Differential Diagnosis in Neurology

12.4. Periodic Paralysis

Hyperkalemic Periodic Paralysis (Hyper PP)

• Genetics: chromosome 7q23:
  • Mutations of the α-subunit of the muscle voltage gated sodium channel gene (SCN4A); Thr704met mutation is common
  • Complete penetrance in both genders is usual
  • Two families with clinical hyper PP without myotonia:
    • Mutation in a potassium channel
  • Most common mutations are Thr704met and met1592 Val
  • Dysfunction of slow inactivation of sodium channels
  • Potassium channel variant
    • Mutation in the KCNE3 gene
• Clinical features:
  • Onset first or second decade (usual is 1–10 years)
  • Attacks of generalized weakness (flaccid paralysis)
  • Vary in frequency; intermittent to daily
  • Usually lasts for 20 minutes to one hour
  • Most often occur in the morning; may occur at any time; legs to arms to neck (ocular extremely rare)
  • Attacks decrease during middle age
  • Premonition of oncoming attacks by a sense of muscle discomfort
  • Provoked by increased potassium, cold, fasting, and exercise
  • Most commonly associated with myotonia, pathologic lid retraction; tongue myotonia
  • May have associated paresthesias
  • Potassium is usually (4.5–8) during attacks; a few patients it may be normal during attacks of weakness
  • Attacks may develop during rest after exercise
  • Attacks may be aborted by mild exercise ("walking off attacks")
  • Paralysis, areflexia, myotonia and Chvostek's sign may be seen concomitantly
  • May have variants in which myotonia is consistently absent
  • Cranial nerves and respiratory muscles are usually spared; permanent weakness may develop
  • During attacks moving the extremities and calcium gluconate may be effective
  • Precipitating factors: exercise followed by rest, cold, hunger, stress, ice water.
  • Diamox, hydrochlorothiazide and frequent meals are preventative
• Laboratory evaluation:
  • Potassium: may be normal; usually 4–8 mm; severe attacks may develop at potassium levels of 6 mm or less (would not affect a normal patient)
  • Calcium may be depressed (Chvostek's sign)
  • EKG: Hyperkalemic charges
  • EMG:
    • May demonstrate myotonia; high frequency discharges, occasional fibrillation potentials
      • CMAP amplitude may decline in proportion to the degree of weakness
    • Myopathic MUAPs may be noted in some patients between attacks
    • Myotonic discharge decrease as weakness progresses
    • Increase in CMAP early in the prolonged exercise test which decline over 20–40 minutes
    • There is no decrement of the CMAP with the short exercise test or with cooling
  • CK: May be slightly elevated during an attack
  • Muscle biopsy:
    • Vacuolar myopathy (vacuoles are in the center of the fibers)
    • Tubular aggregates may be seen
  • DNA testing may be definitive

Hypokalemic Periodic Paralysis (Hypo PP)

• Genetics:
  • Hypo PP (type I):
    • Chromosome 1q31–32
    • CACNAIS
    • Encodes an L-hyper dihydropyridine sensitive calcium channel
  • Hypo PP (Type II)
    • Point mutations of α-subunit of the sodium channel skeletal muscle gene cause phenotypic Hypo PP
• Clinical features:
  • Most common of the periodic paralysis
  • Onset in teens; 7–21 years of age
  • Attacks may occur daily or only two in a lifetime
  • Attacks last hours to days
  • Provoking factors:
    • Sleep (attacks in the morning)
    • High carbohydrate and sodium ingestion
    • Following exercise
    • Insulin
    • Glucose
    • Stress
    • Menses
    • Alcohol
    • Chinese food
  • Serum potassium usually 2–3 meq/dl during attacks
  • Proximal greater than distal weakness; flaccid
  • Paresthesias are common; patients may complain that gastrocnemius muscles feel tight
  • Cranial nerves and respiratory muscles are spared
  • After multiple attacks proximal muscle weakness is permanent
  • May have rare clinical myotonia between attacks
  • Patterns of a characteristic attack:
    • Legs > arms > trunk > neck
    • Cranial nerves and respiratory muscles are unaffected (rarely they are during a severe attack)
    • Proximal greater than distal weakness
    • Rarely: there is thirst, constipation and oliguria
    • Recovery occurs in the reverse order of onset; may be accompanied by diuresis and sweating
    • Examination:
      • Flaccid paralysis
      • Muscles feel swollen and tight (particularly the gastrocnemius)
      • No elicitable myotactic reflex
      • Absent deep tendon reflexes
  • Focal limb weakness may be seen
  • Potassium levels between 2–3 mEq/liter may be associated with:
    • Sinus or brady arrhythmias
    • May not correlate with expected EKG patterns
  • Attacks occur more frequently in men than woman
  • Only eyelid myotonia may be present
  • Proximal weakness develops in adulthood irrespective of frequency of attacks
• Laboratory evaluation:
  • EMG: during an attack no response to electrical stimuli; no myotonia
  • Muscle biopsy:
    • Dilatation of the sarcoplasmic reticulum
    • T-system may be PAS+ and can contain Ca⁺⁺
    • Occurs in both Type I or Type II fibers
    • Tubular aggregates are seen in Type II fibers

Differential Diagnosis of the Periodic Paralysis

Structural lesions of the neck particularly C1-C2 dislocation with cord compression. The cardinal features are an appropriate segmental or dropped sensory level. Patients suffer complete or partial quadriparesis. If the process is epidural, pain is the predominate part of the presentation. Bowel and bladder are involved. Prior to paralysis, ataxia may be noted as the outside lateral components of the spinal cord are the dorsal and ventral spinocerebellar pathways. Reflexes may be increased due to disinhibition of the anterior horn cells or decreased or absent due to spinal shock. Babinski sign is present.

If the problem is intramedullary such as a syrinx, there is disassociated sensory loss (pain and temperature greater than lemniscal properties or the reverse if the syrinx is lateral and compromises the lateral cervical nucleus). There is segmental atrophy and weakness hyperactive lower extremities reflexes and decreased or absent reflexes at the level of the syrinx.

Dural AVMs, most commonly are accompanied by a more apoplectic onset than the periodic paralysis, are dorsally at thoracic levels and are accompanied by bowel and bladder dysfunction. Depending on the size and extradural spread, patients may have hyperactive reflexes and Babinski signs or spinal shock. A sensory and motor level is present.

Spinal cord tumors and hemangiomas as well as intraparenchymal metastases have a different and more indolent tempo of symptoms and signs.

Transverse myelitides, either autoimmune or viral are frequently accompanied by a band-like segmental level of pain or pressure (often at T4–T6 in multiple sclerosis), motor and sensory level, Babinski sign and Beevor's sign.

Myasthenia gravis is dominated by cranial nerve abnormalities, particularly ocular, without sensory loss and with maintained reflexes. Babinski signs are absent. Depressed level of consciousness occurs in patients with respiratory compromise and CO₂ narcosis. Arrhythmias are common under these circumstances.

Guillain-Barré syndrome usually starts with an ascending paralysis that compromises respiration. Paralysis and loss of reflexes predominate. If cranial nerves are involved during complete paralysis there will be a bilateral peripheral facial paralysis. The recurrent variety of chronic inflammatory demyelinating polyneuropathy has frequent mild sensory findings (particularly perioral at the onset of an exacerbation) with loss of reflexes. Attacks last for weeks.

The primary differential diagnosis for hyperkalemic periodic paralysis is the Hypo PP form, secondary forms of hyper PP and Anderson's syndrome. Hypokalemic attacks are precipitated by sleep, high carbohydrate and sodium meals, and rest after exercise and will last for hours. Hyperkalemic attacks start earlier in life, last for 20 minutes to an hour, are complicated by myotonia. Potassium relieves or prevents attacks of Hypo PP. Cold and rest after exercise induces attacks in both types of periodic paralysis. Southeast Asians have a high incidence of Hypo PP. Hypertelorism, short stature, broad base of the nose and cardiac arrhythmias (predominately long QT interval) distinguish Andersen's Syndrome. Hyper PP and AR myotonia may suffer the combination of myotonia and periodic weakness. The later condition demonstrates a greater degree of myotonia as well as distal weakness. Hyper PP demonstrates a progressive decline in the CMAP over 20–40 minutes which is not seen in the congenital myotonias.

Secondary causes of Hyper PP occur at a later age and often have an atypical presentation with no family history.

Hypo PP is differentiated from Hyper PP by an onset in adolescence rather than childhood. As noted earlier Hypo PP is precipitated by carbohydrate ingestion particularly after exercise and symptoms may be abated by potassium ingestion. Hyper PP frequently follows potassium ingestion and is helped by carbohydrate ingestion. Cold affects Hyper PP more than Hypo PP, but rest after exercise may provoke attacks. Potassium levels are generally high during attacks of Hyper PP and low during Hypo PP. Severely low or high potassium may not always correlate with expected EKG manifestations. Myotonic discharges on EMG rules out Hypo PP. The prolonged exercise test produces a decremental response in both. A subset of Hypo PP patients never suffer periodic attacks and present with adult onset proximal myopathy suggestive of polymyositis. Inclusion body myositis frequently presents at a similar age, but is distinctive for steroid resistance and forearm contractures and quadriceps involvement. Muscle biopsy of Hypo PP reveals central vacuoles whereas rimmed vacuoles are noted in IBM. Hypo PP is AD, which may be helpful in discovering women with proximal weakness but without periodic attacks. Secondary causes of Hypo PP occur with later age at onset, no family history or an atypical presentation.

Secondary hyperkalemic periodic paralysis that may have concomitant myotonia:

• Renal failure
• Adrenal failure
• Hypoaldosteronism
• Metabolic acidosis
• Potassium sparing diuretics

The medical conditions underlying these entities are usually clear. The potassium most often is greater than 6 mEq/dl and EKG changes more closely follow the potassium level.

Thyrotoxic Periodic Paralysis

• Genetics: highest incidents in patients of Southeast Asian ancestry
  • Possibly AD
• Clinical presentation:
  • Older age at presentation (20–40 years of age)
  • Provoked by high carbohydrate ingestion
  • More prevalent in men than women
  • Sodium channel inactivation secondary to sarcolemmal depolarization; loss of membrane excitability
  • Responds to normalization of thyroid function

Secondary Hypokalemic Periodic Paralysis

• Hypo PP with hyperthyroidism
• Renal tubular acidosis:
  • Low potassium triggers attacks of flaccid paralysis
  • Seizures secondary to concomitant hypocalcemia
• Hyperaldosteronism (secreting adenoma):
  • Primary (Conn's disease):
    • Abnormally high aldosterone secretion rate
    • Increased plasma and urinary aldosterone
    • Abnormally low plasma rennin activity
  • May be seen with adrenal hyperplasia or morphologically normal adrenal glands
• Barter's syndrome
• Villous adenoma of the intestine or colon
• Alcoholism
• Diuretics
• Licorice ingestion (glyceric acid)
• Amphotericin B
• Long standing corticosteroid use
• Lithium
• EMG:
  • Prolonged exercise test causes a progressive decline in the CMAP

Primary Normokalemic Periodic Paralysis

• Least common of the periodic paralysis
• Clinical presentation:
  • Resembles hyperkalemic periodic paralysis
  • Serum potassium is not elevated even during the most severe attacks
  • Paralysis induced or exacerbated by potassium
  • Attacks can be improved by sodium

Differential Diagnosis of Hypokalemic Periodic Paralysis Hypokalemic PP (1qCACN14A)

• Hypo PP
• Renal tubular acidosis
• Barter's syndrome
• Villous adenoma
• Alcoholism
• Diuretic (potassium wasting)
• Licorice ingestion (glyceric acid)
• Amphotericin B
• Prolonged corticosteroid ingestion
• Thyrotoxicosis (primary)
• Barium salt intoxication
• Thallium poisoning

Differential Diagnosis of Hyperkalemic Periodic Paralysis

• Addison's disease
• Induced aldosterone deficiency
• Chronic heparin therapy
• Rhabdomyolysis
• Drugs:
  • Triamterene
  • Spironolactone
  • Potassium supplements
• Geophagia

Differential Diagnosis of Normokalemic Periodic Paralysis

• Guanidine
• Myasthenia
• High cervical cord structural lesions
• Sleep paralysis (narcolepsy)
• Seizures (atonic)
• Multiple sclerosis
• Autoimmune recurrent neuropathies
• Recurrent neuropathies
• Eaton-Lambert Syndrome
• Metabolic abnormalities (usually with decreased level of consciousness):
  • Hypoglycemia
  • Hepatic insufficiency
  • Urea cycle enzyme defects
  • Mitochondrial defects (Leigh's disease)
  • Acute intermittent porphyria
  • Variegate porphyria
  • Coproporphyrinuria
• Intermittent intoxications