber atrophy = steroid, disuse, cachexia
  • McArdle’s = second wind; Tarui’s = out of wind
  • CPT II = most common cause of recurrent rhabdomyolysis in adults
  • DM1 = distal; DM2 = proximal
  • IBM = mixed EMG pattern + doesn’t respond to immunotherapy
  • Perifascicular atrophy = dermatomyositis; rimmed vacuoles = IBM
  • Normal CK in weakness = consider steroid myopathy, endocrine, or non-organic
  • Always screen DM for malignancy; KSS/Emery-Dreifuss/DM1 for cardiac conduction

Nerves & Neuromuscular Junction

Nerve Structure & Organization

Peripheral Nerve Anatomy

Layer Description Clinical Significance
Endoneurium Surrounds individual nerve fibers Must be intact for regeneration; contains blood-nerve barrier
Perineurium Surrounds fascicles (bundles of fibers) Main component of blood-nerve barrier; determines nerve tensile strength
Epineurium Surrounds entire nerve Contains vasa nervorum; surgical repair target

Myelination

Feature PNS (Schwann Cells) CNS (Oligodendrocytes)
Cell:Axon ratio 1 Schwann cell : 1 internode 1 oligodendrocyte : up to 50 internodes
Regeneration Good (Schwann cells guide regrowth) Poor (inhibitory environment)
Diseases GBS, CIDP, CMT MS, leukodystrophies

Nodes of Ranvier

  • Location: Gaps between myelin segments
  • Function: Site of saltatory conduction; high concentration of voltage-gated Na+ channels
  • Paranodal region: Contains K+ channels; exposed in demyelination → conduction block
💎 Board Pearl

Saltatory conduction allows action potentials to “jump” between nodes of Ranvier, greatly increasing conduction velocity. Demyelination exposes paranodal K+ channels → hyperpolarization → conduction failure.

Nerve Fiber Classification

Erlanger-Gasser Classification (Sensory & Motor)

Fiber Type Diameter (μm) Velocity (m/s) Myelination Function
Aα 12-20 70-120 Heavy Motor to skeletal muscle; proprioception (Ia, Ib)
Aβ 5-12 30-70 Heavy Touch, pressure (type II)
Aγ 3-6 15-30 Medium Motor to muscle spindle (intrafusal)
Aδ 2-5 12-30 Light Fast pain, temperature, touch (type III)
B 1-3 3-15 Light Preganglionic autonomic
C 0.5-1.5 0.5-2 Unmyelinated Slow pain, temperature, postganglionic autonomic (type IV)
💎 Board Pearl

Conduction velocity ≈ 6 × diameter (in μm). Large, myelinated fibers (Aα) are affected first by compression/ischemia. Small unmyelinated fibers (C) are affected first by metabolic/toxic neuropathies (diabetes).

Clinical Correlates of Fiber Type Involvement

Fiber Type Affected Clinical Features Example Conditions
Large fiber Loss of proprioception, vibration; sensory ataxia; areflexia GBS, CIDP, B12 deficiency, Friedreich ataxia
Small fiber Burning pain, loss of pinprick/temperature; autonomic dysfunction; preserved reflexes Diabetic neuropathy (early), amyloid, Fabry disease
Motor fiber Weakness, atrophy, fasciculations ALS, MMN, lead toxicity
Autonomic fiber Orthostatic hypotension, anhidrosis, GI/GU dysfunction Diabetes, amyloid, autoimmune autonomic ganglionopathy

Neuromuscular Junction

NMJ Anatomy

  • Presynaptic terminal: Contains ACh vesicles, voltage-gated Ca2+ channels (P/Q type)
  • Synaptic cleft: Contains acetylcholinesterase (AChE)
  • Postsynaptic membrane: Contains nicotinic ACh receptors (nAChR) on junctional folds

Neuromuscular Transmission Steps

  1. Action potential arrives at nerve terminal
  2. Ca2+ influx through P/Q-type voltage-gated calcium channels
  3. ACh vesicle fusion with presynaptic membrane (SNARE proteins)
  4. ACh release into synaptic cleft (quantal release)
  5. ACh binds to postsynaptic nicotinic receptors
  6. Na+ influx → end-plate potential (EPP)
  7. If EPP exceeds threshold → muscle action potential → contraction
  8. ACh hydrolysis by acetylcholinesterase

Safety Factor

Definition: EPP amplitude is normally 3-4x greater than threshold needed for muscle AP

Clinical significance:

  • Ensures reliable transmission even with some receptor loss
  • In myasthenia gravis: reduced AChR → decreased safety factor → transmission failure with repetitive use
  • In Lambert-Eaton: reduced ACh release → facilitation with exercise (increased Ca2+ accumulation)
💎 Board Pearl

P/Q-type Ca2+ channels are the target in Lambert-Eaton myasthenic syndrome. SNARE proteins (synaptobrevin, SNAP-25, syntaxin) are targeted by botulinum toxin and tetanus toxin.

Neuromuscular Junction Disorders

Comparison of Major NMJ Disorders

Feature Myasthenia Gravis Lambert-Eaton Botulism
Target Postsynaptic AChR Presynaptic P/Q Ca2+ channels Presynaptic SNARE proteins
Mechanism Antibody blocks/destroys AChR Antibody reduces Ca2+ influx → less ACh release Toxin cleaves SNAREs → blocks ACh release
Weakness pattern Ocular, bulbar, proximal; fatigable Proximal legs > arms; improves with exercise Descending: cranial → limbs → respiratory
Reflexes Normal Reduced/absent (improve post-exercise) Reduced/absent
Autonomic Usually spared Dry mouth, constipation, impotence Prominent (dilated pupils, dry mouth, ileus)
RNS pattern Decrement at low-frequency (2-3 Hz) Low baseline CMAP; increment >100% post-exercise Low baseline CMAP; small increment post-exercise
Association Thymoma (10-15%); thymic hyperplasia Small cell lung cancer (50-60%) Contaminated food, wound, infant (honey)
Myasthenia Gravis – Details ▼

Antibodies:

  • AChR antibodies: 85% of generalized MG
  • MuSK antibodies: 5-8%; more bulbar, muscle atrophy
  • LRP4 antibodies: Rare; milder phenotype
  • Seronegative: ~10%

Clinical features:

  • Fatigable weakness (worse with activity, better with rest)
  • Ptosis, diplopia (ocular MG in 50% at onset)
  • Bulbar: dysarthria, dysphagia, facial weakness
  • Limb weakness (proximal > distal)

Myasthenic crisis: Respiratory failure requiring intubation; triggered by infection, surgery, medications

Drugs that worsen MG: Aminoglycosides, fluoroquinolones, beta-blockers, magnesium, neuromuscular blockers

Lambert-Eaton Myasthenic Syndrome – Details ▼

Key features:

  • Proximal leg weakness → arms → bulbar (opposite of MG)
  • Facilitation: Strength improves briefly after sustained contraction
  • Autonomic symptoms prominent (dry mouth in >80%)
  • Reflexes absent but may appear after exercise

Cancer association:

  • 50-60% have small cell lung cancer (SCLC)
  • Cancer may present years after LEMS diagnosis
  • Screen with CT chest; repeat if initially negative

Treatment: 3,4-diaminopyridine (blocks K+ channels → prolongs depolarization → more Ca2+ entry)

💎 Board Pearl

MG = fatigable (gets worse with use). LEMS = facilitates (gets better with use). Both have proximal weakness. LEMS has autonomic symptoms; MG does not. Always screen LEMS for SCLC!

Nerve Injury & Regeneration

Seddon Classification

Type Pathology Recovery EMG/NCS
Neurapraxia Local demyelination; axon intact Complete; weeks to 3 months Conduction block; no denervation
Axonotmesis Axon disrupted; endoneurium intact Good; 1 mm/day (1 inch/month) Wallerian degeneration; fibs/PSWs; reinnervation potentials
Neurotmesis Complete nerve transection Poor; requires surgery Complete denervation; no recovery without repair

Sunderland Classification (More Detailed)

Grade Seddon Equivalent Injury Prognosis
I Neurapraxia Myelin only Excellent
II Axonotmesis Axon (endoneurium intact) Good
III Axonotmesis Axon + endoneurium Variable
IV Axonotmesis Axon + endo + perineurium Poor
V Neurotmesis Complete transection None without surgery

Wallerian Degeneration

  • Definition: Degeneration of axon and myelin distal to site of injury
  • Timeline:
    • Begins within 24-48 hours
    • Complete by 7-10 days
    • NCS shows absent/reduced responses distally by day 7-10
    • EMG shows fibrillations/PSWs by 2-3 weeks (proximal) to 4-5 weeks (distal)
  • Schwann cells: Proliferate, phagocytose debris, form “bands of Büngner” to guide regeneration

Nerve Regeneration

  • Rate: ~1 mm/day or ~1 inch/month
  • Factors affecting recovery:
    • Age (younger = better)
    • Distance from target muscle
    • Time since injury (motor end plates degenerate after 12-18 months)
    • Accuracy of reinnervation
  • Signs of reinnervation: Tinel’s sign (advancing), nascent motor unit potentials on EMG
💎 Board Pearl

Neurapraxia = conduction block without Wallerian degeneration. No fibrillations on EMG. Full recovery expected. In axonotmesis, fibs/PSWs appear in 2-5 weeks (earliest in proximal muscles).

Electrodiagnostic Correlates

Nerve Conduction Study (NCS) Basics

Parameter What It Measures Abnormal In
Amplitude Number of functioning axons Axonal loss, conduction block
Conduction velocity Speed of fastest fibers (myelination) Demyelination
Distal latency Time from distal stim to response Distal demyelination

Demyelinating vs Axonal Patterns

Feature Demyelinating Axonal
Conduction velocity Markedly slow (<70% LLN) Normal or mildly slow
Distal latency Prolonged (>130% ULN) Normal or mildly prolonged
Amplitude May be preserved (early) or low Low (proportional to axon loss)
Temporal dispersion Present Absent
Conduction block Present Absent
F-wave latency Prolonged or absent Normal or mildly prolonged
EMG fibrillations Less prominent (unless secondary axonal loss) Prominent
Examples GBS (AIDP), CIDP, CMT1 Diabetic neuropathy, AMAN, CMT2

Key EDX Findings

Conduction Block ▼

Definition: >50% reduction in proximal vs distal CMAP amplitude (excluding common entrapment sites)

Significance:

  • Indicates focal demyelination
  • Axon is intact but impulse cannot pass through demyelinated segment
  • Causes weakness WITHOUT atrophy (no Wallerian degeneration)
  • Potentially reversible with remyelination

Classic conditions:

  • GBS (acute)
  • CIDP (chronic)
  • Multifocal motor neuropathy (MMN)
  • Hereditary neuropathy with liability to pressure palsies (HNPP)
Temporal Dispersion ▼

Definition: Increased CMAP duration with proximal stimulation (>30% increase)

Mechanism: Different degrees of demyelination cause different conduction velocities → desynchronization of impulses

Significance: Feature of acquired demyelinating neuropathies (not seen in uniform hereditary demyelination like CMT1A)

F-Waves and H-Reflex ▼

F-Wave

  • Pathway: Motor nerve → anterior horn → same motor nerve back (antidromic → orthodromic)
  • Tests: Entire motor nerve including proximal segments and roots
  • Abnormal in: Proximal demyelination (GBS), radiculopathy
  • Features: Variable latency and morphology; small amplitude

H-Reflex

  • Pathway: Ia afferent → spinal cord → alpha motor neuron → muscle (monosynaptic reflex)
  • Essentially: Electrical equivalent of ankle jerk (S1 root)
  • Tests: S1 nerve root function; only reliably obtained in tibial nerve/soleus
  • Abnormal in: S1 radiculopathy, polyneuropathy
💎 Board Pearl

Conduction block = demyelinating. Low amplitudes everywhere = axonal. Temporal dispersion indicates acquired (non-uniform) demyelination. F-waves test proximal nerve segments not accessible to routine NCS.

Channelopathies

Sodium Channelopathies

Disorder Gene/Channel Mechanism Clinical Features
Hyperkalemic Periodic Paralysis SCN4A (Nav1.4) Gain of function → prolonged depolarization Attacks with high K+, fasting, rest after exercise; myotonia common
Paramyotonia Congenita SCN4A (Nav1.4) Impaired fast inactivation Cold-induced myotonia; “paradoxical” myotonia (worsens with activity)
Sodium Channel Myotonia SCN4A (Nav1.4) Delayed inactivation Myotonia without weakness; K+-aggravated

Calcium Channelopathies

Disorder Gene/Channel Mechanism Clinical Features
Hypokalemic Periodic Paralysis CACNA1S (Cav1.1) – 70%
SCN4A – 10%		 Loss of function → reduced excitability Attacks with low K+, carbs, rest after exercise; NO myotonia
Malignant Hyperthermia RYR1 (ryanodine receptor) Uncontrolled Ca2+ release from SR Triggered by volatile anesthetics, succinylcholine; rigidity, hyperthermia, rhabdomyolysis

Chloride Channelopathies

Disorder Gene/Channel Clinical Features
Myotonia Congenita (Thomsen/Becker) CLCN1 (ClC-1) Myotonia (muscle stiffness); improves with activity (“warm-up”); muscle hypertrophy; NO weakness

Periodic Paralysis Comparison

Feature Hypokalemic PP Hyperkalemic PP
K+ during attack Low (<3.5) High or normal
Triggers Carbs, rest after exercise, stress Fasting, rest after exercise, cold, K+
Myotonia Absent Often present
Attack duration Hours to days Minutes to hours
Treatment K+ replacement; acetazolamide prophylaxis Carbs, inhaled β-agonist; acetazolamide or dichlorphenamide prophylaxis
💎 Board Pearl

HypoKPP: no myotonia. HyperKPP: myotonia common. Both worsen with rest after exercise. Acetazolamide works for both (metabolic acidosis → reduced attack frequency). Malignant hyperthermia = RYR1 mutation; treat with dantrolene.

Summary Tables & Quick Reference

Nerve Fiber Types Quick Reference

Fiber Function Lost First In
Aα (large, myelinated) Motor, proprioception Compression, ischemia
Aβ (large, myelinated) Touch, pressure Compression, ischemia
Aδ (small, myelinated) Fast pain, temperature Metabolic (later)
C (small, unmyelinated) Slow pain, autonomic Metabolic (diabetes), toxic

NMJ Disorders – RNS Patterns

Disorder Low-Frequency RNS (2-3 Hz) Post-Exercise/High-Frequency
Myasthenia Gravis Decrement >10% Repair of decrement (post-activation facilitation)
Lambert-Eaton Low baseline; may decrement Increment >100%
Botulism Low baseline; may decrement Small increment (20-40%)

Nerve Injury – Timing of EDX Findings

Finding Timing After Injury
Reduced recruitment Immediately
Reduced SNAP/CMAP distal to lesion 7-10 days (Wallerian degeneration complete)
Fibrillations in proximal muscles 2-3 weeks
Fibrillations in distal muscles 4-5 weeks
Nascent MUPs (reinnervation) 2-4 months (depends on distance)

Key Clinical Pearls

High-Yield Points
  • Velocity ≈ 6 × diameter: Large fibers conduct faster
  • Demyelinating = slow velocity, conduction block, temporal dispersion
  • Axonal = low amplitude, fibrillations on EMG
  • MG fatigues; LEMS facilitates
  • Neurapraxia: Best prognosis, conduction block, no fibs
  • Regeneration rate: 1 mm/day (1 inch/month)
  • F-waves: Test proximal nerve; prolonged in GBS
  • Always screen LEMS for small cell lung cancer

Red Flags

Urgent Situations
  • Respiratory muscle weakness in MG: Check FVC; <15-20 mL/kg = intubate
  • Rapidly progressive weakness with areflexia: GBS – monitor respiratory function
  • Descending paralysis with autonomic symptoms: Botulism – antitoxin urgently
  • New-onset LEMS: Search for SCLC (may precede cancer by years)
  • Malignant hyperthermia: Stop anesthesia, give dantrolene, cool patient