Laboratory Studies
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[7] ).
Table 5. Medical Conditions Associated With Hypokalemia (Open Table in a new window)
| Urine K/C Ratio | Acid Base Status | Other Associated Features | Medical Conditions |
| < 1.5 | Metabolic acidosis | Lower GI loss – Laxative abuse, diarrhea | |
| < 1.5 | Metabolic alkalosis | Normal BP | Surreptitious vomiting |
| >1.5 | Metabolic acidosis | DKA, type 1 or type 2 distal RTA | |
| >1.5 | Metabolic alkalosis | Normal BP | Diuretic use, Bartter syndrome, Gitelman syndrome |
| ≥1.5 | Metabolic alkalosis | Hypertension | Primary aldosteronism, Cushing syndrome, renal artery stenosis, congenital adrenal hyperplasia, apparent mineralocorticoid excess, Liddle syndrome |
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)
| Hypokalemic PP | Hyperkalemic PP | |
| Serum potassium | Mildly depressed; may reach 1-5 mEq/L | Increases from baseline but may not increase beyond normal range |
| Serum CPK | Moderately elevated during attacks | Mildly elevated during attacks |
| ECG | Bradycardia Flat T waves, U waves, ST-segment depression | Tall T waves |
Other Tests
Electrodiagnosis and provocative testing can be performed for periodic paralysis.
Electrodiagnosis
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.[8]
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.[8]
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)
| Para- myotonia Congenita | Hyper- kalemic Periodic Paralysis | Hypo- kalemic Periodic Paralysis | |
| Electrophysiological pattern | I | IV | V |
| Channel mutations | Sodium T1313M, R1448C | Sodium T704M | Calcium R528H |
| Short Exercise Test: | |||
| Post exercise myotonic potentials | Yes | No | No |
| CMAP amplitude change after First trial | Increase or decrease | Increase | No |
| CMAP amplitude change after second and third trial | Gradual increase | Gradual increase | No |
| Long Exercise Test: | |||
| Immediate change of CMAP amplitude | Decrease | Increase | No |
| Late change of CMAP amplitude | Decrease | Decrease | Decrease |
| Modified from Fournier et al, 2004.[9] | |||
Needle electrode examination
- 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.
Provocative Testing
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.
Histologic Findings
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.
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- Table 1. Primary Periodic Paralysis
- Table 2. Distinguishing Features Among the Common Forms of Periodic Paralyses
- Table 3. Differential Diagnosis of Secondary Periodic Paralyses
- Table 4. Differential Diagnosis of Other Entities Causing Acute Generalized Weakness
- Table 5. Medical Conditions Associated With Hypokalemia
- Table 6. Diagnostic Studies of Hypokalemic and Hyperkalemic Periodic Paralyses
- Table 7. Electrophysiological Patterns to Exercise Testing
| Sodium channel | Hyperkalemic PP (HyperPP) Hypokalemic PP (HypoPP2) Paramyotonia congenita |
| Calcium channel | Hypokalemic PP (HypoPP1) |
| Potassium channel | Andersen-Tawil syndrome Hyperkalemic PP or hypokalemic PP* |
| *The deficit was described in 2 small families and has not been substantiated by others.[1, 2] | |
| Syndrome | Age of Onset | Duration of Attack | Precipitating Factors | Severity of Attacks | Associated Features |
| Hyper-kalemic periodic paralyses | First decade of life | Few minutes to less than 2 h (mostly less than 1 h) | Low carbohydrate intake (fasting) Cold Rest following exercise Alcohol Infection Emotional stress Trauma Menstrual period | Rarely severe | Perioral and limb paresthesias Myotonia frequent Occasional pseudo-hypertrophy of muscles |
| Hypo-kalemic periodic paralyses | Variable -Childhood to third decade Majority of cases before 16 years | Few hours to almost a week Typically no longer than 72 h | Early morning attacks after previous day physical activity High-carbohydrate meal, Chinese food, alcohol Cold, change in barometric pressure or humidity Fever, upper respiratory tract infections Lack of sleep, fatigue Menstrual cycle | Severe Complete paralysis | Occasional myotonic lid lag Myotonia between attacks rare Unilateral, partial, monomelic Fixed muscle weakness late in disease |
| Potassium- associated myotonia | First decade | No weakness | Cold Rest after exercise | Attacks of stiffness can be mild to severe | Muscle hypertrophy |
| Para-myotonia congenita | First decade | 2-24 h | Cold | Rarely severe | Pseudo-hypertrophy of muscles Paradoxical myotonia Fixed weakness rare |
| Thyrotoxic periodic paralyses | Third and fourth decades | Few hours to 7 d | Same as hypokalemic PP Hyper-insulinemia | Same as hypokalemic PP | Fixed muscle weakness may develop Hypokalemia during attacks |
| Hypokalemic | Hyperkalemic |
Urinary potassium-wasting syndromes
| |
| Alcohol | Addison disease Chronic renal failure Hyporeninemic Hypoaldosteronism |
| Drugs - Amphotericin B, barium | Ileostomy with tight stoma |
| Renal tubular acidosis | Potassium load |
GI potassium-wasting syndromes
| Potassium-sparing diuretics |
| Disorder | Pattern and Distribution of Weakness |
| Transient ischemic attacks | Follow CNS distribution (ie, hemiparetic) May have sensory symptoms and signs |
| Sleep attacks | Occur at onset or termination of sleep Last only minutes |
Myelopathy
| Sensory symptoms Presence of a sensory level Sphincter involvement |
| Myasthenia gravis Lambert-Eaton myasthenic syndrome | Subacute in onset Associated autonomic symptoms in LEMS Hyporeflexia in LEMS Abnormal repetitive nerve stimulation Presence of distinct antibodies |
Peripheral neuropathy of acute onset
| Pattern of weakness Absent stretch reflexes |
Toxins
| Clinical presentation |
| Urine K/C Ratio | Acid Base Status | Other Associated Features | Medical Conditions |
| < 1.5 | Metabolic acidosis | Lower GI loss – Laxative abuse, diarrhea | |
| < 1.5 | Metabolic alkalosis | Normal BP | Surreptitious vomiting |
| >1.5 | Metabolic acidosis | DKA, type 1 or type 2 distal RTA | |
| >1.5 | Metabolic alkalosis | Normal BP | Diuretic use, Bartter syndrome, Gitelman syndrome |
| ≥1.5 | Metabolic alkalosis | Hypertension | Primary aldosteronism, Cushing syndrome, renal artery stenosis, congenital adrenal hyperplasia, apparent mineralocorticoid excess, Liddle syndrome |
| Hypokalemic PP | Hyperkalemic PP | |
| Serum potassium | Mildly depressed; may reach 1-5 mEq/L | Increases from baseline but may not increase beyond normal range |
| Serum CPK | Moderately elevated during attacks | Mildly elevated during attacks |
| ECG | Bradycardia Flat T waves, U waves, ST-segment depression | Tall T waves |
| Para- myotonia Congenita | Hyper- kalemic Periodic Paralysis | Hypo- kalemic Periodic Paralysis | |
| Electrophysiological pattern | I | IV | V |
| Channel mutations | Sodium T1313M, R1448C | Sodium T704M | Calcium R528H |
| Short Exercise Test: | |||
| Post exercise myotonic potentials | Yes | No | No |
| CMAP amplitude change after First trial | Increase or decrease | Increase | No |
| CMAP amplitude change after second and third trial | Gradual increase | Gradual increase | No |
| Long Exercise Test: | |||
| Immediate change of CMAP amplitude | Decrease | Increase | No |
| Late change of CMAP amplitude | Decrease | Decrease | Decrease |
| Modified from Fournier et al, 2004.[9] | |||
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