Periodic Paralyses Workup

Hypokalemic periodic paralyses

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 (K/C) 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.

A random urine potassium-creatinine ratio (K/C) of less than 1.5 is indicative of poor intake, gastrointestinal loss, and potassium shift into the cells. If hypokalemia is associated with paralysis, one should consider hyperthyroidism or familial or sporadic periodic paralysis.

Some of the medical conditions associated with hypokalemia are included in the table below (modified from Assadi 2008 ^[13] ).

Table 5. Medical Conditions Associated With Hypokalemia (Open Table in a new window)

 

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 paralyses

Serum potassium level may increase to as high as 5-6 mEq/L. Sometimes, it may be at the upper limit of normal, and it seldom reaches cardiotoxic levels. Serum sodium level may fall as potassium level rises. This results from sodium entry into the muscle. Water also moves in this direction, causing hemoconcentration and further hyperkalemia. Hyperregulation may occur at the end of an attack, causing hypokalemia. Water diuresis, creatinuria, and an increase in CPK level also may occur at the end of an attack.

ECG may show tall T waves.

Table 6. Diagnostic Studies of Hypokalemic and Hyperkalemic Periodic Paralyses (Open Table in a new window)

Electrodiagnosis and provocative testing can be performed for periodic paralysis.

Nerve conduction studies

The compound muscle action potential (CMAP) amplitude declines during the paralytic attack, more so in hypokalemic periodic paralysis. 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 CMAP (accentuated by cooling) that is steadily progressive without tendency to recover as in myasthenia gravis. The amount of decrement is variable and increases with increased frequency of stimulation. In some patients, it is seen only with stimulation greater than 25 Hz. ^[14]

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.

As the muscle depolarizes at different temperatures in different patients, a muscle temperature of 20-25°C is preferable. This is best achieved by immersing the whole arm in ice water. This alone causes weakness in many patients.

Short periods of exercise (2-3 1-second short exercises) enhance the weakness and result in a very small CMAP. ^[14]

Exercise test in periodic paralyses

This is one of the most informative diagnostic tests for periodic paralyses. The test is based on 2 previously described 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 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. CMAPs are obtained 2 seconds immediately after exercise an then every 10 seconds for 50 seconds. In hyperkalemic periodic paralyses patients carrying T704M mutations, increase in CMAP amplitude (approximately 23%) occurs. In HypoPP1 and HypoPP2 patients, the increase is not significantly different from the control subjects (about 5%).

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 CMAP 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 CMAP. Percentage of decrement is calculated by subtracting the smallest amplitude after exercise from the greatest amplitude after exercise and dividing it by the greatest amplitude after exercise. After a brief increase in CMAP amplitude, a decrease of more than 40% in the CMAP amplitude after 20 minutes is considered abnormal. An abnormal result is highly suggestive of periodic paralyses (98% specificity) but does not distinguish between hyperkalemic, hypokalemic, and thyrotoxic periodic paralyses. Different electrophysiologic patterns are identified in different group of patients with distinct mutations by using both these tests.

Table 7. Electrophysiological Patterns to Exercise Testing (Open Table in a new window)

Needle electrode examination

See the list below:

• Insertional activity: The presence of myotonia usually excludes the diagnosis of hypokalemic periodic paralyses. In hyperkalemic periodic paralyses, no abnormality is detectable between attacks. In those patients with both clinical and electrical myotonia, mild to moderate spontaneous activity is seen, consisting of fibrillation potentials, positive sharp waves, and myotonic discharges.

• Myotonia: Electrical myotonia consists of repetitive discharges at rates of 20-80 Hz. The shape of the potentials can be either positive sharp waves or small biphasic waves; the former is seen while moving the needle electrode and the latter following muscle contraction. Another criterion distinct for myotonia is waxing and waning of the amplitude and frequency of the discharges (ie, dive-bomber discharges). These discharges should last a minimum of 500 milliseconds. They should be elicited in at least 3 areas outside the endplate region in order to distinguish minimal electromyographic myotonia from insertional activity. Demonstration of myotonia may be facilitated by potassium administration and cold temperature.

• Motor unit action potential (MUAP): During the paralytic attack, recruitment is reduced, with few voluntary MUAPs. The amplitude and duration of MUAPs may be reduced. In patients who develop myopathy, the MUAPs tend to show decreased amplitude, reduced duration, and increased proportion of polyphasic potentials.

General precautions for such testing include (1) physician presence during testing, (2) performance of testing in an intensive care setting, (3) avoidance of testing patients with serum potassium disturbances, diabetes mellitus, or renal or cardiac dysfunction, (4) close monitoring of ECG, and (5) capability for rapid electrolyte and glucose testing and correction.

Hypokalemic periodic paralyses

Provocative testing is dangerous and is not the first line of diagnostic 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.

• Intravenous glucose challenge: Good IV access is essential and availability of more than one IV line is preferred. 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. The most dangerous period of the testing is between 75-150 minutes when severe hypoglycemia occurs. This should be reversed immediately.

• 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.

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. Electrolyte profile, 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.

Muscle biopsy is abnormal, more typically in patients with hypokalemic periodic paralysis (PP) than in patients with hyperkalemic periodic paralysis (PP). Histologic findings in hypokalemic PP include the following:

• 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. Reports of muscle biopsy findings in PC are few and the vacuolar changes are less frequent.

• 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 may be seen in some patients. Tubular aggregates are seen in type II fibers. They are subsarcolemmal in location. This abnormality is seen only in hypokalemic PP.

• Muscle fiber necrosis is rare.