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MUSCLE FIBER ACTIVITY & CRAMPS

Myotonia

General features of myotonia

• Clinical: Delayed relaxation of skeletal muscle following voluntary contraction
  • Present with initial activity
  • Usually abates after repeated muscle activity
  • Paradoxical myotonia (in paramyotonia) worsens with repeated activity
  • Delayed myotonia
    • Appears after a period of muscle contraction
      
    • Seen in myotonia fluctuans
  • Some syndromes associated with episodic muscle weakness
  • Age of onset
    • Birth: Myotonia congenita & paramyotonia
    • Teens & adult: Myotonic dystrophy; PROMM
  • Multiple specific myotonic syndromes
  • A variety of pharmacological agents can exacerbate or treat myotonia.
• Classification by ion channel disorder
  • Na⁺ channel myotonic disorders:
    • Features
      • Fluctuations over time in individuals: Common
      • Variation among families: Common; Day-to Day
      • Worse with cold
      • Paradoxical myotonia
      • Transient paralysis
    • Syndromes: Dominant; Potassium-aggravated myotonia (PAM)
      • Myotonia fluctuans
      • Myotonia permanens
      • Acetazolamide responsive myotonia
      • PAM families more common than Cl^- mediated
  • Cl^- channel myotonic disorders
    • Features
      • Fluctuations over time in individuals: Unusual but may occur
      • Variation among families: Uncommon; Over weeks to months when present
      • Muscle hypertrophy
      • Warm-up effect
    • Syndromes
      • Becker's (Recessive)
      • Thomsen's (Dominant)
      • Myotonia Levior (Dominant)
  • Other causes: Dystrophic myotonia
    • Features: Extramuscular common
    • Types
      • DM1
      • DM2
• EMG: Myotonia
  • Electrophysiology: Increased excitability of muscle fibers
  • Repetitive action potentials in individual muscle fibers
  • Occur in response to mechanical or electrical stimulation
  • Temperature sensitivity
    • Increased with cooling: Paramyotonia
    • Increased with warming: PROMM
  • Frequency
    • Variable
    • Often decreasing with time: 50 Hz ® 10 Hz
  • Amplitude: May vary up to 10 fold
  • Duration
    • Myotonic runs: Longer in myotonic dystrophy than in myotonia congenita
      • Myotonic dystrophy: Many runs > 2 sec & longest 30 sec
      • Myotonia congenita: Most runs < 1 sec & longest is 10 sec
• Myotonia: Mexiletine response¹⁵
  • Drug effect: Na⁺ channel blocker
  • Effective in treatment of myotonia
    • Best response when drug blocks voltage-dependent mutant channels
    • Some effect in severe cases with blockade of wild type channels
    • Me7 derivative: More effective than Mexiletine; Inhibits Na⁺ channels in M2 gating mode
  • Mexiletine not effective in treating hyperkalemic periodic paralysis

Myotonia Congenita (Thomsen)

• Genetic features: Mutations
  • Dominant only: Gly200Arg; Ile290Met; R317Q; Pro480Leu
  • Dominant & Recessive: Gly230Glu; Ala313Thr; Arg317Gln; Arg338Gln; Ile556Asn; Arg894X
  • Other: S132C, L283F, T310M, T550M
• Genetic-Physiology Correlations
  • Normal Cl^- channels
    • Formed by tetramer complex
    • Cl^- conductance is necessary to stabilize membrane potential
  • Mutations in Cl^- channels
    • Interfere with dimer & tetramer formation: Dominant negative effects
    • Cl^- conductance through the channels is eliminated or reduced
      • Frame shift mutations: Complete loss of channel protein
      • Missense: Several mechanisms of pathological channel function
        1. Positive shift in voltage range over which gating occurs: Gly200Arg
           • Channel open probability near 0 at resting potential
        2. Change in channel selectivity
           • Higher cation:anion permeability ratio than wild type: G230E
        3. Voltage or [Cl^-]_in dependent alterations in channel function
           • S132C
             • Homodimeric channels: [Cl^-]_in-dependent hyperpolarization-induced activation
             • Heterodimeric channels: Depolarization induced activation with shifted activation
           • L283F
             • Deactivation defect at high [Cl^-]_in
           • T310M
             • Activation curve: Shifted at normal [Cl^-]_in; Normal at high [Cl^-]_in
    • Without Cl^- conductance: ± Increased cation conductance
      • K⁺ accumulates normally in t-tubules after action potentials
        
      • But this produces membrane depolarization 10x > normal
        
      • Even more depolarization if mutant channel permeable to cations
        
      • This heightened after-depolarization can achieve threshold
        
      • Spontaneous triggering of action potentials results
        
      • Integrity of T-tubule required for myotonic discharge
    • Mutations with Dominant and Recessive phenotypes
      • ? Lower expression of mutant allele in recessive families
• Clinical features
  • Onset: Infancy to adult
  • Variable penetrance: 90% symptomatic
  • Myotonia
    • Usually mild
    • Course: Often constant; May be variable over time
    • 90% by EMG; 50% percussion
    • Variability
      • Exacerbations: Myotonia may be worse with cold or stress
      • Long term fluctuations in myotonia: Some mutations (Gly200Arg)
        • Symptom free for weeks to months
        • Symptoms increased by cold, humger, fatigue & emotional upset
      • Myotonia and weakness with pregnancy: Some mutations (Gly230Glu; T310M)
  • Muscle hypertrophy
  • Myalgias: In occasional patients
  • "Warm-up" phenomenon (Reduced myotonia after repeated activity)
  • Muscle strength
    • Normal at rest in many patients
    • Proximal muscles: Functional difficulties (Climbing stairs) or Mild fixed weakness in some
    • Distal weakness may occur with exercise
• Lab
  • CK: Slightly elevated or Normal
  • EMG
    • Myotonia
      • Present even in early childhood
      • Distal > Proximal
      • Warming up effect: Myotonia reduced after a period of maximal contraction
    • Motor unit potentials: Normal, no myopathy
    • Repetitive nerve stimulation
      • Decrement
        • Especially at high stimulation frequencies (30 Hz)
        • Present with some mutations (P480L; R894X) & not others²²
      • No intratetanic facilitation
    • No effect of cooling
• Pharmacology:
  • Aggravated by
    • β2-agonists: Fenoterol; Ritodrine
    • Monocarboxylic amino acids
    • Depolarizing muscle relaxants
  • Treated by
    • Quinine (200 to 1,200 mg/d)
    • Mexiletine (150 to 1,000 mg/day)
    • Dilantin (300 to 400 mg/day; therapeutic level of 10 to 20 μl/mL)
    • Procainamide (125 to 1,000 mg /day)
    • Tocainide (bone marrow suppression is a side effect)
    • Carbamazepine
    • Acetazolamide ( 125 to 750 mg/day)

Myotonia Congenita (Becker)

• Genetic features
  • Most CLCN1 mutations produce recessive syndromes
  • Point mutations
    • Many missense mutations: > 20 identified
    • Location: From N terminus to transmembrane domain XII
  • Other mutations
    • Deletions: Nucleotides 1282-1285 & 1437-1450
    • Nonsense: Q74stop; E193X
    • Splice site nucleotide 979
  • Compound heterozygotes: Many patients; Some homozygotes
  • Mouse (Recessive mutations)
    • Arrested development of righting response (ADR):
      • ETn transposon insertion
    • Myotonic (MTO)
• Physiology: Activating current on hyperpolarization vs. deactivation in wild type
  • No or reduced opening at voltages positive to Cl^- equilibrium potential: M485V
  • Right shift (to more + potentials) of voltage dependence of open probability of ClC-1 channels: I329T; R338Q
  • Inward rectification permits Cl^- efflux but not influx
  • No physiological mechanism identified for some mutations: Y150C; Y261C
• Clinical features
  • Onset: Ages 4 to 12; Legs
  • Myotonia
    • With "warm-up" phenomenon
      
    • More severe than in dominant (Thomsen) form
  • Muscle hypertrophy
    • Especially legs & gluteals
    • ? Males > Females
  • Strength
    • Initially normal
    • Rapid decrease with short exercise
    • Returns to normal with further muscle contraction
    • ± Mild distal weakness
  • Carriers: Myotonia in EMG of males but not females
• EMG
  • Myotonia
    • Distal > Proximal
    • Warm up effect: Less myotonia after maximal contraction
  • Motor units: Mildly myopathic
  • Decremental CMAP response
    • Especially: At high stimulation frequency (30 Hz); Following exercise
    • No effect of cooling

Myotonia levior

• Mutation: Gln552Arg
• Clinical features
  • Myotonia: Mild
  • Onset: Late
  • No muscle hypertrophy

Paramyotonia syndromes

• Definitions
  • Paramyotonia: "Abnormal" myotonia
  • Paradoxical myotonia: Myotonia worsening with repetitive exercise
• Genetics
  • SCN4A Mutation locations
    • Cytoplasmic loops between repeats II & II and III & IV (inactivation gate)
    • Transmembrane segments S2, S3 & S4
      • Especially cytoplasmic side of membrane
    • Paramyotonia correlations
      • Pure paramyotonia: G1456E; L1433R
      • Paramyotonia ± Episodic weakness with exercise: R1448C
      • Overall: Exon 24 mutations commonly cause paramyotonia
    • Quarter horses: Phe-to-Leu mutation in transmembrane domain IVS-3
  • CLCN1 mutation: F428S
• Electrophysiology: SCN4A mutation effects
  • Functional defects in Na⁺ channels: Abnormal inactivation; Less voltage dependence
    • Disruption of fast inactivation of Na⁺ channel
      • Na⁺ ions continue to leak into cell
    • Some mutations also disrupt slow Na⁺ channel inactivation
      • Weakness is common with these mutations
    • Inactivation is prolonged from open channel state, but normal from closed state
    • Channel conductance: Permeation of Na⁺ ions through pore is normal
  • Poor inactivation of Na⁺ channel: Electrophysiologic consequences
    • Prolongs action potential
    • Reduces membrane repolarization
    • Clinical correlates
      • Mild depolarization (> 5mV) produces repetitive discharges (myotonia)
        
      • More severe depolarization (> 20mV) produces weakness
• Clinical features: Weakness or stiffness may occur alone
  • Myotonia: Due to membrane depolarization
    • Caused by mild slowing of Na channel inactivation
    • Worse with cold & exercise
    • Especially in face, neck & upper extremities
    • Onset in infancy
  • Episodic weakness: Due to muscle action potential blockade
    • Caused by very slow Na channel inactivation
    • Associated with Hyper K⁺ periodic paralysis
    • After exercise, cold exposure, or spontaneous
    • Usually lasts few minutes, but occasionally days
    • Onset in adolescence or never
    • Some patients worse after K⁺ load
    • Exacerbated by hyperthyroidism
  • Clinical "myotonia" syndromes
    • Potassium aggravated myotonia (PAM)
      • Attacks precipitated by K⁺ load
      • No weakness
      • Syndromes include:
        • Myotonia fluctuans
          
        • Myotonia permanens
          
        • Acetazolamide responsive myotonia
      • SCN4A Mutations
        Ser804Phe; Ile1160Val; Gly1306Ala;
        Gly1306Val; Gly 1306Glu; Val1589Met
    • Paramyotonia congenita (PMC)
      • "Weakness" due to paramyotonia precipitated by hypokalemia
      • SCN4A Mutations
        Val1293Ile; Thr1313Met; Leu1433Arg; Arg1448Cys;
        Arg1448His; Arg1448Pro; G1456E; Val1458Phe; Phe1473Ser
      • CLCN1 Mutation¹⁸
        • F428S: Missense
        • Channels: Normal physiology; Low expression
    • Paramyotonia congenita without cold paralysis: Val1293Ile
      • Epidemiology: Irish family
      • Onset
        • Childhood
        • Spasms of muscle stiffness: Preferentially affect hands & face
      • Clinical
        • Myotonia
          • Worsens with exertion (Paradoxical myotonia)
          • Most marked exacerbation: Cold weather
        • No periodic paralysis or progressive weakness
      • EMG
        • Profuse myotonic discharges
        • Cooling: 78% drop in CMAP amplitude
• EMG: Myotonia
  • Less prominent than in other myotonias: May be absent at normal temperature
  • Action potentials
    • Frequency: 20 to 50 Hz
    • Burst length: > 1 minute
  • Cooling effects
    • Initial: Repetitive spontaneous motor unit discharges
    • Increased cooling: Depolarization & paralysis ® Myotonia disappears
• Therapy
  • Myotonia: Antiarrhythmic drugs
    • Mexiletine 150 to 1,000 mg/day
      • Use-dependent blockade of sodium channels
      • Reduces repetitive series of action potentials ® Reduced muscle stiffness
    • ? Tocainide
  • Weakness: K⁺-sensitive
    • Hydrochlorothiazide (250 to 1,000 mg/day)
    • ± Supplemental K⁺
    • Acetazolamide (125 to 1,000 mg/d)
    • Dichlorphenamide (50 to 150 mg/day)
  • Weakness: Paramyotonia
    • Mexiletine 150 to 1,000 mg/day
      
    • ? Tocainide
      
    • K⁺

Myotonia Fluctuans

• Mutations: Missense; Exons 22 & 14
• Clinical features
  • Myotonia
    • Mild
    • Varies in severity from day to day
    • Delayed myotonia
      • Appears after a period of muscle contraction
      • Stiffness develops during rest, 20 to 40 minutes after exercise
      • Lasts for ~1 hour
    • Stiffness exacerbated by
      • Potassium
      • Depolarizing agents (e.g. suxamethonium)
        • May interfere with respiration
  • No weakness or cold sensitivity
• EMG
  • Myotonia: Increased after exercise

Myotonia Permanens

• Genetics: Mutations
  • Heterozygous
  • Missense: Gly1306Glu
    • G1306A causes: Myotonia fluctuans
    • G1306V causes: Intermediate myotonic phenotype
  • Region coding for hinge of channel inactivation gate
• Mutation effects on Na⁺ channel function
  • All mutations at 1306 site: Reduced sodium channel inactivation
  • Only myotonia permanens mutation (G1306E) causes a left shift of activation curve
    • Decreased electrical threshhold
• Clinical Features
  • Severe continuous myotonia
    • May interfere with respiration
    • Worse with: Exercise; K⁺ rich foods
  • No paralysis
  • Marked muscle hypertrophy
• Laboratory
  • EMG: Constant myotonic activity
  • Serum CK: Increased 6x to 8x normal
    • High CK also seen in: Recessive Cl^- channel myotonia

Acetazolamide-responsive Myotonia Congenita

• Clinical features
  • Muscle hypertrophy
  • "Paradoxical" Myotonia: Worse with repeated activity
    
  • Muscle pain & stiffness
    • Aggravated by potassium
      
    • Improved by acetazolamide
  • No weakness

Myotonic Dystrophy (DM1)

Proximal Myotonic Myopathy (PROMM; DM2)

• DM2: Epidemiology
  • Most families European, especially German/Polish
  • Anticipation⁶
    • Mild: 0.5 to 1.9 decades (vs 2.9 decades in myotonic dystrophy)
    • ? More prominent with paternal transmission
• Genetics: Mutation in CCTG repeat sequence in intron 1 of ZNF9 gene¹²
  • Normal CCTG repeat sequence
    • Complex repeat motif: (TG)_n(TCTG)_n(CCTG)_n
    • Size: 104 to 176 base pairs
    • Interruptions: GCTG + TCTG motifs, or one or two TCTG motifs
  • CCTG expansion
    • (CCTG)_n repeat size: Range 75 to ~11,000; Mean ~5000
    • Interruptions: None
    • Somatic instability
      • Different repeat sizes in different tissues
      • ? Correlation with age
      • Especially great in peripheral blood
      • Greater than in DM1
    • Intergenerational features: Repeat size in blood of affected child shorter than parent
  • Genetics & DM2 disease pathogenesis
    • CCTG expansion produces RNA with excessive repeats
    • RNA with expanded repeats located focally in muscle cell nucleus
    • CCTG expression at RNA level may be pathogenic
    • Functional effects of long repeat RNA: Abnormal splicing of muscle CLC1 (chloride) channel RNA
      • Altered splicing adds exon 7a to Cl^- channel RNA
      • Aberrantly spliced RNA produces altered Cl^- channel protein with reduced function
      • Reduced Cl^- channel function produces myotonia
      • Longer repeat RNA produces more abnormal splicing of Cl^- channel: More myotonia
      • Effect is expressed as mosaic: Some muscle fibers with more reduction of Cl^- channel than others
      • Similar effect of elongated CTG repeat sequence in DM1
  • Clinical-Genetic correlations
    • Unclear correlation between repeat length & disease severity
    • Homozygous for CCTG repeats: Not different from heterozygotes²⁸
  • Other disease expansions in transcribed but untranslated DNA
    

    DM2: Hypertrophic calves

    • DM1 (CTG)
    • SCA8 (CTG)
    • SCA10 (ATTCT)
• ZNF9 protein
  • ZNF9 expression: Most abundant in heart & Skeletal muscle
  • Single stranded DNA-binding
  • Sterol regulatory element: Involved in sterol-mediated repression
  • Subcellular location: Cytoplasmic, also in endoplasmic reticulum
• Clinical features
  • Onset
    • 8 to 60 years
    • With stiffness or pain
    • Congenital form: Rare³⁹
  • Intrafamilial variability
  • Weakness
    • Proximal: Legs > Arms; Hip flexors & extensors early
    • Distal arms: May be involved early; Thumb & Finger flexors
    • Face: Weak in 12%
    • Normal: Distal legs; Respiratory
    • Variation: Over hours
    • Progression: Slow
  • Muscle Enlargement: Calf
  • Muscle Pain or Discomfort²⁹: 56%
    • Stimuli
      • Exercise-related, or at rest
      • Temperature-modulated: Increased with cold
      • Palpation-induced
      • No relation to myotonia
    • Proximal; Legs > Arms
    • Painful stiffness
    • Variable from day-to-day
  • Myotonia
    • Symptomatic: Asymmetric
    • Intermittent: Exacerbations during pregnancy
    • Temperature sensitive (Warm more; Cold less)
    • Induced by: Grip; Percussion
  • CNS
    • Clinical: Usually normal; Occasional CNS signs
    • MRI: White matter hyperintensity on T₂ weighted images
      
  • Systemic
    • Cataracts: 100% over 20 years with slit lamp
    • Cardiac arrhythmias: 20%; Conduction defects
    • Diabetes mellitus: 20%
    • Hearing loss: 20%
    • Fertility: Normal or Reduced
    • Cardiovascular autonomic function: Normal
  • See: Comparison to DM1
• Lab
  • Serum
    • CK
      • Mild elevation (< 10x) or Normal
      • May be high in asymptomatic DM2 patients³⁰
    • FSH: High
    • IgG level: Reduced
  • EMG
    • Myotonia
    • CMAP amplitude with exercise
      • Progressively reduced (by 40%) during rest 20 to 40 min after initial increment (60% of patients)
      • No decrement: On short exercise, or slow or rapid repetitive stimulation
      • Normals: Mild increase in CMAP amplitude after exercise
    • Myopathic motor unit potentials: Proximal > Distal
  • MRI: Muscles involved³²
    • Selective muscle involvement: Erector spinae; Gluteus maximus
    • Abnormality more common
      • Females
      • Increasing age
    • Abnormality less common
      • Males
      • Milder weakness
      • Myalgias
  • Muscle biopsy
    • Internal nuclei
    • Fiber size variation: Type 2 atrophy
    • Pyknotic nuclear clumps
      • Especially type 2 fibers
      • Beter seen by myosin heavy chain histochemistry
    • No fiber type grouping
  • Cell pathology: Intranuclear inclusions
• Prognosis: More benign than DM1 myotonic dystrophy

PROMM

• German family
• Myotonia
• Weakness; Proximal
• Cataracts
• MRI: White matter changes

Acquired myotonia: Drug toxicity

• 20,25-Diazacholesterol
• Clofibrate
• 2,4-Dichlorophenoxyacetate
• Chloroquine
• Colchicine
• Hydroxymethylglutaryl CoA reductase inhibitors

Hyperkalemic periodic paralysis

• Mutations⁴
  • Locations: Thr704Met; Ser906Thr; Ala1156Thr; Met1360Val; R1448C; Met1592Val
  • Mechanism of action: Defective inactivation of Na⁺ channel
• Genetic-Clinical correlations
  • Thr704Met
    • Permanent weakness common
    • Most frequent mutation: 60% of HRPP cases
  • Met1592Val
    • Myotonic
    • Non-Dystrophic
    • Frequency: 30% of HRPP cases
  • Ala1156Thr & Met1360Val: Reduced penetrance
  • Other SCN4A mutations in
    • Paramyotonia congenita
    • Acetazolamide-responsive Myotonia Congenita
    • Myotonia Permanens
    • Myotonia Fluctuans
    • Hypokalemic periodic paralysis
    • Malignant hyperthermia
    • Myasthenic syndrome
    • Quarter horses: Hyperkalemic periodic paralysis
• Physiology: "Gain of function" mutations
  

  Mechanisms of Episodic Weakness

  Extracellular K+ increase: 2° to K+ intake, or Rest after exercise           ê Membrane depolarization: Mild           ê Na+ channels open: Abnormal Na+ channels to non-inactivating mode           ê                                                     é Persistent inward Na+ current           é           ê                                                     é           í Extracellular K+ increase Sustained depolarization of muscle membrane î           é           ê                                                                         K+ efflux Inactivation of normal Na+ channels           ê Loss of electrical excitability of muscle membrane           ê Weakness

• Clinical features
  • Episodic weakness: Flaccid
    • Onset: 1st decade
    • Distribution
      • Usually proximal & symmetric
      • Occasionally distal & asymmetric in exercised muscles
    • More frequent with increasing age
    • Onset
      • Early am before breakfast
      • During rest after exercise
      • May be associated with paresthesias
    • Lasts 15 to 60 minutes: Occasionally hours or days
    • Provoked by

      Exercise Potassium loading   Cold environment Pregnancy

      Glucocorticoids Stress Ethanol Fasting

    • Relieved by: Carbohydrate intake; Mild exercise
      
    • Prognosis: Weakness
      • May become permanent with some SCN4A mutations (Thr704Met)
        
      • Others (Met1592Val) only episodic
    • Comparison of attacks to hypokalemic periodic paralysis
      • Frequency: Greater
      • Duration: Shorter
  • Myotonia ± Paramyotonia
    • Episodic
    • Present between episodes of weakness
    • Frequency: In majority of patients on EMG
    • Stiffness with cooling less common than in paramyotonia
  • Cardiac dysrhythmias: Rule out Andersen's syndrome
• Laboratory
  • Attacks associated with high serum K⁺ (>4.5 mEq/l) & high urinary K⁺
  • Serum CK: Normal to 300 U/L
  • CMAP amplitude
    • Increased immediately after sustained (5 min) maximal contraction
    • Progressively reduced (by 40%) during rest 20 to 40 min after initial increment (80% of patients)
    • Normals: Mildly increased CMAP amplitude after exercise
• Provocative tests
  • Oral K⁺ load
    • Only if renal & cardiac function & serum K⁺ normal
    • Perform fasting, in am, after exercise
    • 0.05 g/kg KCl in sugar-free liquid over 3 minutes
    • If negative may give 0.10 to 0.15 g/kg KCl
    • Monitor electrolytes, EKG & strength every 20 minutes
    • Weakness typically most at 90 to 180 minutes
  • Exercise
    • Bicycle ergometer
      • 30 minutes
      • Pulse to 120 to 160
    • Then absolute bed rest
    • Measure serum K⁺
      • Normal: K⁺ rises during exercise; Then falls to near preexercise level
      • Hyperkalemic PP: 10 to 20 minutes after exercise ® 2nd hyperkalemic period & Paralysis
• ? Variant: Normokalemic periodic paralysis
• Animal disease: Quarter Horses
  • Genetic
    • Offspring of American Quarter Horse sire, Impressive
    • Phe1421Leu mutation in transmembrane domain IVS-3
  • Clinical
    • Weakness may be severe
    • Muscle hypertrophy
    • Homozygotes more severe than heterozygotes: Laryngeal & Pharyngeal dysfunction
• Treatment
  • Many attacks brief & do not need treatment
  • Acute attack: Carbohydrate ingestion
  • Chronic: Acetazolamide; Thiazide diuretics
  • No benefit for weakness: Mexiletine
• Genetic testing: Washington Children's

Rippling Muscle Syndromes¹⁷

• Genetics
  • Caveolin-3 mutations: Missense
    • R26Q: AD-RMD; HyperCKemia
    • Asp27Glu: AD-RMD; Distal weakness
    • A45T: AD-RMD & HyperCKemia with muscle discomfort
    • Ala45Val: AD-RMD
    • Ser52Gly: Rippling muscle disease
    • P104L: AD-RMD & LGMD1C
    • Homozygous L86P & A92T: Rippling muscle disease, Severe
  • Mutations in Caveolin-3 also cause
    • LGMD 1C
    • Increased CK with normal strength
• Clinical features
  • Epidemiology
    • Females less involved than males
    • Variable within families
  • Onset
    • Usual: 1st or 2nd decades
    • Range: 5 to 54 years
    • 15% asymptomatic
  • Discomfort
    • Muscle cramps, pain & stiffness
    • Legs > Arms
    • Neck stiffness in some patients
    • Worse with: Exercise; Occasionally cold
    • Toe walking: On awakening or after rest
  • Rippling of muscle: Wave-like
    • Evoked by muscle stretch
    • Moves laterally along muscle over 5 to 20 seconds (0.6 M/s)
    • 10x slower than muscle fiber action potential
    • Electrically silent
    • Present in 60% of patients
    • Localization: Especially prominent in large proximal muscles
  • Mounding of muscle (Myoedema)
    • Evoked by percussion: All patients
    • Rapid
    • Differential diagnosis: Malnutrition; Cachexia; Hypothyroidism
  • Contraction
    • Evoked by: Muscle percussion (Mild); Pressure
      • Amplitude increases with strength of percussion
      • No habituation
    • Common feature: Up to 100%
    • Rapid onset
    • Duration: Up to 30 seconds
    • Painful in 30%
    • Distribution: Generalized or in isolated muscles
    • Clinically similar to myotonia or myoedema
  • Muscle hypertrophy: Calf or Generalized
  • Weakness: Some mutations (Asp27Glu)
    • Proximal or Distal
    • Scapular winging
    • May be exacerbated by dantrolene
  • Systemic
    • Strabismus: Intermittent
    • Pigmenturia: Recurrent
    • Cardiomyopathy: Some genetic types
      • Hypertrophic
      • Arrhythmias
• Laboratory
  • EMG
    • Muscle activity is electrically silent
    • Some increased insertional activity
  • Serum CK
    • Usually high: Up to 10x Elevated
    • Occasionally Normal
  • Muscle pathology
    • Muscle fiber size: Varied
    • Type 2 fiber hypertrophy
    • Central nuclei
    • Dysferlin staining reduced, especially with compound heterozygous mutations
    • Caveolin staining: Reduced
    • Ultrastructure: More severe changes in homozygous mutations
      • Complete absence of caveolae in the sarcolemma
      • Plasmalemma: Discontinuities; Papillary projections
      • Subsarcolemmal vacuoles
  • Muscle physiology: Altered Ca⁺⁺ regulation by sarcoplasmic reticulum
    • "After-contraction" of single muscle fibers
    • Altered release or uptake of Ca⁺⁺ by sarcoplasmic reticulum
• Treatment
  • Dantrolene: May increase weakness
  • Benzodiazepines

• Epidemiology
  • Oman families
• Onset
  • Childhood
  • Motor development: Delayed
  • Fatigue
• Clinical: Severe
  • Muscle features
    • Involvement of proximal & distal muscles
    • Rippling
    • Mounding
    • Hypertrophy: Generalized; Including face
    • Tone: Normal
    • Strength: Normal
  • Skeletal
    • Bone age: Delayed
    • Short stature
    • Contractures: Ankle
  • Cardiac: Variably present
    • Intraventricular septum: Thickened
    • Arrhythmia: Ventricular ectopy & tachycardia; PVCs
    • Sudden death
• Laboratory
  • Serum CK: Very high; 1,000 to 6,000
  • EMG: No spontaneous activity
  • Muscle pathology
    • Fiber size: Varied; Some hypertrophy
    • Occasional central nuclei
• External link: Movies - Stephan laboratory
  • Case1
  • Case 3

• Mutations: Homozygous L86P or A92T²¹
• Clinical
  • Motor development: Delayed
  • Muscle stiffness: Severe; Permanent
  • Percussion/pressure-induced rapid muscle contractions
  • Muscle hypertrophy
  • Ankle contractures: L86P mutation
  • Proximal weakness: A92T mutation
• Laboratory
  • Serum CK: 1,500 to 5,000
  • Muscle pathology
    • Variation muscle fiber size
    • Muscle fiber hypertrophy
    • Atrophic muscle fibers
    • Internal nuclei: Increased
    • Caveolin-3: Reduced in muscle
    • Caveolae: Absent in sarcolemma
    • Ultrastructure: More severe changes in homozygous mutations
      • Complete absence of caveolae in the sarcolemma
      • Plasmalemma: Discontinuities; Papillary projections
      • Subsarcolemmal vacuoles

• Associated with
  • Thymoma
  • Myasthenia gravis: Rippling muscles may precede dx of MG
• Onset: 30 to 55 years
• Clinical features
  • Cramps
    • Induced by exercise or touching muscle
    • Spread: Transverse direction across muscle
  • May be painful
  • Distribution: Cranial; Proximal; Distal
  • Bulbar: Dysphagia; Dysarthria
  • Normal sensation & tendon reflexes
  • Similar to hereditary rippling muscle syndrome
• Laboratory
  • Serum CK: Mildly elevated
  • Muscle biopsy: Inflammation, lymphocytic
  • EMG: Normal; Cramps are silent
  • Antibodies: Skeletal muscle
• Treatment
  • Immunosuppression: Prednisone or Azathioprine; Benefit over 2 to 4 months
  • Exacerbated by Pyridostigmine

Schwartz-Jampel Syndrome (Chondrodystrophic myotonia) ²⁴

From: Ho et al. BMC Neurology

• Gene
  • Mutations
    • Truncation (insertions or deletions) most common
    • Missense or splicing in some patients
  • Null mutations in
    • Dyssegmental dysplasia, Silverman-Handmaker type
• Perlecan
  • Heparan sulfate proteoglycan
  • Major component of basement membranes & interstitial matrix in cartilage
  • Functions
    • Coreceptor for FGF2
    • Interacts with basement membrane components & cell surface receptors
      • β1 integrin
      • Domain V binds to: Heparin; Fibulin-2; α dystroglycan
      • Domain IV binds to: Nidogen-1 & and -2; Fibulin-2; Fibronectin; Heparin
    • Localizes acetylcholinesterase to NMJs
    • Protects cartilage components from hydrolysis
• Type 1A
  • Onset
    • Childhood, Usually < 3 years
    • Respiratory & Feeding difficulties
    • Prenatal
      • Impaired swallowing: Polyhydramnios; Absent stomach bubble
      • Skeletal: Contractures; Short femurs
  • Clinical features
    • Neuromuscular
      • Muscle stiffness
        • Myotonia: Onset after birth
        • Face: Fixed expression, Pursed lips, Small mouth
        • Thighs
        • Waddling gait
        • Crouched stance
        • Treatment: Carbamazepine
      • Muscle hypertrophy: Especially thighs; Generalized
      • Malignant Hyperthermia: Increased risk during anesthesia
      • Tendon reflexes: Reduced
    • Mental retardation: Mild; Rare
    • Skeletal
      • Bone dysplasia (moderate)
        • Micrognathia
        • Spine: Platyspondyly; Cleft vertebrae
        • Reduced height
        • Kyphoscoliosis
      • Contractures: Progress until mid-adolescence
    • Ocular
      • Myopia
      • Cataracts
      • Blepharophimosis
      • Medial displacement of outer canthi
    • Hirsutism
    • Small testes
    • Anesthetic problems
      • Mechanical difficulty during intubation: Microstomia & jaw muscle rigidity
      • Limitation of respiratory excursion: Deformity of the spine and chest
  • Laboratory
    • EMG: Continuous muscle discharges
      • Myotonia or Complex repetitive discharges
      • Present from age 7 months
      • No modulation of frequency or amplitude
      • ? Activity due to Muscle or Neural basis
    • Serum CK: Mildly high or Normal
    • Muscle biopsy
      • Histochemistry: Fiber type changes; Internal nuclei; Varied fiber size
      • Perlecan: Reduced or mutated molecule secreted into extracellular matrix
    • X-rays: Osteochondrodysplasia
• Type 1B
  • Perlecan mutations
  • Onset: Birth
  • More severe bone dysplasia: Like Kneist

Schwartz-Jampel Type 2/Stuve-Wiedemann syndrome (SWS)²⁶

• LIFR genetics: Null mutations
• LIF receptor protein
  • Binds several cytokines
    • LIF
    • OSM
    • Ciliary neurotrophic factor (CNTF)
    • Cardiotrophin 1
    • Neurotrophin-1/B-cell stimulating factor 3
  • Related proteins causing syndromes
    • Crisponi
    • Cold-induced sweating
    • Cold induced sweating 2
• Onset: Birth
• Clinical
  • Congenital
    • Hypotonia
    • Respiratory & feeding difficulties
    • Hyperthermic episodes
    • High mortality in infancy
  • Skeletal
    • Joint contractures
    • Bent bone dysplasia: Campomelic-metaphyseal (Like Pyle disease )
      • Bowing of lower limbs
      • Internal cortical thickening
      • Wide metaphyses: Abnormal trabecular pattern
      • Camptodactyly
    • Spontaneous fractures
    • Short stature
  • Autonomic
    • Malignant Hyperthermia: Recurrent episodes
    • Temperature instability
    • Corneal reflex: Absent
    • Smooth tongue
    • ? Pathogenesis: ? Due to Impairment of STAT3 signaling
      • Reduced induction of cholinergic & peptidic properties of sympathetic neurons
  • Tendon reflexes: Reduced
• Laboratory
  • Mitochondrial disorder: Complex I and IV activity reduced
• LIFR knockout mouse
  • Reduction of fetal bone volume: Increased number of osteoclasts
  • Reduction of astrocyte numbers in spinal cord & brain
  • Perinatal death

Brody's disease

• ATP2A1 Gene mutations⁵
  • Present in 6 of 8 recessive Brody's syndrome families
  • Types
    • Stop or frameshift in 5 families
    • Missense with reduced function in 1 family (Pro789Leu)
  • No ATP2A1 mutations in 2 dominant families
• Ca⁺⁺ ATPase protein
  • Location: Fast-twitch skeletal muscle sarcoplasmic reticulum
  • Lower cytoplasmic Ca⁺⁺: Pumps Ca⁺⁺ to luminal or extracellular spaces
  • Promotes muscle fiber relaxation after contraction
  • Neonatal & adult isoforms produced by alternative splicing
  • Distribution: Type 2 muscle fibers
  • Structure: HPRD
• Epidemiology
  • Male preponderance
  • Rare: 1 in 10,000,000 births
• Clinical features
  • Onset: Childhood; Limb muscles
  • Impaired muscle relaxation; Stiffness; Cramping & Myalgias
    • Exercise induced
      • Onset: Minutes after onset of exercise
      • Worse with progressive exercise
    • Cold: Symptoms worsen
    • Rest: Improvement of symptoms after seconds to minutes
    • Painless cramps
    • Distribution: Limbs & Face (Eyelids)
  • Strength
    • Resting: Normal
    • Exercise, During: Reduced
    • Exercise, After: Strength returns to normal within minutes
  • Muscle size: May be enlarged
  • Course: Slow progression; Permanent weakness rare
  • Rhabdomyolysis in some patients
• Laboratory
  • Serum CK: May be mildly elevated
  • EMG
    • Electrically silent cramps
    • Normal motor units
  • Muscle pathology
    • Type II atrophy
    • No myopathic changes
    • Absent ATP2A1 (SERCA 1) staining with truncating, but not missense, mutations
• Treatment: ? Dantrolene; Nifedipine; Verapamil
• Clinical variant: Brody's syndrome
  • Inheritance: May be dominant
  • Onset in teens
  • Selective muscular involvement
  • No ATP2A1 mutations

• Epidemiology: Italian family
• Genetics: Cosegregates with an apparently balanced constitutional translocation (2;7)(p11.2;p12.1)

Myokymia & Benign Neonatal Epilepsy ¹³

• Epidemiology: One German family
• Mutation: R207W
• Physiology: Mutation
  • Shifts voltage dependence to more positive voltages
  • Slows depolarization-induced activation
• Clinical
  • Onset: Neonatal convulsions
  • Myalgias: Childhood
  • Myokymia
    • Increased with age
    • Exacerbated by: Fever, Cold, Alcohol & Pregnancy
    • Distribution: Trunk; Limbs; Not face
    • EMG
      • Spontaneous discharges of grouped motor unit potentials
      • Repetitive discharges after nerve stimulus
      • Activity inhibited by NMJ blockade
    • Treatment: Carbamazepine
  • Neonatal epilepsy, Benign
• Variant syndrome: Peripheral nerve hyperexcitability (Myokymia)
  • Epidemiology: Egyptian patient
  • KCNQ2 mutation: R207Q; Heterozygous
  • KCNQ2 channel (K_v7.2): Mutation effects
    • Abnormal voltage-dependent activation
      • Depolarizing shifts of conductance-voltage relationships
      • Marked slowing of activation time course
    • Mechanisms
      • R207Q & R207W: Dominant negative effect on wild type channels
      • Other mutations cause neonatal seizures by haploinsufficiency
  • Clinical
    • Onset: 1st decade; Cramps
    • Continuous muscle activity
      • Small amplitude movements of fingers
      • Cramps: Exercise-induced
      • Muscle stiffness: Episodic
        • Generalized: Most prominent distally
        • Duration: Up to 30 minutes
        • Exacerbated by physical exertion & anxiety
      • Most prominent distally
    • No seizures
    • Treatments
      • Lamotrigine (200 mg/day): Partial improvement
      • Retigabine
        • Activator of neuronal Kv7 channels
        • Reverses depolarizing shift
  • Laboratory
    • EMG: Spontaneous irregular multiplets (Myokymic discharges)
    • Motor & sensory nerve conduction studies: Normal
    • Potentials generated in distal axons
  • Other: Differential diagnosis

Myoedema

• Localized, persistent, electrically silent swelling of muscle after percussion
• Duration: Few seconds
• Differs from dimpling due to myotonia
• Due to local contraction after release of calcium from the sarcoplasmic reticulum
• Disease associations: Cachexia; Myxedema; Hyponatremia; Rabies; Occasional normals

Muscle Spasms & Dwarfism

• Clinical features
  • Onset: Childhood
  • Painful trunk & limb muscle contractions
  • Short stature, large nose & Low-set ears
  • Hair: Scalp - thin; Body - none

• Nosology: “komura–gaeri” disease
• Epidemiology
  • Frequency: 30 cases described
  • Sporadic: All patients
• Onset: 4 to 36 years; Mean 10 years
• Clinical
  • Muscle
    • Muscle spasms: Progressive, Painful, Intermittent
    • Myoglobinuria
  • Systemic
    • GI (50%): Diarrhea; Malabsorption; Abdominal spasms
    • Endocrine: Amenorrhea; Hypoplastic uterus & Ovaries
    • Alopecia universalis
  • Skeletal
    • Bone pathology: Slipped epiphyses; Cysts; Fatigue fractures; Osteolysis
    • Short stature: ? Related to poor nutrition
  • Lifespan: Shortened
• Laboratory
  • Serum antibody: Binds to 90 kDa protein in brain, stomach & duodenal tissue
  • Associated with other autoimmune disorders
    • Myasthenia gravis
    • Idiopathic thrombocytopenia
    • Nephritis
  • NCV & EMG: Normal
• Treatment
  • Corticosteroids²³
  • IVIg
  • Tacrolimus

Cramps

• Clinical features
  • Acute onset
  • Short duration
  • Muscle contraction: Strong & palpable
  • Relief by stretching muscle
• Common type: In normals
  • Sudden involuntary painful muscle contractions.
  • Precipitants
    • 2° to hyperexcitable terminal nerve arborization
    • Most often following voluntary contractions: Especially Contraction of shortened muscle
    • Occasionally during rest or sleep
    • 10 Hz electrical stimulation
  • Relief: Passive muscle stretch; Local massage
  • Location
    • Usually involve single muscles rather than groups
    • Especially gastrocnemius
    • Local cramps in other muscles often associated with denervation or other neuromuscular disorders
  • Common sequelae
    • Muscle soreness & swelling
    • High serum CK
  • EMG
    • Triphasic action potentials: Irregular
    • Rate: 40 to 60 Hz
    • Origin: Motor nerve terminals
• Systemic disorders associated with cramps
  • Dehydration: Hidrosis; Diuretics; Hemodialysis
  • Metabolic: Low Sodium, Magnesium, Calcium, Glucose
  • Endocrine: Thyroid (Hyper- or Hypo-); Adrenal insufficiency
  • Pregnancy
  • Drugs & toxins
• Neuromuscular disorders associated with cramps
  • Nerve
    • Motor system disorders
      • Amyotrophic Lateral Sclerosis
      • Motor neuropathies
      • Hereditary motor neuron disorders
    • Other denervation
      • Spinal stenosis
      • Polyneuropathies
    • Spontaneous activity syndromes
      • Episodic ataxia 1 (EA1)
      • Neuromyotonia (Isaac's syndrome)
      • Stiffman syndrome
      • Cramp-fasciculation syndromes
  • Muscle
    • Becker muscular dystrophy
    • Type II muscle fiber predominance
• Familial cramp disorders
  • Cramp syndromes: Autosomal dominant
    • Familial cramp syndrome
    • Familial dwarfism with muscle spasms
    • Satoyoshi syndrome
    • Muscle cramp & neuropathy syndrome
    • HANAC
    • Cramps & myalgias
  • Becker muscular dystrophy
  • Electrically silent
    • Phosphorylase deficiency (McArdle's)
    • Rippling muscle syndrome
    • Brody's syndrome
• Treatments for cramps

  Normalize metabolic abnormalities Quinine sulfate: 260 mg qhs or bid Carbamazepine: 200 mg bid or tid Phenytoin: 300 mg qd Tocainide: 200 to 400 mg bid Verapamil: 120 mg qd

  Amitriptyline: 25 to 100 mg qhs Vitamin E: 400 IU qd Riboflavin: 100 mg qd Diphenhydramine: 50 mg qd Calcium: 0.5 to 1 g elemental Ca++ qd

• Also see: Muscle pain

Electrical activity with few clinical manifestations

• Pseudomyotonia (e.g. in acid maltase deficiency)
• Fibrillations: Denervation; Inflammatory myopathies

Electrically silent cramps

• Muscle contractures
  • Painful prolonged muscle contraction
  • Provoked by
    • Depletion of muscle energy stores
    • Continuous muscle contraction; Ischemia
  • Electrically silent
  • Association: Glycogen metabolic disorders
• Rippling muscle syndrome
• Brody's syndrome
• Myoedema
  

Muscle Activity: Neural origin

Tetanus²⁰

Clinical features Clostridium tetani Diagnosis Epidemiology Mechanism of action Prophylaxis Protein structure Treatment History: Case description

C Bell 1865: From NLM

• Tetanus toxin (Tetanospasmin) : Protein structure
  • Produced as a protein (protoxin) with molecular weight 150 kDa
  • 30% to 40% homology to botulinum toxins
  • Cleaved into heavy (100 kDa) & light chain (50 kDa) subunits linked by disulfide bond
  • Double chain product more, or equally, active compared to single chain
  • Protein domains & Functions
    • Light chain
      • Contain tetrahedral zinc binding motif
        • 2 histidines, glutamate & water molecule
          
        • Resembles amino acid sequence of thermolysin-like endoproteases
      • Cleavage of synaptobrevin: Prevents release of transmitter from presynaptic terminal
    • Heavy chain, Carboxyl terminal
      • Immunogenic
      • Neuronal cell binding
      • Ganglioside binding
      • Retrograde transport
    • Heavy chain, N-terminal
      • Endosome
  • Produced by Clostridium tetani
    • Under anaerobic conditions
    • Released by autolysis as a prototoxin
    • Genetic information resides on plasmids
    • Spores ubiquitous; More in warm, manure-rich soil
  • Link: Saier classification
• Tetanus toxin: Mechanism of action

  Clostridium toxins	Target proteins cleaved
  Tetanus Botulinum     A     B     C     D     E     F     G	VAMP (Synaptobrevin) SNAP-25 VAMP (Synaptobrevin) SNAP-25; Syntaxin VAMP (Synaptobrevin) SNAP-25 VAMP (Synaptobrevin) VAMP (Synaptobrevin)

  • Membrane binding
    • Receptors
      • ? Gangliosides with more than one neuraminic acid, e.g. GT1b
      • ? Protein receptor
      • C-terminal of tetanus heavy chain binds to gangliosides
  • Uptake by endocytosis
  • Retrograde transport
    • Mediated by tetanus heavy chain
      
    • N-terminal forms pores in lipid bilayers
      • ? marks vesicles for retrograde transport
  • Transsynaptic transport to inhibitory presynaptic terminals
  • Light chain of tetanus toxin moves from vesicle to cytosol
    • Facilitated by low pH in vesicle
      
    • Pore formed by N-terminal of heavy chain
  • Inhibits release of inhibitory transmitters: Glycine or GABA
    • Cleaves synaptobrevin II (involved in synaptic vesicle release)
      
    • Cleavage occurs at Glutamate 76
  • Produces unrestrained reflex activity of skeletal muscles & autonomic nervous system
  • Lethal dose: 500pg/kg
  • 2nd most potent microbial toxin: After botulinum toxin
• Clostridium tetani
  • Gram positive bacilli
  • Spore producing
    • Spores resistant to: Heat, usual antiseptics & chemical agents
    • Spores destroyed by: Autoclaving at 120°C for 15 minutes; Boiling for at least 4 hours
  • Anaerobic: Obligate
  • Distribution in environment: Wide
    • Soil
    • Intestinal flora
      • Animals: Horses, sheep, cattle, dogs, cats, rats, chickens
      • Humans: 10%; Especially in agricultural areas
  • Toxin production
    • Due to plasmid contained in some C. tetani organisms
    • 2 toxins produced
      • Tetanospasmin: Disease producing
      • Tetanolysin : Uncertain effects
  • External link: Microvet
• Tetanus: Epidemiology
  • Prior tetanus does not provide immunity
  • Deaths
    • 800,000 to 1,000,000 per year
    • Most in Africa and Southeast Asia
    • 50% Neonatal tetanus
    • Causes of death
      • Respiratory failure
      • Autonomic dysfunction
      • Prolonged critical illness
  • Geography
    • Neonatal tetanus (from umbilical stump infections)
      • Common in 3rd world; 500,000 deaths/year
        
      • Rare in U.S.
    • Western
      • Generalized type
      • Most common in elderly, blacks, young males & older females
      • Low or absent anti-tetanus titers
  • Mortality
    • Highest in elderly
      • > 50% over 60 years
      • Possibly related to a decline in protective levels of antibodies
    • Low in US adults < 30 years
    • Greatly reduced by supportive ventilation: Especially Neonatal tetanus
  • Primary immunization
    • > 90% of patients never completed series
    • Full immunization: ~ 100% protective
    • Immunization of mother prevents neonatal tetanus in child
    • Risk factors
      • Incomplete vaccine deployment among population
      • Quality of vaccine: Method of storage
  • Source of toxin
    • Acute wound in 75%
    • Wound types: Puncture, laceration or abrasion; Drug abuse; Burns...
• Tetanus: Clinical features & types
  • Presentation
    • 3 to 21 days after injury (rarely months)
      
    • More severe disease: Shorter incubation periods; Especially < 7 days
  • Localized type
    • Uncommon
    • Painful spasms in muscles near region of injury
    • Self-limited, lasting < 2 weeks
    • Occasionally becomes generalized
    • Mortality: 1% to 16%; Due to generalization
  • Cephalic type
    • Frequency: 6%
    • Infection types: Otitis media; Head injuries; Tongue piercing
    • Localization: Cranial nerves
      • Facial weakness: Most common
      • Other: EOM (6, 3, 4): Hypoglossal
      • Trismus: Follows other cranial nerve involvement
    • May progress to generalized tetanus
    • Prognosis
      • Often poor: Mortality 15% to 30%
      • Milder disease reported
  • Neonatal type
    • Frequency
      • Developing countries: Common; 500,000 deaths per year
      • Developed world: Rare
    • Causes
      • Unhygienic child birth practices: Traditional midwifery
        • Cutting umbilical cord with grass or dirty scissors
        • Smearing cow dung or ghee (clarified butter) on umbilical stump
      • Social taboos
      • Improper immunization of pregnant mothers
    • Onset
      • Time: 5 to 15 days after birth
      • Signs: Poor sucking; Excessive crying; Vomiting
    • Progresses to
      • Trismus
      • Dysphagia
      • Generalized spasms: May be more severe than in adults
      • Fever
      • Seizures
    • Prognosis: Death (70%) unless agressive medical management
  • Generalized type
    • Most common form
    • Onset
      • Head & Neck often affected first: Dysphagia may be presenting symptom³³
      • Trismus: Increased tone in masseter
      • Other: Reflex spasms, Neck rigidity, Stiffness
    • Clinical features
      • Muscle rigidity
        • Face: Risus sardonicus
        • Trunk
      • Tetanic "spasms"
        • Distribution: May be generalized
        • Duration: May last second to minutes
        • Stimuli: Noise; Touch; Movement
        • Often painful
        • "Spatula test": Spatula inserted into pharynx
          • Positive result: Patient bites spatula due to masseter spasm
          • Negative result: Gag & Expelling of spatula
      • Respiratory insufficiency
      • Autonomic overactivity
        • Blood prressure: Hypertension; Hypotension
        • Dysrhythmias: Tachycardia, episodic; Bradycardia & Asystole
        • Urinary retention
        • Peripheral vasoconstriction
        • Hidrosis
        • Hyperpyrexia
      • Secondary injuries
        • Fractures
        • Complications of immobilizing illness
        • Rhabdomyolysis
      • Sensation: Normal
      • Mental status: Normal
    • Prognosis worse
      • Short incubation period
      • Internal or facial site of infection
      • Lack of immune protection
      • After intramuscular injections of quinine
    • Time course
      • Worst at 4 to 14 days
      • Recovery over months
• Tetanus: Diagnosis
  • Clinical - no specific test
  • History: Unusual with
    • Hx of immunization in past 10 years
      
    • Serum levels of anti-toxin > 0.01 IU/ml
  • EMG
    • Motor unit activity
      • Spontaneous
      • Continuous
      • No voluntarily suppression
    • Stretcth reflex: Absent silent period after reflex, or motor-evoked, response
  • Wound cultures: Positive in 30% to 50%
  • Rule out: Drug withdrawal; Dystonic reaction; Meningitis; Stiffman
• Tetanus: Treatment
  • Neutralization of circulating toxin
    • 3,000 to 6,000 U of human tetanus immune globulin, i.m.
  • Intensive care unit management
    • Respiratory support
    • Prevent metabolic complications
  • Prevent muscle spasms
    • Anti-spasm drugs
      • Diazepam: Up to 20 mg q 2 to 6 hours
      • Baclofen
    • Neuromuscular blocking agents, if necessary
    • Magnesium sulfate: If respiratory support is not available
  • Dysautonomia treatment
    • Benzodiazepines
    • Morphine
    • Magnesium sulphate
    • Adrenergic blockers
    • Baclofen
  • Elimination of toxin source by surgical excision
    • Delay debridement until several hours after anti-toxin treatment
    • Obtain specimens for culture
    • Antibiotic Rx
      • Metronidazole
      • Also: Penicillin G, Erythromycin, Tetracycline
• Tetanus: Prophylaxis
  • Tetanus-diphtheria toxoid
    • A safe vaccine
      
    • Use for all wounds in patients with
      • < 3 previous doses, or
        
      • > 5 to 10 years since last dose
  • Tetanus immune globulin
    • Unclean or major wounds in patients with fewer than 3 previous doses of toxoid

Isaac's Syndrome

• Onset: 9 to 80 years; Most < 60 years; Mean 46 years
• Clinical Features
  • Symptoms fluctuate
    • In severity over periods of months
    • Precipitated by exercise or muscle contraction
  • Muscle twitching: Symptomatic in 12% to 40%
  • Cramps & Stiffness
    • Stiffness at rest
    • May be induced or exacerbated by exercise
    • Distribution
      • Distal > Proximal
      • Face, tongue & Pharyngeal muscles may be involved
    • Intermittent
    • Delayed muscle relaxation
    • No percussion induced contraction
    • Muscle activity continues during sleep
  • Fatigue: Associated with Isaac's; Does not predict MG or Polyneuropathy
  • Weakness
    • Absent or Mild (30%)
    • Especially in overactive muscles
  • Muscle hypertrophy (20%)
  • Sensory symptoms (30%): Paresthesias, Numbness
  • Hyperhidrosis (33% to 55%)
  • Visible myokymia/neuromyotonia
  • Tendon reflexes: Often normal
  • Mental disturbances (25%)
    • Morvan's syndrome
    • Personality change
    • Insomnia
    • Irritability
  • Course: Fluctuations, but no spontaneous remissions
• EMG¹⁶: Spontaneous axonal action potentials
  • General: Peripheral nerve hyperexcitability
    • Origin of activity: Potentials arise along course of motor axon, especially distally
    • Increased excitability of nodal membrane
    • Potentials persist during general anesthesia
    • Muscle activity eliminated by NMJ blockade
    • Distribution: Limbs > Trunk & Face
  • Fasciculations
    • May be only sign of disease & occur without myokymia
    • Less disability when only EMG feature
  • Myokymia
    • EMG patterns
      • Continuous spontaneous activity: Mild
      • Spontaneous bursts of motor unit potentials
        • Brief (Less than 1 second)
        • Double, triple or multiple
        • 5 to 70 Hz
          
        • 2 to 5 potentials per burst
          
        • Recur regularly or irregularly (0.1 to 3 per second)
    • Mechanism
      • Commonly caused by loss of function of voltage-gated potassium channels (VGKC)
      • Channel disorder results in decreased outward potassium current
      • Originate in distal axon
    • Course: May persist after treatment
    • Isaacs syndrome
      • Myokymia is present in some, but not all, patients
      • May develop on subsequent study
    • See
      • Myokymia image
      • Differential diagnosis
  • Neuromyotonia
    • More persistent activity & muscle contraction
    • Spontaneous bursts of single motor unit potentials
      • Prolonged (Several seconds)
      • 40 to 300 Hz
      • Bursts very irregular
      • Associated with persistent muscle contraction
    • Often reduced by treatment
  • Repetitive F-waves
• Associated disorders
  • Neoplasm
    • Lung, Thymus & Hodgkin's
    • Isaac's syndrome often predated neoplasm
  • Penicillamine
  • Polyneuropathy: Sensory-Motor
  • IgM M-protein
  • Myasthenia gravis & Anti-AChR antibodies
    • Frequency: 10% to 20%
    • With thymoma: Patients > 40 years
    • Overactivity begins with or after MG
  • HIV infection
  • Morvan's fibrillary chorea
  • Other associated immune or systemic disorders
    • Thyroid
    • Diabetes
    • SIADH
• Myokymia & Peripheral nerve hyperexcitability: Differential diagnosis
  • Isaac's Syndrome
  • Benign myokymia
    • Repetitive single polyphasic action potentials with varying shapes
  • Cramp-fasciculation syndrome
    • Neuromyotonia without fibrillations
      
    • ? Mild variant of Isaac's
  • Hereditary
    • Dominant
    • Gamstorp-Wohlfart Syndrome : Autosomal Dominant
      • Myokymia; Myotonia; Muscle wasting; Hyperhidrosis
    • Episodic Ataxia/Myokymia Syndromes: EA 1; EA 4
    • Distal spinal muscular atrophy
    • KCNQ2 mutations
      • Myokymia & Benign neonatal epilepsy
      • Peripheral nerve hyperexcitability
    • Schwartz-Jampel syndrome
    • Familial dyskinesia with facial myokymia
  • Drugs: Penicillamine; Clozapine; Oxaliplatin
    
  • Toxins: Herbicide; Insecticide; Toluene
  • Polyneuropathies
    • Immune: Guillain-Barré; CIDP
    • Toxic: Gold; Mercury; Alcohol
  • Systemic disease
    • Hypocalcemia: Hypoparathyroid
      
    • ? Addison's
      
    • Amyloidosis: Acquired with M-protein
      
    • ? K⁺ channel blockade: 4-aminopyridine
    • Thyroid: Hyper- or Hypo
    • Uremia
  • Focal myokymia or neuromyotonia
    • Focal nerve lesions
      • Multifocal motor neuropathy
      • Radiation injury to nerve or plexus
      • Focal nerve injury (Carpal tunnel syndrome)
    • Toxic: Rattlesnakes - Timber
      • Mojave (binds to Ca⁺⁺ dihydropyridine receptor)
    • Faciolingual
      • Machado Joseph Syndrome (SCA3)
      • Multiple sclerosis
        
      • Brainstem neoplasm: Glioma; Schwannoma
      • PEO & Scoliosis
      • Familial Dyskinesia & Facial myokymia¹⁰
      • Immune: K⁺ channel antibodies
    • Transposed muscle flaps
    • Other localized neuromyotonia
      • Finger flexion⁸
      • Eyelid
      • Superior oblique
      • Hemifacial spasm: Occasional
• Isaac's syndrome: Laboratory
  • Serum CK: Elevated in 50%
  • Antibodies
    • Potassium channels: Prevalence 28% to 100%
      • Frequency of antibodies depends on antigen used
      • Antibody targets
        • Voltage gated, α-dendrotoxin sensitive: 50%
          
        • KCNA6 : 83%
          
        • Also KCNA2 & KCNA1a
      • Neoplasm associations
        • More common with associated thymoma
        • Small cell lung cancer: SOX1 antibodies
      • General: Antibodies bind to fast VGKCs located at paranodes & internodes
      • Other syndromes with K⁺ channel antibodies
        • Cramp-fasciculation syndrome
        • Morvan's fibrillary chorea
        • Limbic encephalitis
      • KCNA1 mutations in Episodic ataxia
    • Nicotinic AChR: α3 subunit (50%)
    • Nicotinic AChR α1 subunit: With thymoma
  • Nerve conduction studies: Usually normal
  • CSF occasionally abnormal: Oligoclonal bands; Mildly high protein
  • Muscle biopsy: Fiber hypertrophy; Type I predominance
• Isaac's syndrome: Treatment
  • Symptomatic
    • Carbamazepine (200 to 600 mg/day)
    • Phenytoin (200 to 400 mg/day)
    • Mexiletine
  • Immunosuppression
    • Plasma Exchange (short-term benefit)
    • Prednisone

Stiffman (Stiffperson) syndrome

• Epidemiology
  • Female (70%) > Male (30%)
• Prodrome: Pains & tightness in axial muscles
• Onset
  • Age
    • Childhood or Adult
    • Anti-GAD antibody positive: Mean 41 years; Most common 3rd to 5th decades
  • Prodromes: Episodic stiffness or falling
  • Course: Slowly progressive (insidious); Occasional rapid onset
  • Reported hereditary forms : May be hyperekplexia
• Stiffness
  • Distribution
    • Especially in axial & proximal limb muscles
    • Asymmetric, or Prominent in 1 leg (30% to 75%)
  • Involvement of limbs impairs walking
  • Hyperlordosis: Lumbar; Limits truncal flexion
  • Fluctuates over time: Reduced in sleep
• Muscle spasms
  • Triggers
    • Stretching
    • Emotion
    • Sensory stimulation
    • Fear of open spaces
    • May occur spontaneously
  • Course of spasm
    • Sudden myoclonic jerk: May produce falling
    • Followed by tonic activity that subsides over seconds
  • Usually bilateral
  • Typical movements
    • Arms: Extension & Pronation
    • Trunk: Extension
    • Legs: Extension & mild abduction; foot inversion
  • Co-contraction of agonist & antogonists
    • Abdominal & thoracic paraspinous muscles
    • Spasms may produce little movement due to co-contraction around joints
  • Discomfort: May be associated with severe pain
  • May be severe enough to cause fractures
  • Relaxation of spasms: Sleep & Benzodiazepines
  • Disability: Cane or Walker commonly needed 2° frequent falls
• Reflexes
  • Tendon reflexes: Normal or Increased
  • Abdominal cutaneous: May be lost
  • Startle responses: Increased
• Gait: "Tin soldier"
• Autonomic dysfunction
• Extraocular movements: Some patients
  • Gaze-holding nystagmus
  • Limited abduction
  • Vertical & horizontal ocular misalignment
  • Deficient smooth pursuit
  • Impaired saccade initiation
• Otherwise normal neurologic exam: Most patients
• Disease course
  • Usual: Slow progression or static over years
  • Focal syndromes may progress to more generalized involvement
  • Sudden death: Occasional patient
  • Trismus unusual
    • Cardiac arrhythmias
    • Restrictive respiratory arrest
    • Rapid tapering of intrathecal baclofen

• Epilepsy
  • Treated with anti-GABA agents
  • Suggests PERM variant
• Diabetes mellitus, type I (30% to 60%)
• Neoplasms
  • Breast cancer
  • Other: Lung; Thymoma
• Immune disorders
  • Thyroiditis (13%)
    
  • Pernicious anemia (7%)
    
  • Myasthenia gravis
    
  • Ovarian or adrenal failure
  • Vitiligo
  • Similar immune disorders may occur in family members
    • More common with anti-GAD antibodies
• HLA: DRβ1 0301 (40% to 70%)

• Serum CK: Transiently elevated
• ANA (30%)
• Anti-GAD antibodies
• CSF
  • Oligoclonal bands (60%)
  • Protein high (20%)
  • Pleocytosis: 10% in SPS; 63% in PERM variant
  • Normal: 40% in SPS; 12% in PERM variant
  • Anti-GAD antibodies: May be present
    • Usually lower titer than in serum
    • Intrathecal anti-GAD synthesis may occur
• CNS MRI: Non-diagnostic
• EMG
  • Continuous action potentials
    • Indistinguishable from voluntary activity: Normal motor units
    • Persist during attempts at relaxation
    • Most prominent in axial muscles
  • Persistent bursts: 50 to 60 ms duration; 5 - 6 Hz; Rhythmic; Synchronous
  • Interruption of bursts by spasms: Rapid activity; Full interference pattern; > 4 sec
  • Activity reduced by intravenous diazepam
  • No fibrillations or grouped rhythmic discharges
  • Poor relaxation after contraction
• CNS pathology
  • Perivascular inflammation
  • Spinal cord: Neuronal loss
  • Lateral vestibular nucleus: Loss of neurons

• Pathophysiology
  • Disorder of presynaptic inhibition of Ia terminals
    • Exaggerated polysynaptic reflexes
    • ? Defect in descending control pathways
  • Normal motor neuron excitability & Renshaw cell function
  • Differs from tetanus which produces defective segmental inhibition & hyperexcitable motor neurons
• Pharmacology & Pathways
  • Descending monoaminergic reticulospinal pathways
    • Inhibit short latency spinal flexor reflex afferents
    • Facilitate long latency spinal flexor pathways
    • ? Relative overactivity in SPS
    • Monoaminergic inhibition reduces spasms & stiffness: Clonidine; Tizanidine
  • GABA activity: Inhibitory
    • ? Relative underactivity
    • Enhanced GABA-ergic inhibition reduces spasms & stiffness: Baclofen; Diazepam

• Glutamic acid decarboxylase (GAD2)
  • Age spectrum: Adults
  • Tissue staining pattern: GABAergic nerve terminals
  • Anti-GAD antibody titers
    • Levels: Low to High
    • Vary with clinical syndromes
    • High in Stiffman syndrome
  • Location of antibodies
    • Present in serum & CSF
    • Usually higher titer in serum
  • GAD epitope structure: Linear & Conformational
  • GAD targets: 65 & 67 kD variants
  • Stiffman syndrome
    • Prevalence: 50% to 90%
    • Specificity: More with higher anti-GAD antibody titers
  • Other syndromes: Anti-GAD antibodies also found in
  • Palatal myoclonus
  • Epilepsy: Therapy-resistant, Localization-related
    • Frequency: 15%
    • Anti-GAD antibody titers: High or Moderate
    • Anti-GAD antibodies not found in generalized epilepsy
  • Cerebellar ataxia: May have high titer anti-GAD antibodies
  • Insulin-dependent diabetes mellitus (IDDM)
    • Age spectrum: Childhood & Adolescence
    • Anti-GAD antibody titers: Low to moderate titer
    • GAD epitope structure: Conformational
    • GAD targets: 65 kD variants
    • Association with
      • Antibodies to tyrosine phosphatase IA-2
      • T-cell immunity
  • Autoimmune polyendocrine syndrome II
• Other antibodies with stiffman syndrome
  • Pancreatic islet cell (60%)
    • Also found in type I diabetes: Lower titer, different staining pattern
  • Amphiphysin (128kDa) : Associated with breast cancer
  • 80 kDa protein
  • Purkinje cell cytoplasm
  • Oligoclonal bands in CSF: 50%
• External link: Yale

• Symptomatic
  • Diazepam (very high doses; 20 mg to 300 mg/day); Clonazepam
    • May exacerbate depression
  • Baclofen
    • Baclofen (Oral): Adjunct medication
    • Baclofen pump (Intrathecal)
      • Indication: Severe syndromes
      • Acute withdrawal has been fatal
  • Valproate
  • Tiagabine: 6 mg qd
• Immunomodulating therapies
  • Corticosteroids: High dose solumedrol with tapering; Improvement over months
  • Intravenous immunoglobulin
  • Plasma exchange
  • Rituximab³¹

• Focal SPS: Usually Stiff Leg Syndrome
  • Onset: 35 to 60 years
  • Stiffness & spasms of lower limbs
    • Stimuli: Especially voluntary movement; Also reflex stimuli
    • Asymmetric
    • Posturing of feet
    • Trunk spared
  • Anti-GAD antibodies: Present
  • Treatment (Partial): Baclofen & Diazepam
  • Stiff arm syndrome: May suggest paraneoplastic disorder
  
  
• Subacute (Brainstem) Encephalomyelitis (PERM)
  • Onset: Subacute (Weeks)
  • Clinical
    • Stiffness
      • Distal > Proximal at disease onset
      • Rigidity
    • Spasms: Episodic
    • Muscle wasting & weakness
    • Autonomic
      • Hyperhidrosis associated with spasms
      • Failure may occur
    • Cranial nerves
      • EOM: Nystagmus & ophthalmoplegia
      • Blindness
      • Deafness
      • Dysarthria
    • Other CNS
      • Long tract
      • Vertigo
      • Intellect preserved
    • Progression
      • Months
      • Death in 1 to 39 months
      • Some mild cases
      • Some cases may evolve from SPS presentation
  • Laboratory
    • CSF: Inflammatory
    • Neurophysiology: Similar to SPS; Brainstem myoclonus
  • Pathology
    • Inflammation: Perivascular
    • Gliosis in spinal cord, pons & medulla
    • Neuronal loss: Spinal gray
  
  
• Jerking Stiffperson Syndrome
  • Clinical
    • Stiffness: Axial & Lower limb
    • Later features
      • Brainstem myoclonus
      • Upper motor neuron signs
      • PERM
    • Progression over decade
  • Antibodies: GAD
  
  
• Paraneoplastic SPS: Suggestive features
  • SPS confined to upper limbs
  • Rapid disease progression: To fixed joint deformities
  • Associated sensory ganglionopathy
  • Neoplasms: Breast; Small cell lung
  • Antibodies: Amphiphysin I; GAD
  
  
• Cerebellar syndrome with anti-GAD antibodies²⁷
  • Epidemiology
    • Onset age: 20 to 74 years
    • Females
  • Clinical
    • Onset: Slowly progressive
    • Ataxia: Limb & Trunk; Nystagmus; Dysarthria (50%)
    • Stiffness (15%)
    • No brainstem involvement
    • Associated disorders
      • ID Diabetes mellitus (Late-onset)
      • Thyroiditis
      • Poly-endocrine syndrome
    • Treatment: Not described
  • Laboratory
    • Anti-GAD antibodies: High titer
    • Anti-parietal cell Ab: Common
    • MRI: Non-diagnostic
  
  
• Differential diagnosis
  • Hyperekplexia (Stiff-baby syndrome)
  • Childhood onset: DYT1 gene mutations
  • Rule out: Associated perniciaous anemia

Strychnine¹¹

• Actions
  • Blocks glycine receptors: Competitive antagonist
  • Blocks inhibitory neurons in brainstem & spinal cord
• Sources
  • Rodenticide
  • Adulteration of street drugs
  • Herbal remedies: made with Strychnos nux-vomica
• Metabolism
  • Chemical type: Alkaloid
  • Intake: Oral with GI absorption
  • Hepatic metabolism: 1/2 life 10 to 16 hours
  • Some urine excretion: Up to 20%
• Clinical syndrome
  • Onset: Acute; 10 to 20 minutes after ingestion
  • Inital signs: Nervousness; Hyperalert; Confusion
  • Stiffness
    • Early: Face & Neck
    • Later: Generalized rigidity
    • May be triggered by minimal stimuli
    • Duration: 1/2 to 2 minutes
    • Respiratory arrest my occur during spasm
    • Muscle contraction may cause rhabdomyolysis
    • Tendon reflexes: Increased
  • CNS: Agitation; Delusions; Disorientation
• Diagnosis: Urine toxicology (Liquid chromatography)
• Differential diagnosis: Tetanus (No CNS)
• Treatment
  • Gastric lavage
  • Stiffness: Benzodiazepines; Barbiturates
  • Rhabdomyolysis: Fluids; pH management
  • Prophylactic ventilation in severe cases
• Also see: Hyperekplexia (Startle disease)
• External links: USDA

Hyperekplexia (Startle disease)

• Clinical features
  • Stiffness, myoclonus & after sudden stimulus
    
  • Onset: as early as infancy with hypertonia or myoclonus
    
  • Onset & severity vary within families
    
  • Treatment: Clonazepam
• Mouse models: Spasmodic & Oscillator

• Definition
  • Spontaneous action potentials in a single muscle fiber
  • Extracellular recording
• General
  • Electrophysiologic markers of denervation of muscle fibers
  • Not visible on physical examination
• Properties
  • Duration: 1 to 5 msec
  • Amplitude: Changes with time after denervation
    • Range: 20 to 600 μV; Generally < 1000 μV
    • 1st 2 months: 600 μV
    • 6 months: 300 μV
    • 1 year: 10 μV to 100 μV
  • Waveform
    • Diphasic or Triphasic
    • Initial positivity
    • Differ from endplate potentials which have initial negativity
  • Firing rate
    • Range: 0.5 to 30 per second; Average 13
    • Rhythm: Usually regular; May slow gradually
    • Increases with: Muscle warming; Cholinesterase inhibitors
  • Influences
    • Increased: Warming; Cholinesterase inhibitors; Needle electrode movement
    • Decreased: Hypoxia
• Other EMG properties
  • Sound: "Rain on the roof"
  • Onset after muscle denervation: 10 to 21 days
  • May change to positive sharp waves with movement of EMG needle
  • Very profuse fibrillations
    • May be recorded with simultaneous denervation of many muscle fibers
    • Common couses: Trauma; Infarction (with Vasculitis
  • Paraspinous muscles: May persist for years after surgery
• Causes
  • Common: Denervation
    • Due to decreased resting membrane potential in denervated muscle
  • Other: Inflammatory myopathy; Newborns
• Fibrillations: Illustration

Positive Sharp Waves

• Spontaneous depolarization of single muscle fiber
• Configuration
  • Initial: Positive (down) wave
  • Followed by: Wide negative wave
• Amplitude: 20 to 200 μV
• Duration: 10-30 ms
• Rhythm: Regular
• Frequency: 0.5 to 30 Hz
• Stable
• Involuntary
• Stimulus: Recording electrode³⁸
  • 2 populations
    • May be induced by EMG electrode: Short maximal depolarizing times (Mean 1.3 ms)
    • Other PSWs are blocked fibrillations: Longer maximal depolarizing times (Mean 2.1 ms)
    • Both populations propagate away from recording electrode
  • PSWs never observed with subcutaneous electrode
• Causes
  • Muscle denervation
  • Same spectrum as fibrillations
• Positive Sharp Waves: Illustration

Endplate Spikes

• Amplitude: 100 to 300 μV
• Duration: 2 to 4 ms
• Frequency: High; 5 to 100 Hz
• Rhythm: Irregular
• Configuration: Initial negative; Biphasic
• Generation
  • Initiated by needle electrode
  • Activity in nerve terminals generates propagated potentials in muscle fibers
• Associated with: Endplate noise

Miniature endplate potentials (MEPPs)

• Recorded near neuromuscular junctions
• Amplitude: 10 to 40 μV
• Duration: 0.5 to 2 ms
• Frequency: 20 to 40 Hz
• Configuration: Negative; Monophasic
• Generation
  • Spontaneous release of individual quanta of acetylcholine

Fasciculations

• Brief discharges of individual axons
  • Cause contraction of muscle fibers in all, or part of, motor unit
  • Produce visible rippling of muscle
  • Origin
    • May originate
      • Locations: Cell body, anywhere along course of axon or axon terminal
      • Most often originate: Distal axon
    • Properties: 2 types
      • Axonal origin
        • May have short interspike intervals
        • Refractory period 3 to 4 msec
        • ISI 5 msec
      • Proximal (Cell body) origin
        • Refractory period 17 to 46 msec
        • ISI 80 msec
  • EMG appearance: Single motor unit
  • Onset
    • Often spontaneous
    • May be precipitated by: Muscle percussion or contraction, fatigue, cold
  • Discharge frequency & patterns
    • Rhythm: Irregular
    • Size & Shape: Same as motor unit potentials
    • Rate & Disease association
      • Benign: Short interval between discharges (0.5s to 1s)
      • Motor neuron disease³⁷
        • Longer interval between discharges (3.5s)
          • Fasciculation frequency not related to disease duration or weakness
        • Accompanied by fibrillations
        • Grouped occurrence from multiple units
        • More common with strength deterioration
        • Related to cortical hyperexcitability
      • Difference from Voluntary activity (Motor unit potentials)
        • Begin firing at 4 to 8 Hz: Differs among muscles
• Differential diagnosis
  • Benign fasciculations
  • Motor neuropathies & motor neuron disorders
  • Cramp-Fasciculation syndromes
  • Metabolic disorders: Hyperparathyroid; Hyperthyroid; Hypomagnesemia
  • Pharmacologic
    • Anti-Cholinesterases; Caffeine; Theophylline; Terbutaline; Lithium
• Movie: Ultrasound image
• Variants
  • Benign fasciculations
    • Common in gastrocnemius in otherwise normal patients
    • Affect same site repetitively
    • Normal strength in fasciculating muscles
    • Exacerbated by exercise, hyperventilation & tension
    • May be associated with tendency to cramp
  • Contraction fasciculations
    • Initiated by muscle contraction
    • End when muscle contraction ceases
    • Common in motor neuron disorders: Especially prominent in BSMA in face & tongue
  • Minipolymyoclonus
    • Small amplitude movements: Especially of fingers & toes
    • Due to fasciculations of enlarged motor units
  • Synchronous fasciculations
    • Location: In muscles supplied by different nerves or on opposite sides
    • May be related to: Spinal disorder; Reflex origin by spindle afferent
  • Doublets, Triplets & Multiplets
    • Spontaneous motor units that fire in groups
    • Same significance as fasciculations
    • Most common: Hypocalcemic tetany; Distal muscles
    • May occur during voluntary contraction

Complex repetitive discharges

• Bursts of recurrently firing complex muscle action potentials
  • Discharges of groups of muscle fibers
    • Activated ephaptically
    • Firing in a regular pattern
  • Begin spontaneously or with muscle irritation
  • Rate
    • Range: 5 to 100 Hz
    • Most common frequencies: 30 to 40 Hz
    • More consistent during burst than myotonia
  • Abrupt onset & end
  • Non-rhythmic bursts
• Often associated with radiculopathy & chronic disorders
• Rarely produce muscle hypertrophy (usually unilateral)

Tetany with carpopedal spasm

• Pathophysiology
  • Abnormal Ca⁺⁺ control of Na⁺ channels
  • Axonal hyperexcitability: Due to
    • Membrane depolarization
    • Reduced action potential threshold
  • Spontaneous repetitive discharges
    • Frequency: 5 to 15 Hz most common
    • Source: Arise in peripheral axons
• Causes
  • Ion changes
    • Hypocalcemia
    • Hypoparathyroidism
    • Hypomagnesemia
  • Alkalosis: Respiratory
  • Normocalcemic tetany: Rare
    • Acquired: Associated with neoplasm
    • Hereditary: Dominant with epilepsy
• Exacerbated by: Hyperventilation; Ischemia
• EMG
  • Spontaneous axonal discharges at high rates: Up to 300 Hz
  • Repetitive discharges: Doublets or Multiplets
  • Intense spasm: Maximal interference pattern
  • Normal doublets occur at < 10 Hz
• Diagnosis: Ischemic forearm test
• Treatment: Calcium; Magnesium; Phenytoin

Barker

Geniospasm

• Vertical movements of the tip of the chin & quivering of lower lip
• Occur spontaneously; Or with stress, concentration, emotion
• Duration: Minutes
• Onset: Infancy & early childhood
• Most common: Childhood & adolescence
• Associated with nocturnal tongue biting
• Reduced frequency with increasing age
• Other causes of chin quivering: BSMA; Oral-facial-digital syndrome I

Palmaris brevis spasm syndrome²

From: M. Al-Lozi

Palmaris brevis spasm

• Palmaris brevis muscle
  • Location: Hypothenar emininence; Subcutaneous
  • Nerve: Ulnar, Superficial branch
  • Action: Creases & ripples in overlying skin
  • Not under voluntary control
• Clinical features
  • Epidemiology
    • Age of onset: 37 to 76 years
    • Males > Females
    • Triggers: Nerve damage or entrapmant; Idiopathic
  • Contractions of palmaris brevis muscle
    • Location of activity:
      • Isolated to palmaris brevis muscle
      • Bilateral or unilateral
      • None in other muscles
    • Spontaneous
    • Timing: Irregular
    • Produce dimpling of ulnar side of hand
  • Influences
    • Contractions increased: Stress; Excitement; Occasionally moving 5th finger
    • Contractions decreased: Rest; Sleep; Muscle stretch; Distal nerve block
  • Sensory change: Variable
  • Systemic (Some patients): Myalgia & Exercise intolerance
  • Course: Benign; Over years
  • Treatment: Dilantin in 1 patient
• EMG
  • Rest: High frequency discharges with irregular occurrence
  • Motor units: Normal amplitude, duration & morphology

Superior Oblique Myokymia

• Disorder of ocular motility
  • Symptom: Paroxysmal oscillopsia
  • Monocular torsional and vertical eye movements
  • Right sided predominance: 80%
  • Due to intermittent contractions of the superior oblique muscle
• Course: Recurring
• EMG: Spontaneous bursts of motor unit potentials
• Pathology: Arterial contact at root exit zone of symptomatic trochlear (IV) nerve¹⁹

Dopa responsive dystonia

• Differential diagnosis: Spastic paraparesis; Congenital myopathy

Crisponi syndrome

• Genetics: CRLF1 mutations also in cold-induced sweating syndrome
• Onset: Congenital
• Clinical
  • Movements: Often episodic
    • Contraction of the facial muscles: "Trismus"
      • Stimuli: Tactile stimuli & crying
    • Neck muscle hypertonia & opisthotonus
    • Generalized muscle contractions: Episodes
      • Occur several times each day
      • Stimuli: External
    • Seizures
    • Hypertonia
  • Anomalies
    • Facial: Large face, Chubby cheeks, Broad nose
    • Bilateral camptodactyly
    • Scoliosis
  • Breathing disorders: Central apnea; Hypopnea
  • Fever: Episodic
  • Feeding difficulty
• Course
  • Excitability may wane over 1st year
  • Death: Some patients; < 1 month to childhood

• Myoclonic ocular and facial jerks (Myorhythmia)
• Ophthalmoplegia: Supranuclear
• Dementia

Muscle Cramp Syndromes: Autosomal Dominant

• Cramps
  • Onset: Childhood to 20's
  • Peak symptoms: Teens & 20's
  • Duration: 2 to 3 minutes
  • Painful; Limbs & Trunk
  • Induction
    • Repeated movements or Maintaining a specific posture
    • Also occur during full relaxation and sleep
• Electrophysiology
  • EMG: Chronic denervation; No fasciculations or myokymia
  • NCV: Mild reduction in SNAP & CMAP amplitudes in legs
• Nerve biopsy: Reduced number of Myelinated axons

• Onset age: 10 to 15 years
• Cramps disappear after age 25
• Serum CK: High
• Pathophysiology: Neurogenic origin
• Muscle biopsy: Denervation

• Epidemiology: 3 families
• Genetics
  • Mutations: Located in glycine coding regions in exons 24 & 25
  • Other COL4A1 mutations
    • Brain small vessel disease with hemorrhage
    • Familial Porencephaly
• Collagens
• Clinical
  • Nephropathy
    • Hematuria, persistent hematuria
    • Cysts: Bilateral; Large
  • Angiopathy
    • Affects both small vessels and large arteries
    • Causes
      • Leukoencephalopathy
      • Retinal arteriolar tortuosity
      • Intracranial aneurysms
  • Cramps
    • Painful
    • Paroxysmal: Last seconds to minutes, occasionally hours
    • Triggers: Exercise; Alcohol
    • EMG: Electrically silent
  • Weakness
    • Proximal
    • Mild
• Laboratory
  • Serum CK: High, 2x to 7x
  • Brain MRI: Leukoencephalopathy

• Familial dwarfism with muscle spasms
• Satoyoshi syndrome

Sporadic Cramp Syndromes

• Onset age: Young to middle aged adults
• Clinical
  • Cramps: Muscle contractions
    • Sudden onset
    • Painful
    • Involuntary
    • Associated with palpable hardening of muscle
    • Location: Calf & Quadriceps
  • Associated with: Muscle pain & Fasciculations; Stiffness
  • Strength: Normal
• Laboratory
  • Anti-K+ channel antibodies: Some patients²⁵
  • Repetitive nerve stimulation (Posterior tibial at 1, 2 &d 5 Hz)³⁴
    • Often produces after-discharges, cramp potentials, or continuous motor unit activity
  • EMG
    • Spontaneous motor unit activity (Fasculations)
    • Slow repetitive nerve stimulation: Provokes after-discharges of motor unit action potentials
• Rule out
  • Fabry disease
  • Localized disorders
    • Post-irradiation
    • Radiculopathy
  • Neuromyotonia

• Frequency: 10% to 30% of pregnancies
• Onset: Most common in 2nd trimester
• Symptoms
  • Duration: ~ 8 weeks
  • Frequency: Every other day
  • Location: Legs
• More common
  • As pregnancy progresses
  • At night: Rarely occur only in daytime
  • ? Association with low serum magnesium
• Treatment
  • ? Magnesium lactate or citrate taken as 5mmol in the morning and 10mmol in the evening
• No relationship to
  • Other complications of pregnancy
  • Fetal outcome