Differential Diagnosis in Neurology

12.3. Myotonic Disorders of Muscle

The Non-Progressive Myotonias

The non-progressive myotonias are differentiated from the progressive dystrophies by lack of systemic features such as cataracts, cardiac defects, endocrine, pulmonary and dysmorphic features and smooth muscle involvement.

Chloride Channel Disorders

• Myotonia congenital (Thomsen's Disease)
  • Genetics: chromosome 7q
    • AD
    • Chloride channel dysfunction; reduced conductance
  • Clinical features:
    • Onset in infancy
    • Affected girls may present in late childhood
    • Prevalence is 4/100,000 people
    • Stiffness with the initiation of movement that decreases with exercise
    • Presents in hands, legs and eyelids; variation between family members
    • Cold is an aggravating factor
    • May affect chewing, speech and swallowing; occasionally causes diplopia
    • Weakness is minimal
    • Pain is slight
    • Myotonia may increase with pregnancy
    • Percussion elicits myotonia in any muscle
    • Muscle hypertrophy is common
  • EMG:
    • True myotonia; no myopathic features
  • Muscle biopsy:
    • Absence of Type II B fibers
    • Fiber hypertrophy

Recessive Myotonia

• Genetics:
  • AR; Becker's variant
  • 7q (chloride channel)
  • More common than AD from
  • Reduced chloride conductance
• Clinical features:
  • Onset 1–2nd decade; rarely in infancy
  • Prevalence: 2/100,000 people
  • Symptoms are progressive during childhood; usually presentation is in the legs
  • Myotonia may be severe
  • Generalized episodes with falling or emotional upset may induce a transient rigid state
  • Prominent muscle atrophy may occur; usually in distal muscles of the lower extremities
  • Muscle hypertrophy of the legs and gluteal muscles; upper extremities may be underdeveloped
  • Stiffness is most severe with muscle contractures after rest and improves with exercise
  • No cardiac or smooth muscle involvement
  • No cataract
  • No deterioration through adult life
  • May have depressed reflexes
  • Aggravated by cold in some patients
  • Men more severely affected than women
• Laboratory evaluation:
  • CK: usually normal; may be slightly elevated
  • EMG:
    • Clear myotonia:
      • Muscle biopsy: normal
      • A few severe AR patients demonstrate mild dystrophic features and increased internal nuclei
      • Decreased 2B muscle fibers
    • True myotonia:
      • High frequency repetitive discharges
      • Vary in frequency and amplitude
      • Dive bomber sound
      • Produced by:
        • Voluntary movement
        • Percussion
        • Needle movement
        • Repetitive stimulation

Characteristics of Pseudomyotonic

• Complex repetitive discharge
• Repetitive discharge with constant frequency
• Variation in amplitude
• Short duration
• High frequency not noted with voluntary movement but requires percussion or needle movement

Differential Diagnosis of Pseudomyotonia

• Polymyositis
• Acid maltase deficiency
• Debrancher deficiency
• Progressive muscular atrophy
• True myotonia

Sodium Channel Disorder

General Overview: Patients with sodium channel disorders may present with episodic weakness, myotonia, stiffness, spasm and mild pain. Those with primary myotonia do not experience true weakness, may vary in day to day symptomatology and may be provoked by a potassium load. Hyperkalemic periodic paralysis and paramyotonia congenital suffer periodic weakness exacerbated or provoked by cold. Hyperkalemic periodic paralysis patients may have clinically symptomatic stiffness and myotonia. There is phenotypic variation of weakness, myotonia and stiffness within families. There are rare families with hyperkalemic periodic paralysis without myotonia. There is persistence of Na⁺ conduction with failure of channel inactivation.

Sodium Channel Myotonia

All are associated with mutations of the α-subunit of the skeletal muscle voltage gated sodium channel gene (SCN4A). They present in childhood or adolescence with stiffness and are aggravated by potassium. The myotonia and stiffness may be painful. Patients are neither weak nor cold sensitive.

Myotonia Fluctuans

• Genetics:
  • AD; chromosome 17q; SCN4A gene
• Clinical features:
  • Presents in adolescence
  • Proximal > distal myotonia
  • Myotonia fluctuates in frequency and severity
  • Myotonia may be painful; may be delayed in onset after exercise (several minutes)
  • Warming up relieves symptoms
  • Cooling does not trigger or worsen myotonia
  • Involvement of extraocular muscles and trunk (distinctive)
  • Bulbar, facial and distal muscles may be severely affected
  • Well-developed musculature without hypertrophy
  • Grip and pathologic lid retraction myotonia is present

Myotonia Permanens

• Genetics: 
  • Chromosome 17q
  • AD
  • SCNA4 gene
• Clinical features:
  • Childhood presentation
  • Severe generalized myotonia
    • May affect thoracic muscles with respiratory involvement
  • Symptoms provoked and exacerbated by potassium

Acetazolamide Responsive Myotonia

• Genetics:
  • Chromosome 7
  • SCNA4 gene
• Clinical features:
  • Childhood onset
  • Axial and proximal muscles are affected more than distal muscles
    • Associated with severe spasms and acute lordosis during exacerbations
  • May respond to mexiletine as well as acetazolamide
• Laboratory evaluation:
  • EMG: true myotonia; cold induced response is electrically silent
  • Muscle biopsy: variation is fiber size; abnormalities of terminal innervation
  • Unclear differentiation between Type I and II fiber types

Paramyotonia Congenita (Von Eulenburg's Disease)

• Genetics: 
  • AD
  • Chromosome 17q23
  • SCNA4 mutation
  • Complete penetrance in both genders
  • Sodium channel mutation alters fast inactivation
• Clinical features:
  • Onset at birth (bulbar facial neck and hands are affected)
  • Paradoxical increase of myotonia with exercise (reverse of the warm up phenomenon in other myotonic disorders)
  • Myotonia induced by cold and exercise
  • May be associated with weakness; flaccid paralysis occurs rarely
  • Can last for hours after rewarming
  • Muscle hypertrophy is present
  • Overlap with hyperkalemic periodic paralysis and sodium myotonias (different mutation) that may present as:
    • Periodic paralysis not associated with cold
    • Fixed weakness between attacks
    • A variant in which weakness may occur at room temperature
  • Diamox may trigger an attack
  • Percussion and electrical myotonia
  • Spontaneous weakness without stiffness in some families
• Laboratory evaluation:
  • EMG:
    • Myotonia
    • cold induced reaction is electrically silent
  • Muscle biopsy:
    • Variation in fiber size;
    • Poor differentiation into Type I and Type II fibers
    • Changes noted in terminal twig innervation

Differential Diagnosis of Myotonia Congenita

The differential is limited to those neuromuscular diseases in which myotonia is a prominent symptom. These include the dystrophic myotonias, myotonic dystrophy 1 and 2, the sodium channel myotonias, paramyotonia-congenita, hyperkalemic periodic paralysis and the Schwartz–Jampel Syndrome.

There are no dystrophic features in congential myotonias such as frontal balding, cardiac, and endocrine, cataract and smooth muscle abnormalities that are noted in DMD 1 and 2. The recessive from (Becker's variant) is more common than the AD (Thomsen's variant), is more severe and may be associated with minor progressive weakness (particularly of the lower extremities) and may have periodic weakness initiated by movement after rest.

The sodium channel myotonias are characterized by: 1) worsening of symptoms with a potassium load; 2) exercise induced delayed onset myotonia (opposite to relief of myotonia with exercise noted in the chloride channel disorders); 3) myotonia may be painful; 4) a fluctuating course (myotonia fluctuans) may occasionally be seen with chloride channel disease.

Myotonia congenita and paramyotonia both have generalized stiffness and myotonia as well as muscle hypertrophy. Some may also worsen with cold. Differential points are that in patients with paramyotonia congenita: 1) patients have extreme cold sensitivity; 2) stiffness followed by true weakness (not seen in the true congenital myotonias) and AD and AR recessive myotonias demonstrate a warm up phenomena whereby the myotonia is relieved by exercise. Attacks of weakness in AR generalized myotonia occur during movement and after rest rather than cold.

Hypokalemic periodic paralysis and Anderson's Syndrome both suffer attacks of periodic weakness and may show some features of AR generalized myotonia with weakness. In hypo PP, the attacks of weakness are longer, provoking factors are high carbohydrate intake after exercise, extraocular and pharyngeal muscle are not affected and there is proximal muscle predominance. The weakness may last for several weeks after attacks. Anderson's cardiac variant of hypo PP is easily distinguished by the dysmorphic features of short stature, scoliosis, micrognathia and hyperthecosis. There is an associated long QT interval with cardiac arrhythmia. Schwartz–Jampal Syndrome has the characteristic dysmorphisms of short stature, bony dysplasia with metaphysical enlargement, arachnodactyly, kyphoscoliosis, and pectus carinatum. There are prominent facial abnormalities. Proximal upper and lower extremity hypertrophy with distal weakness is characteristic.

The major differential points between sodium channel myotonia and chloride channel myotonia are: 1) exacerbation of symptoms with potassium in the sodium channel disorders; 2) painful myotonia in sodium channel and not with chloride channel disease; (3) myotonia fluctuans (Na channel dysfunction) causes exercise delayed onset myotonia; 4) acetazolamide responsiveness is clear in this variant of sodium channel myotonia. Fluctuations may be seen in both disorders.

Paramyotonia congenita demonstrates more severe cold sensitivity associated with true weakness which is not seen in the sodium channel myotonias. The worsening of myotonia with exercise is immediate in paramyotonia congenita as opposed to the delay noted in myotonia fluctuans. Sodium channel myotonias do not suffer periodic paralysis. The dysmorphism and extra muscular manifestation separate the sodium channel myotonias from the dystrophic myotonias and the Schwartz–Jampel Syndrome.

Schwartz–Jampel Syndrome

• Genetics: 
  • Linked to chromosome 1q34–36 or 1p34–36 in different families
  • AR transmission
• Clinical features:
  • Dysmorphic features:
    • Dwarfism
    • Bowing and shortening of long bones
    • Metaphyseal enlargement
    • Arachnodactyly
    • Hip dysplasia
    • Kyphoscoliosis
    • Pectus carinatum
    • Micrognathia and pursed lips
    • Upward slanting eyes
    • Blepharophimosis
    • Exotropia
    • Hypoplastic larynx
    • Short neck
    • Hypertrichosis
    • Joint contractures (particularly elbows)
  • Proximal upper and lower extremity hypertrophy
  • Distal predominant weakness and atrophy
  • 20% of patients are cognitively impaired
  • Clinical phenotype varies within family members
  • Susceptible to malignant hyperthermia
  • Carpal tunnel syndrome frequently associated
  • Develop visual impairment due to blepharophimosis, lens abnormalities, small corneas
  • Gait abnormalities develop due to hip dysplasia
  • Nasal speech
• Laboratory evaluation:
  • Serum CK: mildly to moderately elevated
  • EMG: myotonic discharges; complex repetitive discharges; spontaneous action potentials from individual muscle fibers (primary hyperexcitability from the sarcolemmal membrane
  • Muscle biopsy: A few patients have myopathic changes of excessive variability of fiber size and central nuclei; may be normal
  • Electron microscopy:
    • Subsarcolemma membrane abnormalities
    • Changes in intracellular organelles
    • Abnormal distribution of isoform of contractile and structural proteins

Three Major Clinical Presentations

• Type 1A:
  • Onset in childhood
  • Bone dysplasia
  • Muscle hypertrophy
  • Dysmorphic facial features
  • Myotonia
• Type 1B:
  • Similar to Type 1A
  • Onset at birth
  • More prominent bone dysplasia
• Type 2:
  • Manifests at birth
  • Contractures
  • Severe long bone bowing (camptomelia)
  • Dysplasia of bone
  • Severe dysplasias
  • Myotonia
  • Infantile death

Differential Diagnosis

• Skeletal anomalies distinguish the illness from myotonic dystrophy
• Marden–Walker Syndrome has similar skeletal abnormalities but no myotonia or proximal muscle hypertrophy
• Stuve–Wiedmann Syndrome is similar

Rippling Muscle Disease

• Genetics: heterogeneous; one family maps to 1q41 (family from Oregon)
  • Autoimmune from associated with myasthenia gravis
• Clinical features:
  • Presents in childhoods or adolescence
  • Intermittent pain and cramps induced by exercise
  • Some patients present in adulthood
  • Mechanical percussion or contraction of muscle induces:
    • "Rippling" or rolling waves of contraction that begins proximally and spread laterally across the affected muscle
    • Biceps and quadriceps most often affected
    • Mounding of muscle (may be painful)
    • Rapid muscle contraction
    • Prolonged muscle contraction similar to percussion myotonia
  • EMG silence during contractions
  • Muscle hypertrophy of the calves
  • One family with mild proximal muscle and facial weakness
  • Variable penetrance
  • Men may be more affected than women
  • Mounding and muscle contraction more common than the rippling phenomena
  • One family; cardiac arrhythmia
  • One family; pigmenturia with exercise

Drug Induced Myotonia

• Hypocholesterolemic drugs:
  • 10/25 diazacholesterol
    • Decreased chloride conductance
  • 2–4 dichlorophenoxyacetic acid
    • Decreased chloride conductance 
• Clofibrate
• 3-Hydroxy-3methylglutaryl coenzyme A reductase inhibitors (statins)
• Inderal/beta blockers
• Fenoterol
• Terbutaline
• Colchicine
• Penicillamine
• Cyclosporine

Muscle Disorders with Myotonia

• Acid maltase deficiency
• Polymyositis/dermatomyositis complex
• Myotubular myopathy (centronuclear myopathy)
• Malignant hyperthermia

Myotonia with Myokymia, hyperhydrosis and Muscular Wasting

• Genetics: not determined
• Clinical features:
  • Benign
  • Myotonia of all muscle groups
  • Distal wasting and weakness
  • Widespread fasciculations
  • Hyperhidrosis
• Laboratory evaluation:
  • EMG: myotonia on needle movement