Periodic paralysis or rather paralyses is a heterogeneous group of muscle diseases known as is characterized by recurrent episodes of flaccid muscle.
Most of these conditions are hereditary.
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Types of Periodic Paralysis
Periodic paralysis can be divided conveniently into primary and secondary disorders.
Primary Periodic Paralysis
Primary periodic paralysis are
- Hereditary
- Associated with alteration in serum potassium levels
- Myotonia sometimes coexists
- There is a defect in ion channels.
These are also called familial Periodic paralysis or myoplegia paroxysmalis familiaris. These are rare, transmitted genetically and often triggered by common triggers such as cold, heat, carbohydrate meals, stress or excitement and physical activity.
Malfunctions in the ion channels in skeletal muscle cell membranes causes leakage of electrically charged ions to leak in or out of the muscle cell, causing paralysis of the muscles.
All these conditions have an autosomal dominant inheritance but there is with considerable variation in penetrance.
That means that only one gene is required to cause the disorder but not all family members who share the gene are affected to the same degree).
Following diseases are included in primary periodic paralysis-
Hypokalemic periodic paralysis
This is a disorder where the potassium leaks into the muscle cells from the bloodstream.
Hyperkalemic periodic paralysis
The potassium leaks out of the cells into the bloodstream.
Paramyotonia congenita
This often accompanies hyperkalemic periodic paralysis, but may present alone.
There is muscle contracture that develops during exercise or activity. Paramyotonia congenita attacks may also be triggered by a low level of potassium in the bloodstream.
Andersen-Tawil syndrome
It is a form of periodic paralysis that includes significant heart rhythm problems, fainting and risk of sudden death. Potassium levels may be low, high, or normal during attacks.
Other skeletal abnormalities like scoliosis (curvature of the spine), syndactyly), clinodactyly, micrognathia and low-set ears may be present.
Patients need to have another form of periodic paralysis to have the Andersen-Tawil. If a patient has hypo or hyper periodic paralysis they have a 50% chance of getting Andersen-Tawil. They just have to have the gene that causes it.
Secondary Periodic Paralysis
Thyrotoxicosis periodic paralyses are the most common secondary hypokalemic PP. Thyrotoxicosis periodic paralyses is most common in adults aged 20-40 years. Hyperinsulinemia, a carbohydrate load, and exercise are important in precipitating paralytic attacks. Weakness is proximal and, if severe, may involve respiratory or bulbar muscles. Attacks last hours to days.
Thyrotoxic periodic Paralysis is a rare condition that occurs only in people with high thyroid hormone levels (thyrotoxicosis). It is common in Asian and Hispanic men.
It is cause of periodic paralysis but not all authors consider it familial though there is a familial clustering of TPP indicating unmasking of an inherited disease (which is sporadic) by thyrotoxicosis.
The frequencies of hyperkalemic periodic paralysis, paramyotonia congenita , and potassium-aggravated myotonias are not known
Pathophysiology
Muscles normally contract when electric impulses reach them. This excitability of the muscles is brought about by sarcolemma.
During periodic paralysis, sarcolemma or muscle membrane becomes inexcitable.
Thus muscle fibers are electrically inexcitable during the attacks.
The altered levels of potassium in the serum are due to the altered potassium metabolism is a result of the periodic paralysis and is not principal cause in itself.
Moreover, the potassium level changes are not very marked in periodic paralysis as compared to when potassium level changes are prime cause.
The weakness of periodic paralysis is usually generalized but may be localized.
Cranial muscles and respiratory muscles usually are spared.
Stretch reflexes are either absent or diminished during the attacks.
Between the attack, though, the muscle strength is normal.
Some degree of fixed weakness develops in some cases after many years.
All forms of primary periodic paralyses are either autosomal dominant inherited or sporadic (most likely arising from point mutations).
Different types of paralyses and their features
Hyperkalemic periodic paralysis
As the name suggests there is increase in potassium levels of serum during this paralysis. This usually occurs during rest after a period of strenuous exercise or during fasting.
Potassium intake, cold, ethanol, or stress are triggering factors. Muscle pains and paresthesias may occur.
It may be relieved by mild prolonged exercise or carbohydrate intake.
Myotonia is present in the majority of patients in between the attacks. Some families have no myotonia.
Interictal weakness is usually not present and if so, is mild.
The age of onset is < 10 years. Weakness starts in the thighs and calves, which then spreads to arms and neck. Often a myotonic lid lag (lagging of upper eyelid on downward gaze) may be the earliest symptom.
Proximal weakness predominates but distal muscles may become involved after vigorous exercise.
Usually the attack resolves within an hour but may last up to 4 hours.
Abdominal muscle weakness may cause bowel and bladder dysfunction but sphincters are often spared.
Respiratory muscles are rarely involved.
Hypokalemic periodic paralyses
It is associated with reduction in serum potassium levels during the attack and is of two types
- HypoPP1 (calcium channel mutation) – earlier onset< 10 yrs, lasts longer, more frequent fixed proximal weakness, vacuolar myopathy on biopsy, not aggravated by acetazolamide
- HypoPP2 (sodium channel mutation) – onset around 16 years, last about hour and no fixed weakness, tubular aggregates in muscle biopsy, aggravation by acetazolamide
Majority of cases present before age 16 years. Severe cases present in early childhood and mild cases may present as late as the third decade.
The paralysis attack may range from a transient weakness of an isolated muscle group to severe generalized weakness.
This paralysis is characterized by early morning attacks often with a history of strenuous exercise or a high carbohydrate meal on the preceding day.
Patients wake up with severe symmetrical weakness, often with truncal involvement.
Mild attacks are frequent and involve a particular group of muscles. These may be unilateral, partial, or involve single limb. Legs are predominantly involved in such attacks.
Attacks may also be provoked by stress, infections, menstruation, lack of sleep, and drugs like beta-agonists, insulin, corticosteroids.
Attacks may last from less than 72 hours to 7 days.
These are 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.
Urinary output is decreased during the attack because water accumulates intracellularly in muscles.
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.
Paramyotonia congenital
- Myotonia worsens with activity (paradoxical myotonia) or cold temperatures.
- Symptoms are most pronounced in the face, tongue, and hand muscles
- Lesser involvement of lower limb.
- Muscle hypertrophy > 30% of patients.
- Myotonia lasts for seconds to minutes, but weakness may persist for hours and sometimes days.
- Frequency of paralytic attacks declines with age.
- Episodic weakness also may develop after exercise or cold temperatures and usually lasts only a few minutes, but may last as long as days.
- In some cases, lowering the serum potassium level precipitates the attacks.
Andersen-Tawil syndrome
Andersen-Tawil syndrome is characterized by variable expression of the triad of
- Dysmorphic features
- Periodic paralysis
- Cardiac arrhythmias.
Patients may have short stature, hypertelorism, low-set ears, micrognathia, fifth finger clinodactyly, and scoliosis. Episodic weakness lasting a few hours to several days may arise spontaneously but usually follows physical activity. The periodic paralysis is not associated with myotonia.
ECG abnormalities
- Prolonged QT interval and ventricular arrhythmias [most common]
- Premature ventricular contractions
- Ventricular bigeminy
- Supraventricular and ventricular tachycardias
- Prominent U waves
- Torsades de pointes.
- Bidirectional ventricular tachycardia,
- Beat-to-beat alternating QRS axis polarity
Patients may be completely asymptomatic or may feel symptoms like palpitations, syncopal episodes, and cardiac arrest. Sudden cardiac death is less frequent in Andersen-Tawil syndrome than other causes of long QT syndrome.
Lab Studies
Hypokalemic periodic paralysis
The potassium levels are decreased but not necessarily below normal.
Creatine phosphokinase (CPK) level rises during attacks.
Transtubular potassium concentration gradient (TTKG) and potassium-creatinine ratio are used to distinguish it from potassium deficiency. Values of more than 3.0 mmol/mmol (TTKG) and 2.5 mmol/mmol (PCR) indicated secondary hypokalemic PP.
Similarly, a random urine potassium-creatinine ratio < 1.5 is indicative of poor intake, gastrointestinal loss, and potassium shift into the cells.
ECG may show sinus bradycardia and evidence of hypokalemia (flattening of T waves, U waves in leads II, V 2 , V 3 , and V 4 , and ST-segment depression).
Hyperkalemic periodic paralysis
Serum potassium level may increase but rarely reaches cardiotoxic levels. Serum sodium level may fall with rise in potassium level rises due to sodium entry into the muscle. The eater follows and hemoconcentration results.
Hemoconcentration further causes hyperkalemia.
Hyperregulation at the end of an attack may lead to hypokalemia water diuresis, creatinuria, and an increase in CPK level.
ECG may show tall T waves.
Electrodiagnosis
Nerve conduction studies
Sensory nerve conduction study findings are normal in most patients with periodic paralyses. Nerve conduction findings may be abnormal when the patient has peripheral neuropathy associated with thyrotoxicosis.
Repetitive nerve stimulation in hyperkalemic periodic paralysis may show a decrement in compound muscle action potential which gets accentuated by cooling
Muscle cooling
Cooling of muscle to 20°C leads to force reduction and prolonged twitch-relaxation in PC and hyperkalemic periodic paralyses. Muscle paralysis is prolonged and persistent even after rewarming. The best method to cool is to immerse the whole limb in ice water.
Exercise test
This is one of the most informative diagnostic tests base on observations: that CMAP amplitude is low in the muscle weakened by periodic paralyses and the weakness can be induced by exercise.
Recording electrodes are placed over the hypothenar muscle and a compound muscle action potential [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.
Two kinds of exercise tests can be performed.
A short exercise test is one in which the muscle is contracted strongly in isometric conditions for 10-12 seconds and CMAPs are obtained 2 seconds immediately after exercise an then every 10 seconds for 50 seconds.
In the long exercise test, the muscle is contracted for 5 minutes, with brief (3- to 4-second) rests every 15 seconds to prevent muscle ischemia.
The compound muscle action potential is recorded every minute during exercise and every 1-2 minutes after exercise for a period of 30 minutes or until no further decrement is observed in the amplitude of compound muscle action potential.
A decrease of more than 40% in the compound muscle action potential amplitude after 20 minutes is considered abnormal and highly suggestive of periodic paralyses. The test however, does not differentiate between different types.
Provocative Testing
Provocative testing is dangerous and is not the first line of diagnostic testing.
The test should be done in an intensive care setting and should be avoided in patients serum potassium disturbances, diabetes mellitus, or renal or cardiac dysfunction. Measures for correction should be at disposal.
Hypokalemic periodic paralyses
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. If weakness is not found, intravenous glucose challenge may be tried.
Intravenous glucose challenge
Glucose is infused IV over a period of 1 hour at a dose of 3 g/kg to a maximum of 200 g (in water at 2 g/5 mL). If no weakness is detectable at 30 minutes, 0.1 U/kg of IV insulin is given. Insulin can be repeated in 60 minutes if weakness is not detected.
Strength is evaluated every 15 minutes for 2 hours. Electrolytes, glucose, and carbon dioxide are measured every 30 minutes and once more after the patient becomes weak. ECG is repeated every 30 minutes. Severe hypoglycemia must be watched for and corrected when needed.
Intra-arterial epinephrine test
2 mcg/min of epinephrine is infused into the brachial artery for 5 minutes and the amplitude of the compound muscle action potential is recorded from a hand muscle. Compound muscle action potential are recorded before, during, and 30 minutes after infusion. The result is considered positive if a decrease of more than 30% occurs within 10 minutes of infusion.
Hyperkalemic periodic paralyses
Potassium chloride 0.05 g/kg in a sugar-free liquid is given orally over 3 minutes in a fasting state, just after exercise. If no weakness occurs, an additional amount of potassium chloride (0.10-0.15 g/kg) is given. Electrolytes, ECG, and strength are tested every 15 minutes for 2 hours and then every 30 minutes for the next 2 hours. Weakness usually is detected between 90-180 minutes after initiation of testing.
Histologic Findings
- Signs of myopathy
- Muscle fiber size variability
- Split fibers
- Internal nuclei
- Presence of vacuoles in the muscle fibers.
- More marked in hypokalemic PP than in hyperkalemic PP.
- Tubular aggregates – seen only in hypokalemic PP.
Treatment of Periodic Paralysis
Treatment is often necessary for acute attacks of hypokalemic periodic paralysis but seldom for hyperkalemic periodic paralysis. Prophylactic treatment is necessary when the attacks are frequent.
Hypokalemic periodic paralyses
During attacks, oral potassium supplementation is preferable to IV supplementation. Potassium chloride is the preferred agent for an acute attack (assuming a normal renal function).
Usual initial dose is 60 mEq. Additional 0.3 mEq/kg may be given if no response. Should not exceed >200 mEq
Intravenous potassium is reserved for cardiac arrhythmia or airway compromise due to ictal dysphagia or accessory respiratory muscle paralysis.
For prophylaxis, dichlorphenamide, a carbonic anhydrase inhibitor 50-100 mg BID may be considered for the management of primary hypokalemic periodic paralysis.
Acetazolamide is is administered at a dose of 125-1500 mg/d in divided doses.
Triamterene and spironolactone are second-line drugs to be used in patients in whom the weakness worsens, or in those who do not respond to carbonic anhydrase inhibitors.
Approximately 50% of genotyped patients with HypoPP respond to acetazolamide.
Hyperkalemic periodic paralyses
Fortunately, attacks are usually mild and rarely require treatment. Weakness promptly responds to high-carbohydrate foods. Beta-adrenergic stimulants, such as inhaled salbutamol, also improve the weakness but should not be used in patients with cardiac arrhythmias.
In severe attacks, therapeutic measures that reduce hyperkalemia are utilized.
Thiazide diuretics and carbonic anhydrase inhibitors [Dichlorphenamide ] are used as prophylaxis. Occasionally, thiazide diuretics may result in paradoxical hypokalemic weakness, which responds to potassium supplementation.
Paramyotonia congenita
Because weakness is uncommon, treatment is aimed at reducing myotonia. While the above-mentioned diuretics can be tried, they are often not effective. Mexiletine has been shown to be helpful but is contraindicated in patients with heart block.
Andersen-Tawil syndrome
Carbonic anhydrase inhibitors are used for preventing periodic paralysis.
Potassium supplementation prevents periodic paralysis and also reduces cardiac arrhythmia, shortening the QT interval.
For the control of cardiac symptoms, β-blockers or calcium channel blockers may be used.
Thyrotoxic Periodic Paralysis
In the acute phase of an attack, administration of potassium will quickly restore muscle strength and prevent complications. Rebound hyperkalemias should be watched for.
Beta blocker, such as propranolol counter the effects of increased thyroid hormones level.
Treatment of the thyroid disease usually leads to resolution of the paralytic attacks.