Study atlas · EURO-NMD Basics webinar

Muscle hyperexcitability & cramps

Every phenomenon in this field can be placed on three axes: where it starts, what the EMG hears, and why it happens. Learn the axes and the individual diseases fall into place.

Dr Federica Montagnese · Friedrich-Baur-Institut, LMU Munich Watch the talk (62 min) ↗
nerve origin in the motor nerve (neurogenic) muscle origin in the muscle fibre (myogenic) 12:20 jumps to that moment of the video
The thesis in five lines
  1. Two compartments.Hyperexcitability starts either in the motor nerve or in the muscle fibre. Each side has its own repertoire of signs.
  2. The EMG is the first fork.On the muscle side, only myotonia produces discharges. Rippling, Brody stiffness and contractures are electrically silent.
  3. Same sign, different meaning.Cramps and fasciculations are usually benign. A few features mark the ones that signal disease.
  4. History, an extended exam and EMG usually make the diagnosis. The routine exam needs additions: test for myotonia, rippling, the warm-up phenomenon and fasciculations.
  5. Most of these conditions can be treated, and an accurate label lets you reassure the patient or give a real prognosis.
Part I

The ontology

Two axes to hang everything on.

Axis 1 · Where

One motor unit, nine places to misfire

  • Motor nerve: lower motor neuron soma, axon, distal terminals. Cramps, fasciculations, myokymia, neuromyotonia, tetany.
  • Muscle fibre: ion channels, caveolae, calcium release and reuptake, energy supply. Myotonia, rippling, Brody stiffness, contractures.
  • Neuromuscular junction: one of the hypotheses for Schwartz–Jampel syndrome.

Tap a station

spinal cord → filaments
NERVE MUSCLE FIBRE neuromuscular junction
Axis 2 · Sign → EMG → Cause

Three layers of the same phenomenon

  • What you see at the bedside is not the diagnosis.
  • What the needle hears narrows it.
  • The cause (gene, antibody, metabolic state) is where treatment and prognosis come from.

Tap any item to trace its chain

Clinical sign
EMG signature
Cause

Tap Silent in the middle column to see how many different conditions share one negative EMG.

Part II

The machinery

Excitation–contraction coupling, read as a list of failure points. 2:50

  • Skeletal muscle has three properties: excitability, contractility, extensibility.
  • Hyperexcitability syndromes come from disorders of the first two.
  • Four levels can fail: ion channels, the DHPR–RyR1 coupling, ATP supply, and Ca²⁺ reuptake.
sarcolemma T-tubule DHPR sarcoplasmic reticulum · Ca²⁺ store RyR1 SERCA1 actinmyosin ATP releases the cross-bridges
Part III

Myogenic

The fibre itself misbehaves. One loud entity, three silent ones.

Myotonia

loud on EMG8:03

Delayed relaxation after a voluntary contraction or after percussion.

Mechanism
  • Na⁺ or Cl⁻ channel dysfunction.
  • The membrane depolarises too easily, or repolarises too poorly.
  • Result: repetitive action potentials after the stimulus has ended.
Bedside
  • Grip: make a fist or shake hands; the hand opens slowly.
  • Percussion: tap the thenar eminence.
  • 14-step test: repeated stair climbing reveals leg myotonia.
  • Tongue myotonia and lid lag: look up for a few seconds, then quickly down; the lid trails. Typical of Na⁺-channel myotonia.
  • Warm-up: myotonia eases with repetition. Named in the talk's summary.
EMG
  • Myotonic runs: sustained rhythmic discharges of single muscle fibres.
  • Rate and amplitude wax and wane: a dive bomber, or a motorbike revving.
  • Runs are often incomplete: only waxing, or only waning.

Real or mimic? Listen to both

11:43
Myotonic run · waxes and wanes
Pseudomyotonic (HFD) · abrupt, flat

High-frequency discharges start and stop suddenly with constant rate and amplitude. Seen in Pompe disease, other glycogen storage diseases and necrotising myopathies. They do not mean a myotonic syndrome. Sounds are synthesised from each pattern's rules, not recorded from patients.

Causes
  • Primary channelopathy (non-dystrophic myotonia): mutations in the Na⁺ (SCN4A) or Cl⁻ (CLCN1) channel genes.
  • Secondary channelopathy (myotonic dystrophy DM1, DM2): RNA missplicing of targets such as CLCN1 produces dysfunctional channel isoforms.

Sort the features: dystrophic or non-dystrophic?

Test
  • Non-dystrophic: multigene panel.
  • Dystrophic: Southern blot or a repeat-specific test. DM1 and DM2 are repeat expansions, which a normal panel misses.
Treat
  • The myotonia itself is treatable.
  • First choices: mexiletine or lamotrigine. Both are effective, with different side-effect profiles.
  • Mexiletine is the only approved anti-myotonic drug; others are off-label.
  • Newer drugs are reserved for refractory cases.

Rippling muscle disease

silent19:11

Waves rolling under the skin after a stretch or a light tap. A caveolinopathy. In bodybuilding videos it is called "alien gains".

Provoke the three signs

Stretch shows rippling. Tap shows a rapid contraction, then a mound.
Signs
  • Rippling (harp phenomenon): waves after stretch or slight percussion.
  • PIRC, percussion-induced rapid contraction: clinically hard to tell from percussion myotonia.
  • PIMM, percussion-induced muscle mounding (myoedema): a focal tonic lump. Also seen in hypothyroidism.
Mechanism
  • Caveolae are flask-shaped membrane pits built from caveolin-3 (the muscle isoform) and cavins 1–4.
  • A membrane reservoir that opens on stretch: the visible wave.
  • They organise T-tubules and modulate RyR, and so intracellular Ca²⁺.
  • They help hold the resting potential through K⁺ channels.
  • They bind the dystrophin–glycoprotein complex and help cluster ACh receptors at the NMJ.
Causes
  • CAV3: RMD, but also LGMD (formerly 1C), isolated hyperCKaemia, a pseudometabolic picture (exercise intolerance, myalgia, rhabdomyolysis), distal myopathy, isolated cardiac disease.
  • CAVIN1: secondary caveolin-3 deficiency; rippling with lipodystrophy and glucose intolerance.
  • Acquired: linked to myasthenia or thymoma; can respond to immunotherapy.
Test
  • Genetic: CAV3; without a CAV3 mutation, consider CAVIN1.
  • Suspected acquired form: cavin-4 IgG (Milone group).

Brody disease

silent27:30

Stiffness after sudden, fast exercise, because calcium is not pumped back into the sarcoplasmic reticulum.

Cytosolic Ca²⁺ after one burst

Mechanism
  • SERCA1 (gene ATP2A1) deficiency, mainly in type 2 fibres.
  • Cytosolic Ca²⁺ stays high, so the fibre stays contracted.
  • The gene was found partly by studying "pseudomyotonia" in Romagnola cattle.
Clinical
  • Very rare, autosomal recessive, starts in childhood.
  • Stiffness on phasic exercise, with myalgia, contractures and mild weakness.
  • Some cases of malignant hyperthermia under general anaesthesia.
EMG
  • No discharges: a silent contracture.
Test
  • ATP2A1 sequencing.
  • For a variant of uncertain significance: show SERCA activity and expression in muscle (immunohistochemistry, immunoblot).
Relatives
  • Calcium-related myopathies: myalgia, cramps and contractures are possible, but weakness usually dominates.

Contracture

silent30:58

A hard, shortened muscle that cannot release because there is not enough ATP to break the cross-bridges. The same mechanism as rigor mortis.

Same pain, opposite physiology: stretch both

Cramp · neurogenic
Contracture · myogenic
ContractureCramp
OriginMuscle: ATP deficitNerve: distal terminals
DurationLongerTransient
StretchingAvoid: it adds damageRelieves it
EMGSilentDense interference
Think ofMetabolic myopathy, e.g. McArdlePhysiological, idiopathic, or symptomatic
Part IV

Neurogenic

The motor nerve fires by itself. 32:42

  • Activity can start at the soma of the lower motor neuron, along the axon, in its distal terminals, or at the voltage-gated K⁺ channels of the terminals.
  • The four classic signs: cramps, fasciculations, myokymia, and the muscle spasms of tetany.
  • Terminology: "spasm" strictly means involuntary contraction of central origin, as in spasticity or multiple sclerosis.
  • Each of these can be benign or idiopathic, or a sign of neuromuscular disease.

Muscle cramps

dense interference34:33

Sudden, very painful, supramaximal contraction. Transient, and relieved by stretching. Reported by about 37% of the general population, more with age.

Inside a cramp: motor-unit recruitment

each row = one motor unit

Units are recruited progressively and fire faster, then drop out slowly. Fasciculations or high-frequency discharges can appear just before or after.

Clinical
  • Sudden onset, very painful.
  • Supramaximal contraction, transient.
  • Stretching relieves it.
  • Post-cramp pain is common, probably local hypoxic and metabolic injury.
Origin
  • Still debated.
  • Most experiments point to the distal motor nerve terminals.
  • The spinal cord modulates it: activating the antagonist helps, and the H-reflex changes after a cramp.
Physiological
  • An expected response to extreme conditions: intense exercise, severe electrolyte imbalance.
  • Mostly distal muscles.
  • Benign, not progressive.
Idiopathic
  • More frequent than physiological cramps.
  • Nocturnal cramps; benign cramp-fasciculation syndrome.
  • Benign, not progressive.
Symptomatic
  • A warning sign of disease.
  • Motor neuron disease, neuropathy, plexopathy, radiculopathy, myopathy.
Non-neuro causes
  • Electrolyte disturbances
  • Medications
  • Pregnancy
  • Endocrine disease
  • Liver or kidney dysfunction
Work-up
HistoryFrequency, muscles involved, new medications, consistent triggers or relievers.
ExaminationRed flags of a neuromuscular disease.
LabsExclude non-neurological causes. Rarely revealing.
EMG / NCSWhen neuromuscular disease is suspected; it guides what comes next.
Treatment, as ranked in the talk 41:16
No drugs
  • Hydration; avoid triggers; stop suspect medications.
  • Regular stretching protocols. A Cochrane review suggests less severity, not fewer cramps.
Best evidence
  • Vitamin B complex, diltiazem.
  • Trial each for at least two weeks.
Not first line
  • Quinine: effective, but risks arrhythmia, allergic reactions and haemolytic-uraemic syndrome.
Some patients
  • Magnesium (evidence doubtful).
  • Pickle juice or other acetic-acid drinks.
  • Gabapentin, pregabalin.
ALS
  • Mexiletine reduced cramps in a clinical trial.

The evidence base is thin. The last evidence-based review of cramp treatment dates from 2010.

Fasciculations

popcorn44:42

Brief twitches that recur sporadically and wander across the muscle belly.

EMG
  • Spontaneous, random, irregular discharges of single motor units.
  • Variable waveform from one discharge to the next.
  • Muscle ultrasound detects them well. The talk recommends Nens van Alfen's EAN lecture.

Listen: irregular pops

Origin
  • Debated.
  • In early ALS: probably the soma of the lower motor neuron.
  • As denervation progresses: more distal, with nodal hyperexcitability in the axon and terminals.
Benign
  • After exercise, mostly calves and lower limbs.
  • Cramp-fasciculation syndrome.
  • Anxiety.
Symptomatic
  • Motor neuron disease: ALS (tongue), Kennedy disease (perioral, on speaking).
  • PNH, multifocal motor neuropathy, plexopathy, radiculopathy.
Clues to ALS
  • More frequent fasciculations.
  • Proximal rather than distal limb muscles.
  • Fasciculations in bulbar and truncal muscles are highly indicative.
  • Morphology: higher amplitude, longer duration, complex with many turns or phases.

Myokymia

marching soldiers49:48

Continuous, undulating movement under the skin, "like worms". A fasciculation that never stops.

One unit, regular bursts

EMG
  • Bursts of 3–6 spikes from a single motor unit, at a uniform rate.
  • The bursts repeat regularly and sound like marching soldiers.
Focal
  • Eyelid myokymia, e.g. after sleep deprivation.
  • Facial muscles.
  • Post-radiation, e.g. one side of the tongue.
Generalised
  • Think peripheral nerve hyperexcitability (next).
Case from the talk
  • Young patient, five years of continuous twitching.
  • Hyperhidrosis and diarrhoea.
  • Worm-like movements in the calves, thighs and small foot muscles; calf hypertrophy.
  • EMG: myokymic discharges and fasciculations; no neuromyotonic discharges or triplets.
  • CASPR2 weakly positive. Very good response to immunotherapy (steroids).

Peripheral nerve hyperexcitability

spectrum52:46

Three syndromes on one clinical spectrum. The further along, the more systems involved and the likelier antibodies are.

Move along the spectrum

    Probability of finding antibodies rises along the spectrum
    Antibodies
    • Against the VGKC complex: CASPR2 more often than LGI1.
    • Can be paraneoplastic or occur with other autoimmune disease.
    EMG
    • Myokymic discharges and fasciculations.
    • Neuromyotonic discharges: rarely captured. They can resemble myotonic discharges in sound and shape, but fire much faster (above 150 Hz) with a "pinging" sound.

    Neuromyotonic discharge · "pinging"

    53:53
    Treat
    • Acquired PNH is treatable.
    • Mild: symptomatic drugs.
    • Immunosuppression: steroids.
    • Refractory: rituximab.
    Hereditary
    • Episodic ataxia type 1: episodic ataxia plus myokymia, especially in facial muscles.
    • Myokymia also occurs in some neonatal-onset epilepsies linked to a centrally expressed K⁺ channel.
    • HINT1 neuropathy: early, severe axonal neuropathy with neuromyotonic discharges.
    • Schwartz–Jampel (perlecan, HSPG2): generalised hypertrophy, stiffness, blepharophimosis, bone deformities. Both myotonic and neuromyotonic discharges. Perlecan clusters acetylcholinesterase, so its loss may leave more ACh in the cleft; it may also affect Na⁺/Cl⁻ channels. 56:07

    Tetany

    doublets57:53

    Hyperexcitability of nerve, both peripheral and central, caused by low plasma calcium. More common than the rare syndromes above.

    Mechanism
    • Low Ca²⁺ increases Na⁺-channel permeability.
    • The nerve membrane depolarises more easily.
    Bedside
    • Trousseau: ischaemia from a cuff produces the "obstetric hand".
    • Chvostek: tapping the facial nerve makes the innervated muscles twitch.
    EMG
    • Doublets, triplets, multiplets, e.g. recorded during a Trousseau manoeuvre.

    Doublets

    Part V

    Consolidate

    Retrieval beats rereading.

    Sources

    Go deeper

    • The talk: Montagnese F. Muscle hyperexcitability and cramps. EURO-NMD Basics Series, 2023. YouTube ↗
    • Cramp treatment review: Katzberg HD et al. Assessment: symptomatic treatment for muscle cramps (an evidence-based review). Neurology 2010. PubMed ↗
    • Non-drug therapies for cramps: Cochrane review. PubMed ↗
    • Quinine for cramps: Cochrane review. PubMed ↗
    • Cavin-4 IgG in acquired rippling muscle disease. PubMed ↗
    • Mexiletine for cramps in ALS. PubMed ↗
    • Muscle ultrasound for fasciculations: van Alfen N. PubMed ↗
    • Networks: EURO-NMD ↗ · EAN ↗