Periodic Paralyses

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Periodic Paralyses

• Dan Imler
• Morning Report

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Background

• The heterogeneous group of muscle diseases known
  as periodic paralyses (PP) is characterized by
  episodes of flaccid muscle weakness occurring at
  irregular intervals. Most of the conditions are
  hereditary and are more episodic than periodic.
• The frequencies of hyperkalemic PP, PC, and PAM
  are not known. Hypokalemic PP has a prevalence of
  1 case per 100,000 population.
• Thyrotoxic PP is most common in males (85) of
  Asian descent with a frequency of approximately
  2.
• Patients with HypoKPP typically begin showing
  symptoms in the first or second decade of life,
  often as they enter puberty. About 65 develop
  symptoms before the age of 16

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Pathophysiology
Sodium channel Hyperkalemic PPHypokalemic PP (HypoPP2)Paramyotonia congenitaPotassium-aggravated myotonia
Calcium channel Hypokalemic PP (HypoPP1)
Potassium channel Andersen-Tawil syndromeHyperkalemic PP or hypokalemic PP
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Pathophysiology

• The physiologic basis of flaccid weakness is
  inexcitability of the sarcolemma.
• Alteration of serum potassium level is not the
  principal defect in primary PP the altered
  potassium metabolism is a result of the PP.
• In primary and thyrotoxic PP, flaccid paralysis
  occurs with relatively small changes in the serum
  potassium level, whereas in secondary PP, serum
  potassium levels are markedly abnormal.

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Pathophysiology

• No single mechanism is responsible for this group
  of disorders.
• Thus they are heterogeneous but share some common
  traits.
• The weakness usually is generalized but may be
  localized.
• Cranial musculature and respiratory muscles
  usually are spared.
• Stretch reflexes are either absent or diminished
  during the attacks.
• The muscle fibers are electrically inexcitable
  during the attacks.
• Muscle strength is normal between attacks but,
  after a few years, some degree of fixed weakness
  develops in certain types of PP (especially
  primary PP).

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Pathophysiology

• Voltage-sensitive ion channels closely regulate
  generation of action potentials (brief and
  reversible alterations of the voltage of cellular
  membranes).
• These are selectively and variably permeable ion
  channels.
• Energy-dependent ion transporters maintain
  concentration gradients.
• During the generation of action potentials,
  sodium ions move across the membrane through
  voltage-gated ion channels.
• The resting muscle fiber membrane is polarized
  primarily by the movement of chloride through
  chloride channels and is repolarized by movement
  of potassium.
• Sodium, chloride, and calcium channelopathies, as
  a group, are associated with myotonia and PP. The
  functional subunits of sodium, calcium, and
  potassium channels are homologous.

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Muscle sodium channel gene

• Mild depolarization (5-10 mV) of the myofiber
  membrane, which may be caused by increased
  extracellular potassium concentrations, results
  in the mutant channels being maintained in the
  noninactivated mode.
• The persistent inward sodium current causes
  repetitive firing of the wild-type sodium
  channels, which is perceived as stiffness (ie,
  myotonia).
• If a severe depolarization (20-30 mV) is present,
  both normal and abnormal channels are fixed in a
  state of inactivation, causing weakness or
  paralysis.
• Thus, subtle differences in severity of membrane
  depolarization may make the difference between
  myotonia and paralysis.
• Temperature may differentially affect the
  conformational change in the mutant channel.
• Lower temperatures may stabilize the mutant
  channels in an abnormal state.
• Mutations may alter the sensitivity of the
  channel to other cellular processes, such as
  phosphorylation or second messengers.

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Calcium channel gene

• How a defect in the calcium channel might lead to
  episodic potassium movement into the cells is not
  known. Intracellular calcium is increased in
  these patients so the defect in the receptor may
  promote increased calcium entry into the cells.
• However, the mechanism may not involve calcium
  movement the dihydropyridine-sensitive calcium
  channel also acts as a voltage sensor for
  excitation-contraction coupling and the defect in
  hypokalemic periodic paralysis is associated with
  a reduced sarcolemmal ATP-sensitive potassium
  current.

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Hyperthyroidism

• The mechanism by which hyperthyroidism can
  produce hypokalemic periodic paralysis is not
  well understood.
• Thyroid hormone increases Na-K-ATPase activity
  (thereby tending to drive potassium into cells),
  and thyrotoxic patients with periodic paralysis
  have higher sodium pump activity than those
  without paralytic episodes.
• Excess thyroid hormone may therefore predispose
  to paralytic episodes by increasing the
  susceptibility to the hypokalemic action of
  epinephrine or insulin.
• It is also possible that Asians who are
  susceptible to thyrotoxic periodic paralysis have
  a mutated calcium channel which, in the euthyroid
  state, is not sufficient to produce symptoms.

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Hypokalemic periodic paralysis

• Acute attacks, in which the sudden movement of
  potassium into the cells can lower the plasma
  potassium concentration to as low as 1.5 to 2.5
  meq/L, are often precipitated by rest after
  exercise, stress, or a carbohydrate meal, events
  that are often associated with increased release
  of epinephrine or insulin.
• The hypokalemia is often accompanied by
  hypophosphatemia and hypomagnesemia.

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Hypokalemic periodic paralysis

• Hypokalemic periodic paralysis may be familial
  with autosomal dominant inheritance (in which the
  penetrance may be only partial) or may be
  acquired in patients with thyrotoxicosis.
• Asian males are at particular risk for thyrotoxic
  periodic paralysis it has been estimated, for
  example, that the risk of developing the disease
  is 15 to 20 percent in hyperthyroid Chinese
  subjects.
• In another report, 44 of 45 affected Chinese
  patients were male. In this study, only 29
  percent were known to be hyperthyroid, 60 percent
  had clinical symptoms compatible with
  thyrotoxicosis, and 11 percent had subclinical
  disease.

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Hypokalemic periodic paralysis

• The recurrent attacks with normal plasma
  potassium levels between attacks distinguish
  periodic paralysis from other causes of
  hypokalemic paralysis, such as that seen in some
  cases of severe hypokalemia due to distal renal
  tubular acidosis (RTA).
• However, the ability to distinguish among these
  disorders is sometimes clinically difficult, as
  characteristic signs and symptoms may be absent.

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History

• Severe cases present in early childhood and mild
  cases may present as late as the third decade.
• A majority of cases present before age 16 years.
• Weakness may range from slight transient weakness
  of an isolated muscle group to severe generalized
  weakness.
• Severe attacks begin in the morning, often with
  strenuous exercise or a high carbohydrate meal on
  the preceding day.
• Attacks may also be provoked by stress, including
  infections, menstruation, lack of sleep, and
  certain medications (eg, beta-agonists, insulin,
  corticosteroids).
• Patients wake up with severe symmetrical
  weakness, often with truncal involvement.

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History

• Mild attacks are frequent and involve only a
  particular group of muscles, and may be
  unilateral, partial, or monomelic.
• This may affect predominantly legs sometimes,
  extensor muscles are affected more than flexors.
• Duration varies from a few hours to almost 8 days
  but seldom exceeds 72 hours.
• The attacks are intermittent and infrequent in
  the beginning but may increase in frequency until
  attacks occur almost daily.
• The frequency starts diminishing by age 30 years
  it rarely occurs after age 50 years.

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History

• Permanent muscle weakness may be seen later in
  the course of the disease and may become severe.
• Hypertrophy of the calves has been observed.
• Proximal muscle wasting, rather than hypertrophy,
  may be seen in patients with permanent weakness.

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Lab Studies

• Serum potassium level decreases during attacks,
  but not necessarily below normal.
• Creatine phosphokinase (CPK) level rises during
  attacks.
• In a recent study, transtubular potassium
  concentration gradient (TTKG) and
  potassium-creatinine ratio (PCR) distinguished
  primary hypokalemic PP from secondary PP
  resulting from a large deficit of potassium.
  Values of more than 3.0 mmol/mmol (TTKG) and 2.5
  mmol/mmol (PCR) indicated secondary hypokalemic
  PP.
• ECG may show sinus bradycardia and evidence of
  hypokalemia (flattening of T waves, U waves in
  leads II, V2, V3, and V4, and ST segment
  depression).

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Nerve conduction studies

• The compound muscle action potential (CMAP)
  amplitude declines during the paralytic attack,
  more so in hypokalemic PP.
• Sensory nerve conduction study findings are
  normal in most patients with PP.
• Nerve conduction findings may be abnormal when
  the patient has peripheral neuropathy associated
  with thyrotoxicosis.

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Exercise test in periodic paralyses

• This is one of the most informative diagnostic
  tests for PP.
• The test is based on 2 previously described
  observations that CMAP amplitude is low in the
  muscle weakened by PP and the weakness can be
  induced by exercise.
• Recording electrodes are placed over the
  hypothenar muscle and a CMAP is obtained by
  giving supramaximal stimuli.
• The stimuli are repeated every 30-60 seconds for
  a period of 2-3 minutes, until a stable baseline
  amplitude is obtained.

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Provocative testing

• Oral glucose loading test Glucose is given
  orally at a dose of 1.5 g/kg to a maximum of 100
  g over a period of 3 minutes with or without
  10-20 units of subcutaneous insulin.
• Muscle strength is tested every 30 minutes. Full
  electrolyte profile is tested every 30 minutes
  for 3 hours and hourly for the next 2 hours.
• Weakness usually is detected within 2-3 hours,
  and if not patients should be considered for
  intravenous (IV) glucose challenge.

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Provocative testing

• Intra-arterial epinephrine test Two mcg/min of
  epinephrine is infused into the brachial artery
  for 5 minutes and the amplitude of the CMAP is
  recorded from a hand muscle. CMAPs are recorded
  before, during, and 30 minutes after infusion.
• The result is considered positive if a decrement
  of more than 30 occurs within 10 minutes of
  infusion.

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Muscle biopsy

• The most characteristic abnormality is the
  presence of vacuoles in the muscle fibers.
  Sometimes, they fill the muscle fibers, and in
  some patients, groups of vacuoles may be noted.
• These changes are more marked in hypokalemic PP
  than in hyperkalemic PP. In the latter, the
  vacuoles are small and peripherally located.
• Signs of myopathy include muscle fiber size
  variability, split fibers, and internal nuclei.
  Muscle fiber atrophy may be present in clinically
  affected muscles.
• Tubular aggregates are seen in type II fibers.
  They are subsarcolemmal in location. This
  abnormality is seen only in hypokalemic PP.

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Prevention and treatment

• The oral administration of 60 to 120 meq (dose
  dependent in pediatrics) of potassium chloride
  usually aborts acute attacks of hypokalemic
  periodic paralysis within 15 to 20 minutes.
  Another 60 meq can be given if no improvement is
  noted.

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Prevention and treatment

• However, the presence of hypokalemia must be
  confirmed prior to therapy, since potassium can
  worsen episodes due to the normokalemic or
  hyperkalemic forms of periodic paralysis.
• Furthermore, excess potassium administration
  during an acute episode may lead to posttreatment
  hyperkalemia as potassium moves back out of the
  cells.
• In addition, potassium should not be administered
  in dextrose containing solutions as patients have
  an exaggerated insulin response to carbohydrate
  loads.

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Prevention and treatment

• Prevention of hypokalemic episodes consists of
  the restoration of euthyroidism in thyrotoxic
  patients and the administration of a ß-adrenergic
  blocker in either familial or thyrotoxic periodic
  paralysis.
• ß-blockers can minimize the number and severity
  of attacks and, in most cases, limit the fall in
  the plasma potassium concentration.
• A nonselective ß-blocker (such as propranolol)
  should be given ß1-selective agents are less
  likely to inhibit the ß2 receptor-mediated
  hypokalemic effect of epinephrine and may
  therefore be less likely to prevent paralytic
  episodes.
• Other modalities that may be effective for
  prevention include K supplementation, K-sparing
  diuretics, a low-carbohydrate diet, and the
  carbonic anhydrase inhibitor acetazolamide.