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PERIODIC PARALYSES
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METABOLIC MYOFATHIES
PERIODIC PARALYSES Laurie Gutmann, MD
The periodic paralyses are a rare group of disorders previously linked by their distinct clinical features. They have an autosomal dominant inheritance pattern. Classification of these disorders in the past has been on the basis of the patients' potassium levels or response to changes in potassium levels. Disorders to be discussed in this article include hypokalemic periodic paralysis, potassium-sensitive periodic paralysis, and paramyotonia congenita. A better understanding and classification of these disorders has developed with the identification of specific skeletal muscle channel abnormalities. The presentation of these patients can be dramatic, with severe episodic weakness of limb muscles. This weakness most commonly follows exercise and resolves within hours to days. The patient is usually asymptomatic between attacks. The quick resolution of acute attacks may not allow electrodiagnostic studies to be performed during a symptomatic episode. Some distinguishing electrodiagnostic features may be found when the patient is asymptomatic, and provocative studies also may be performed, leading to the diagnosis. Making the diagnosis allows preventative therapy to be initiated to avoid further attacks.
FAMILIAL HYPOKALEMIC PERIODIC PARALYSIS
Hypokalemic periodic paralysis (hypoPP) is the most common form of periodic paralysis. It has been estimated to have a prevalence of 1:100,000. It is autosoma1 dominant, with reduced penetrance in women.'O This disease is linked to chromosome 1q31-32, associated with the dihydropyridine receptor, an a1 subunit of the L-type calcium channel of the skeletal m ~ s c l e .Genetic ~ , ~ heterogeneity and some sporadic cases may occur. Owing to the variable penetrance that can occur, familial disease can go unrecognized if symptoms are mild or absent.
From the Department of Neurology, West Virginia University School of Medicine, Morgantown, West Virginia
NEUROLOGIC CLINICS VOLUME 18 *NUMBER 1 * FEBRUARY 2000
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GUTMANN
Clinical Findings
Symptoms usually appear after puberty, but may present in early childhood or occasionally into the third decade.I7 Patients develop episodes of paresis or paralysis of limb muscles most commonly after rest following strenuous exercise or a carbohydrate-rich meal. The paralysis may occur in the night or early morning hours on awakening. Skeletal muscle only is involved, with respiratory muscles rarely involved to the point of respiratory fai1~re.l~ There are no sensory changes or alterations in level of consciousness. Muscles are flaccid, and reflexes are decreased or absent. Strength usually improves over hours without intervention, but may occasionally last several days. Patients have a full recovery. In long-standing disease, however, mild to moderate weakness may become permanent. Triggers for attacks may be high sodium intake or carbohydrate load. Cold may exacerbate or cause local weakness. Abnormal laboratory findings during an attack include a decrease of serum potassium level from patient's baseline (although the level still may be in the normal range) and serum phosphorous. ECG changes may be seen if the potassium level is low enough. ECG changes would include sinus bradycardia and T wave changes. Frequency and severity of the attacks is highly variable, depending on the severity of the disease. Some patients may have resolution of symptoms by the fifth or sixth decade. Patients with severe disease may have daily attacks, with strength variability throughout the day, which is worse during the night and early morning. As mentioned earlier, a permanent myopathy may eventually occur, even if the patient has mild or moderate disease. Muscles most commonly affected by the myopathy are in the lower body and limbs, proximal greater than distal.
Diagnostic Evaluation
In patients with hypokalemic periodic paralysis, the decrease in serum potassium levels may be seen during an attack. If serum potassium is abnormally low, the periodic paralysis may be secondary rather than primary. In these cases, renal and gastrointestinal causes for low potassium levels must be considered. Serum creatine kinase levels may be elevated between attacks and worse after a major attack. Thyroid function tests also must be done to rule out thyrotoxic periodic paralysis. This secondary form of periodic paralysis is be discussed later on in this article. Nerve conduction studies (NCS) and needle electromyography (EMG) may be normal when the patient is asymptomatic. During symptoms, however, NCS may show small or absent compound muscle action potentials (CMAP) amplitudes. There may be absent or decreased insertional activity with few voluntary motor unit action potentials (MUAP) on EMG. Prolonged testing after exercise may show typical results of reduction of at least 2 mV in the CMAP amplitude following exercise with slow return to normal. (Fig. 1).Other provocative testing can be done to elicit symptoms. Provocative testing should not be done in patients with abnormal potassium levels or thyrotoxicosis, even when the patient is asymptomatic because of the potential morbidity to the patient. All patients should have ECG monitoring and potassium and glucose monitored closely. Provocative tests should not be done in patients with renal or adrenal disease. Details of provocative testing can be found in several review^,'^,'^ and include monitoring of CMAP following an oral glucose load followed by subcutaneous insulin. Other provocative tests include carbohydrate load and exercise the night before testing, with the addition of intravenous insulin during testing to help precipitate an attack, if
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Figure 1. CMAP amplitude in a patient with hypoPP before exercise and after 3 minutes of exercise. Note the marked drop in CMAP amplitude and slow return to baseline more than 6 hours after exercise. necessary. The test result is positive if the patient becomes weak. CMAP amplitudes may be decreased or absent during the weakness. Serum potassium levels should be 3.0 mmol/L or less. A negative test result does not, however, rule out hypoPP because patients may be refractory at times.lo The electrodiagnostic findings and clinical presentation of hypoPP and the other periodic paralyses are better understood since the identification of these diseases as channelopathies. It has been known that during a symptomatic state, the affected muscles will remain depolarized at - 60 to - 40 mV from - 95 mV (normal resting potential), flaccid and i n e ~ c i t a b l e . The ~ ~ , 'abnormal ~ L-type skeletal calcium channel in hypoPP is localized to the T-tubule, essential for excitationcontraction ~ o u p l i n gThis . ~ specific channel abnormality relates to the decreased insertional activity noted when electrophysiologic studies are performed while the patient is symptomatic, although it is still not clear exactly how the clinical manifestations occur. Muscle biopsy findings in hypoPP and other periodic paralyses may show typical pathologic changes of tubular aggregates (Fig. 2). Tubular aggregates were first described in periodic paralysis but are a nonspecific finding that occurs in other disease states. Their significance is unclear, although they are known to be associated with the sarcoplasmicreticulum. Calcium regulation or disturbance has been proposed as a possible cause for development of tubular aggregate^.^
Treatment Options
In hypoPP, dietary manipulation can help prevent attacks to some extent. Patients should avoid ingestion of large amounts of carbohydrates. Oral potassium
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Figure 2. Muscle biopsy of a patient with hypoPP. NADH staining shows tubular aggregates in type I fibers.
may help alleviate symptoms when they have already begun. Acetazolamidemay help prevent attacks by causing a metabolic acidosis and preventing intracellular potassium shifts. Despite treatment and avoidance of attacks, patients may develop permanent weakness over time. SECONDARY HYPOKALEMIC PERIODIC PARALYSIS
Secondary forms of hypoPP have been described. These are thyrotoxicosis and the multiple causes for renal and gastrointestinal potassium wasting. The author also has seen the symptoms in a patient with undiagnosed diabetes mellitus. In patients with a significant decrease in potassium levels, secondary causes always should be considered, although screening for thyroid disease should be done in all patients with symptoms consistent with periodic paralysis. Other clues indicating a secondary cause are the lack of family history and the time of onset of symptoms. Patients who have their first attack of weakness in adulthood should be screened carefully for a secondary cause. Provocative testing should not be performed in these patients because of the higher risk of morbidity associated with the tests in patients who have a low serum potassium level. In secondary causes of hypoPP, treatment of the underlying disorder causes a resolution of symptoms. Therefore, the importance of looking for these secondary causes cannot be stressed enough. The abnormality in these secondary causes of hypoPP is also in the calcium channels. POTASSIUM-SENSITIVE PERIODIC PARALYSIS
Primary potassium-sensitive periodic paralysis (KPP) also has autosomal dominant inheritance, usually with complete penetrance. Sporadic cases also have been described. The channel abnormality occurs in the (Y subunit of the sodium channel of skeletal muscle. This subunit is linked to chromosome 17q.1,2,5 The
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associated electrolyte changes in the muscle environment result in prolonged electrical inexcitability of the muscle membrane, owing to inactivation of sodium channel~.~ Some , ~ ~patients , ~ ~ with similar clinical phenotypes have not shown abnormalities of sodium channels, however, indicating a possible separate disorder. A triad of abnormalities consisting of KPP, ventricular dysrhythmias, and dysmorphic features has been described as Andersen’s syndrome. This syndrome has distinct abnormalities of skeletal muscle sodium channels and cardiac muscle potassium channels. Some the channel defects are distinct from hypoPP or KPP. The periodic paralysis in this syndrome has been described with hypokalemia or hyperkalemia. Affected patients also have a prolonged QT interval noted on ECG.I6 Clinical Findings Patients with KPP present with symptoms similar to patients with hypoPP. Presentation is most common in early childhood, usually in the first decade. Symptoms may be infrequent initially, but increase frequency with time. The paresis or paralysis of the skeletal muscles occurs after rest following exercise, often occurring on awakening. It may last 15 minutes to 4 hours, with complete recovery. Aggravating factors include cold temperature, stress, glucocorticoids, pregnancy, and potassium loading. As opposed to hypoPP, only a brief rest after exercise may bring on the symptoms. A warning sensation of muscle tension or parasthesias may occur in a few patients before the onset of weakness. At times, sustaining mild exercise may abort the attack or reduce its severity. Although it is normal between attacks, the serum potassium level is usually significantly elevated during episodes of weakness, sometimes only in the upper limits of normal. Rarely, the level may be cardiotoxic and life-threatening.” T waves on ECG increase in amplitude with increasing levels of potassium. The increase in serum potassium level also causes sodium to enter the muscles, followed by water influx. This influx results in lower serum sodium levels and increased urinary potassium excretion. The increase in urinary potassium excretion may help end the attack. At the end of an attack, mild weakness may persist, with myalgias, elevation of creatine kinase, and diuresis. There are three forms of KPP: without myotonia, with myotonia (clinical or electrical), or with paramyotonia. The form of KPP with paramyotonia is usually is referred to as paramyotonia congenita and is discussed later. For the first two forms, weakness but not stiffness may be precipitated by cooling and improved with warming. Electromyographic studies help to distinguish between the two types, with absence of clinical and electrical myotonia in one group and presence of it in the other. The myotonia is mild but noted between attacks. It usually does not interfere with daily living activities. Cooling does not affect the myotonia. There is a group of patients with KPP who do not have an elevation of serum potassium during attacks. These patients have been referred to as having normokalemic periodic paralysis. There are some slight differences in response to treatment, specifically glucose loading, and there may be urinary potassium retention noted. The genetic mutations noted in some families are the same as for KPP.” Diagnostic Evaluation The best diagnostic test for KPP is still the clinical history combined with the family history and the possible presence of myotonia. Electrodiagnostic studies
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help to identify the myotonia, as noted earlier. The clinical myotonia in patients may be subtle and not noticed by the patient. NCS and EMG are usually otherwise unremarkable, as in hypoPP, although fibrillation potentials during EMG have been noted at the onset of weakness." If permanent weakness has developed, as in later stages of the disease, small polyphasic motor unit potentials and fibrillation potentials may be seen. Provocative testing also can be done for KPP. In a monitored setting, 2 to 10 g KC1 (40-120 mmol) in an unsweetened solution should be given, preferably in the morning, in a fasting state, and immediately after exercise. An attack should occur in 1 to 2 hours. Alternatively, the patient can use a bicycle ergometer for 30 minutes (pulse 120-160 beats/minute) followed by absolute bedrest. Ten to 20 minutes after the onset of rest weakness should begin. CMAPs following exercise should show progressive decrease in amplitude. Corresponding serum potassium levels show an increase during exercise and a decrease to the pre-exercise level after exercise. This level is the same as individuals without disease. However, there is a second increase in potassium associated with the paralysis in these patients. The initial increase in serum potassium level causes the abnormal sodium channels to open and prolonged inactivation of these sodium channels occurs. The prolonged inactivation allows an increase in the sodium influx into muscle. As the sodium continues to move in, pulling water in with it, hemoconcentrationoccurs, increasing the potassium further. The cycle continues until kaliuresis lowers the serum potassium level again.I0 As described earlier, the abnormality of the voltage-gated sodium channel in KPP results in the clinical and electrophysiologic mixture of paralysis and myotonia. The prolonged depolarization of the muscle is caused by the impairment of the sodium channel inactivation. The exact role or effect that potassium has on this channel abnormality, as in hypoPP, is not fully understood.
Treatment Options
For KPP, dietary changes may be helpful in preventing attacks of paralysis. Frequent high-carbohydrate,low-potassium meals with avoidance of fasting have been the most successful dietary change for attack prevention. Carbohydrate ingestion at the onset of weakness may reduce the severity of or abort an attack. The addition of continued mild exercise at the onset of an attack also may be helpful. Cold exposure may trigger an attack and should be avoided if possible. Acetazolamide may help prevent attacks, as in hypoPP. The mechanism of action in KPP is most likely by reduction of serum potassium. Thiazide diuretics that lower serum potassium levels may actually be preferable for preventative therapy. A successful abortive therapy is inhalation of a P-adrenergic agent, such as metaproterenol, albuterol, or salbutamol.8,10 These agents are believed to be effective by stimulating the sodium-potassium pump. Intravenous calcium glyconate also may abort attacks in some patients.
PARAMYOTONIA CONGENITA
The original description of paramyotonia congenita was in 1886 by Eulenberg3 This autosomal dominant disease has complete penetrance. Patients have paradoxical myotonia; myotonia increases with repeated muscle contractions, rather than decreasing. The genetic defect is at the same locus as that for KPP. The
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sodium channel a-subunit is encoded by SCN4A with its locus on chromosome 17q and is linked to these d i ~ o r d e r s . ~ , ~ , ~ ~ , ~ ~
Clinical Findings
Symptoms of paramyotonia are present at birth and do not change significantly over a patient's lifetime. Episodic weakness usually presents in the second decade, if it occurs at all. Cold exposure may exacerbate the paramyotonia. The weakness is most severe after exercise and cold exposure, although in some families spontaneous episodic weakness occurs similar to that seen in patients with KPP. Most patients have myotonia predominantly in the face, neck, and hands. Some variations of symptoms occur in some families. For example, myotonia may occur without cold exposure, stiffness may occur in the cold without weakness, and cold may induce stiffness but not weakness. Symptoms often begin early in the morning and last several hours. As in KPP, oral potassium supplementation may induce an episode.
Diagnostic Evaluations
As in KPP, the best diagnostic test is the combination of cold-induced or exercise-related paramyotonia with a positive family history. Patients with paramyotonia congenita do not develop muscle atrophy or permanent weakness. Myotonic discharges are evident on EMG. The creatine kinase level may be elevated markedly. Cooling of the muscles to elicit more evidence for paramyotonia congenita is the best provocative test for this disorder. NCS then shows a decrease in CMAP amplitude. With isometric testing after cooling, there is decreased force with maximal voluntary contraction in most patients and prolongation to relaxation time of muscles in all patients with paramyotonia congenita. Isometric testing after cooling is done by testing finger flexor muscles before and after immersion in a cool water bath (15°Cfor 30 minutes).IoThe changes may be marked. With cooling, spontaneous activity in the cooled muscles that is more like fibrillation potentials than myotonic discharges can be seen on EMG. The changes seen in these muscles occur in all skeletal muscle, although diaphragm is spared, as is cardiac muscle. The basis of the weakness is the prolonged inactivation of sodium channels, resulting in membrane inexcitability.
Treatment
Most patients with paramyotonia congenita do not require treatment. Most learn quickly how to cope with their disease. Some antiarrhythmic drugs (e.g., mexilitene) have been shown to help prevent stiffness and weakness occurring in cold and with exercise. The combination of one of these drugs plus a thiazide diuretic can help prevent the paramyotonic symptoms and the spontaneous episodic weakness that occurs in some patients with paramyotonia and the more typical symptoms of KPP.1,2,10
SUMMARY
The periodic paralyses are an interesting group of disorders with unusual clinical presentations. The genetics of these disorders have become better understood and they are now recognized as muscle channelopathies.Understanding the channel defects has led to further research, but the full mechanism of action to produce weakness in each disease still is not completely understood. Further research for more specific understanding and treatment for these diseases is necessary.
References 1. Cannon SC: Sodium channel defects in myotonia and periodic paralysis. Annu Rev Neurosci 19:141-164,1996 2. Cummins TR, Sigworth FJ: Impaired slow inactivation in mutant sodium channels. Biophys 71:227-236,1996 3. Eulenberg A: Ueber eine familiare, durch 6 generationen verfolgbare form congenitaler paramyotonie. Neurol Central 5:265-272,1886 4. Fardeau M, Tome FMS: Congenital myopathies. In Engel AG, Franzini-Armstrong C (eds): Myology, Vol. 2. McGraw-Hill, 1994, pp 1516-1519 5. Feero WG, Wang J, Barany F, et al: Hyperkalemic periodic paralysis: Rapid molecular diagnosis and relationship of genotype to phenotype in 12 families. Neurology 43:668673,1993 6. Fontaine 8, Vale Santos JM, Jurkat-Rott K, et al: Mapping of hypokalemic periodic paralysis (HypoPP) to chromosome lq31-q32 by a genome-wide search in three European families. Nat Genet 6:267-272, 1994 7. Greenberg DA: Calcium channels in neurological disease. Ann Neuro 42:275-282,1997 8. Hanna MG, Stewart J, Schapira AH, et a1 Salbutamol treatment in a patient with hyperkalaemic periodic paralysis due to a mutation in the skeletal muscle sodium channel gene (SCN4A).J Neurol Neurosurg Psvchiatr 65:248-250, 1998 9. Hayward LJ, Brown RH, Cannon SC: Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis. Biophys J 72:1204-1219, 1997 10. Lehmann-Horn F, Rudel R Channelopathies: The nondystrophic myotonias and periodic paralyses. Sem Ped Neurol, 3:122-139, 1996 11. Lehmann-Horn F, Rudel R, Ricker K, et al: Two cases of adynamia episodica hereditaria: In vitro investigation of muscle membrane and contractile parameters. Muscle Nerve 6:113-121,1983 12. Ptacek LJ, Trimmer JS, Agnew WS, et al: Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium channel gene locus. Am J Hum Genet 492351854,1991 13. Ptacek LJ: Channelopathies: Ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system. Neuromuscul Disord 7250-255,1997 14. Riggs JR: The periodic paralyses. Neurologic Clinics 6:485-498, 1988 15. Rudel R, Lehmann-Horn F, Ricker K, et al: Hypokalemic periodic paralysis: In vitro investigation of muscle fiber membrane parameters. Muscle Nerve 7110-120, 1984 16. Sansone V, Griggs RC, Meola G, et al: Andersen's syndrome: A distinct periodic paralysis. Ann Neurol42:305-312,1997 17. Talbott JH: Periodic paralysis. Medicine 20:85-143, 1941
Address reprint requests to Laurie Gutmann, MD Department of Neurology Health Sciences Center Room 103G P.O. Box 9180 West Virginia University School of Medicine Morgantown, WV 26506
METABOLIC MYOFATHIES
PERIODIC PARALYSES Laurie Gutmann, MD
The periodic paralyses are a rare group of disorders previously linked by their distinct clinical features. They have an autosomal dominant inheritance pattern. Classification of these disorders in the past has been on the basis of the patients' potassium levels or response to changes in potassium levels. Disorders to be discussed in this article include hypokalemic periodic paralysis, potassium-sensitive periodic paralysis, and paramyotonia congenita. A better understanding and classification of these disorders has developed with the identification of specific skeletal muscle channel abnormalities. The presentation of these patients can be dramatic, with severe episodic weakness of limb muscles. This weakness most commonly follows exercise and resolves within hours to days. The patient is usually asymptomatic between attacks. The quick resolution of acute attacks may not allow electrodiagnostic studies to be performed during a symptomatic episode. Some distinguishing electrodiagnostic features may be found when the patient is asymptomatic, and provocative studies also may be performed, leading to the diagnosis. Making the diagnosis allows preventative therapy to be initiated to avoid further attacks.
FAMILIAL HYPOKALEMIC PERIODIC PARALYSIS
Hypokalemic periodic paralysis (hypoPP) is the most common form of periodic paralysis. It has been estimated to have a prevalence of 1:100,000. It is autosoma1 dominant, with reduced penetrance in women.'O This disease is linked to chromosome 1q31-32, associated with the dihydropyridine receptor, an a1 subunit of the L-type calcium channel of the skeletal m ~ s c l e .Genetic ~ , ~ heterogeneity and some sporadic cases may occur. Owing to the variable penetrance that can occur, familial disease can go unrecognized if symptoms are mild or absent.
From the Department of Neurology, West Virginia University School of Medicine, Morgantown, West Virginia
NEUROLOGIC CLINICS VOLUME 18 *NUMBER 1 * FEBRUARY 2000
195
196
GUTMANN
Clinical Findings
Symptoms usually appear after puberty, but may present in early childhood or occasionally into the third decade.I7 Patients develop episodes of paresis or paralysis of limb muscles most commonly after rest following strenuous exercise or a carbohydrate-rich meal. The paralysis may occur in the night or early morning hours on awakening. Skeletal muscle only is involved, with respiratory muscles rarely involved to the point of respiratory fai1~re.l~ There are no sensory changes or alterations in level of consciousness. Muscles are flaccid, and reflexes are decreased or absent. Strength usually improves over hours without intervention, but may occasionally last several days. Patients have a full recovery. In long-standing disease, however, mild to moderate weakness may become permanent. Triggers for attacks may be high sodium intake or carbohydrate load. Cold may exacerbate or cause local weakness. Abnormal laboratory findings during an attack include a decrease of serum potassium level from patient's baseline (although the level still may be in the normal range) and serum phosphorous. ECG changes may be seen if the potassium level is low enough. ECG changes would include sinus bradycardia and T wave changes. Frequency and severity of the attacks is highly variable, depending on the severity of the disease. Some patients may have resolution of symptoms by the fifth or sixth decade. Patients with severe disease may have daily attacks, with strength variability throughout the day, which is worse during the night and early morning. As mentioned earlier, a permanent myopathy may eventually occur, even if the patient has mild or moderate disease. Muscles most commonly affected by the myopathy are in the lower body and limbs, proximal greater than distal.
Diagnostic Evaluation
In patients with hypokalemic periodic paralysis, the decrease in serum potassium levels may be seen during an attack. If serum potassium is abnormally low, the periodic paralysis may be secondary rather than primary. In these cases, renal and gastrointestinal causes for low potassium levels must be considered. Serum creatine kinase levels may be elevated between attacks and worse after a major attack. Thyroid function tests also must be done to rule out thyrotoxic periodic paralysis. This secondary form of periodic paralysis is be discussed later on in this article. Nerve conduction studies (NCS) and needle electromyography (EMG) may be normal when the patient is asymptomatic. During symptoms, however, NCS may show small or absent compound muscle action potentials (CMAP) amplitudes. There may be absent or decreased insertional activity with few voluntary motor unit action potentials (MUAP) on EMG. Prolonged testing after exercise may show typical results of reduction of at least 2 mV in the CMAP amplitude following exercise with slow return to normal. (Fig. 1).Other provocative testing can be done to elicit symptoms. Provocative testing should not be done in patients with abnormal potassium levels or thyrotoxicosis, even when the patient is asymptomatic because of the potential morbidity to the patient. All patients should have ECG monitoring and potassium and glucose monitored closely. Provocative tests should not be done in patients with renal or adrenal disease. Details of provocative testing can be found in several review^,'^,'^ and include monitoring of CMAP following an oral glucose load followed by subcutaneous insulin. Other provocative tests include carbohydrate load and exercise the night before testing, with the addition of intravenous insulin during testing to help precipitate an attack, if
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Figure 1. CMAP amplitude in a patient with hypoPP before exercise and after 3 minutes of exercise. Note the marked drop in CMAP amplitude and slow return to baseline more than 6 hours after exercise. necessary. The test result is positive if the patient becomes weak. CMAP amplitudes may be decreased or absent during the weakness. Serum potassium levels should be 3.0 mmol/L or less. A negative test result does not, however, rule out hypoPP because patients may be refractory at times.lo The electrodiagnostic findings and clinical presentation of hypoPP and the other periodic paralyses are better understood since the identification of these diseases as channelopathies. It has been known that during a symptomatic state, the affected muscles will remain depolarized at - 60 to - 40 mV from - 95 mV (normal resting potential), flaccid and i n e ~ c i t a b l e . The ~ ~ , 'abnormal ~ L-type skeletal calcium channel in hypoPP is localized to the T-tubule, essential for excitationcontraction ~ o u p l i n gThis . ~ specific channel abnormality relates to the decreased insertional activity noted when electrophysiologic studies are performed while the patient is symptomatic, although it is still not clear exactly how the clinical manifestations occur. Muscle biopsy findings in hypoPP and other periodic paralyses may show typical pathologic changes of tubular aggregates (Fig. 2). Tubular aggregates were first described in periodic paralysis but are a nonspecific finding that occurs in other disease states. Their significance is unclear, although they are known to be associated with the sarcoplasmicreticulum. Calcium regulation or disturbance has been proposed as a possible cause for development of tubular aggregate^.^
Treatment Options
In hypoPP, dietary manipulation can help prevent attacks to some extent. Patients should avoid ingestion of large amounts of carbohydrates. Oral potassium
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Figure 2. Muscle biopsy of a patient with hypoPP. NADH staining shows tubular aggregates in type I fibers.
may help alleviate symptoms when they have already begun. Acetazolamidemay help prevent attacks by causing a metabolic acidosis and preventing intracellular potassium shifts. Despite treatment and avoidance of attacks, patients may develop permanent weakness over time. SECONDARY HYPOKALEMIC PERIODIC PARALYSIS
Secondary forms of hypoPP have been described. These are thyrotoxicosis and the multiple causes for renal and gastrointestinal potassium wasting. The author also has seen the symptoms in a patient with undiagnosed diabetes mellitus. In patients with a significant decrease in potassium levels, secondary causes always should be considered, although screening for thyroid disease should be done in all patients with symptoms consistent with periodic paralysis. Other clues indicating a secondary cause are the lack of family history and the time of onset of symptoms. Patients who have their first attack of weakness in adulthood should be screened carefully for a secondary cause. Provocative testing should not be performed in these patients because of the higher risk of morbidity associated with the tests in patients who have a low serum potassium level. In secondary causes of hypoPP, treatment of the underlying disorder causes a resolution of symptoms. Therefore, the importance of looking for these secondary causes cannot be stressed enough. The abnormality in these secondary causes of hypoPP is also in the calcium channels. POTASSIUM-SENSITIVE PERIODIC PARALYSIS
Primary potassium-sensitive periodic paralysis (KPP) also has autosomal dominant inheritance, usually with complete penetrance. Sporadic cases also have been described. The channel abnormality occurs in the (Y subunit of the sodium channel of skeletal muscle. This subunit is linked to chromosome 17q.1,2,5 The
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associated electrolyte changes in the muscle environment result in prolonged electrical inexcitability of the muscle membrane, owing to inactivation of sodium channel~.~ Some , ~ ~patients , ~ ~ with similar clinical phenotypes have not shown abnormalities of sodium channels, however, indicating a possible separate disorder. A triad of abnormalities consisting of KPP, ventricular dysrhythmias, and dysmorphic features has been described as Andersen’s syndrome. This syndrome has distinct abnormalities of skeletal muscle sodium channels and cardiac muscle potassium channels. Some the channel defects are distinct from hypoPP or KPP. The periodic paralysis in this syndrome has been described with hypokalemia or hyperkalemia. Affected patients also have a prolonged QT interval noted on ECG.I6 Clinical Findings Patients with KPP present with symptoms similar to patients with hypoPP. Presentation is most common in early childhood, usually in the first decade. Symptoms may be infrequent initially, but increase frequency with time. The paresis or paralysis of the skeletal muscles occurs after rest following exercise, often occurring on awakening. It may last 15 minutes to 4 hours, with complete recovery. Aggravating factors include cold temperature, stress, glucocorticoids, pregnancy, and potassium loading. As opposed to hypoPP, only a brief rest after exercise may bring on the symptoms. A warning sensation of muscle tension or parasthesias may occur in a few patients before the onset of weakness. At times, sustaining mild exercise may abort the attack or reduce its severity. Although it is normal between attacks, the serum potassium level is usually significantly elevated during episodes of weakness, sometimes only in the upper limits of normal. Rarely, the level may be cardiotoxic and life-threatening.” T waves on ECG increase in amplitude with increasing levels of potassium. The increase in serum potassium level also causes sodium to enter the muscles, followed by water influx. This influx results in lower serum sodium levels and increased urinary potassium excretion. The increase in urinary potassium excretion may help end the attack. At the end of an attack, mild weakness may persist, with myalgias, elevation of creatine kinase, and diuresis. There are three forms of KPP: without myotonia, with myotonia (clinical or electrical), or with paramyotonia. The form of KPP with paramyotonia is usually is referred to as paramyotonia congenita and is discussed later. For the first two forms, weakness but not stiffness may be precipitated by cooling and improved with warming. Electromyographic studies help to distinguish between the two types, with absence of clinical and electrical myotonia in one group and presence of it in the other. The myotonia is mild but noted between attacks. It usually does not interfere with daily living activities. Cooling does not affect the myotonia. There is a group of patients with KPP who do not have an elevation of serum potassium during attacks. These patients have been referred to as having normokalemic periodic paralysis. There are some slight differences in response to treatment, specifically glucose loading, and there may be urinary potassium retention noted. The genetic mutations noted in some families are the same as for KPP.” Diagnostic Evaluation The best diagnostic test for KPP is still the clinical history combined with the family history and the possible presence of myotonia. Electrodiagnostic studies
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help to identify the myotonia, as noted earlier. The clinical myotonia in patients may be subtle and not noticed by the patient. NCS and EMG are usually otherwise unremarkable, as in hypoPP, although fibrillation potentials during EMG have been noted at the onset of weakness." If permanent weakness has developed, as in later stages of the disease, small polyphasic motor unit potentials and fibrillation potentials may be seen. Provocative testing also can be done for KPP. In a monitored setting, 2 to 10 g KC1 (40-120 mmol) in an unsweetened solution should be given, preferably in the morning, in a fasting state, and immediately after exercise. An attack should occur in 1 to 2 hours. Alternatively, the patient can use a bicycle ergometer for 30 minutes (pulse 120-160 beats/minute) followed by absolute bedrest. Ten to 20 minutes after the onset of rest weakness should begin. CMAPs following exercise should show progressive decrease in amplitude. Corresponding serum potassium levels show an increase during exercise and a decrease to the pre-exercise level after exercise. This level is the same as individuals without disease. However, there is a second increase in potassium associated with the paralysis in these patients. The initial increase in serum potassium level causes the abnormal sodium channels to open and prolonged inactivation of these sodium channels occurs. The prolonged inactivation allows an increase in the sodium influx into muscle. As the sodium continues to move in, pulling water in with it, hemoconcentrationoccurs, increasing the potassium further. The cycle continues until kaliuresis lowers the serum potassium level again.I0 As described earlier, the abnormality of the voltage-gated sodium channel in KPP results in the clinical and electrophysiologic mixture of paralysis and myotonia. The prolonged depolarization of the muscle is caused by the impairment of the sodium channel inactivation. The exact role or effect that potassium has on this channel abnormality, as in hypoPP, is not fully understood.
Treatment Options
For KPP, dietary changes may be helpful in preventing attacks of paralysis. Frequent high-carbohydrate,low-potassium meals with avoidance of fasting have been the most successful dietary change for attack prevention. Carbohydrate ingestion at the onset of weakness may reduce the severity of or abort an attack. The addition of continued mild exercise at the onset of an attack also may be helpful. Cold exposure may trigger an attack and should be avoided if possible. Acetazolamide may help prevent attacks, as in hypoPP. The mechanism of action in KPP is most likely by reduction of serum potassium. Thiazide diuretics that lower serum potassium levels may actually be preferable for preventative therapy. A successful abortive therapy is inhalation of a P-adrenergic agent, such as metaproterenol, albuterol, or salbutamol.8,10 These agents are believed to be effective by stimulating the sodium-potassium pump. Intravenous calcium glyconate also may abort attacks in some patients.
PARAMYOTONIA CONGENITA
The original description of paramyotonia congenita was in 1886 by Eulenberg3 This autosomal dominant disease has complete penetrance. Patients have paradoxical myotonia; myotonia increases with repeated muscle contractions, rather than decreasing. The genetic defect is at the same locus as that for KPP. The
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sodium channel a-subunit is encoded by SCN4A with its locus on chromosome 17q and is linked to these d i ~ o r d e r s . ~ , ~ , ~ ~ , ~ ~
Clinical Findings
Symptoms of paramyotonia are present at birth and do not change significantly over a patient's lifetime. Episodic weakness usually presents in the second decade, if it occurs at all. Cold exposure may exacerbate the paramyotonia. The weakness is most severe after exercise and cold exposure, although in some families spontaneous episodic weakness occurs similar to that seen in patients with KPP. Most patients have myotonia predominantly in the face, neck, and hands. Some variations of symptoms occur in some families. For example, myotonia may occur without cold exposure, stiffness may occur in the cold without weakness, and cold may induce stiffness but not weakness. Symptoms often begin early in the morning and last several hours. As in KPP, oral potassium supplementation may induce an episode.
Diagnostic Evaluations
As in KPP, the best diagnostic test is the combination of cold-induced or exercise-related paramyotonia with a positive family history. Patients with paramyotonia congenita do not develop muscle atrophy or permanent weakness. Myotonic discharges are evident on EMG. The creatine kinase level may be elevated markedly. Cooling of the muscles to elicit more evidence for paramyotonia congenita is the best provocative test for this disorder. NCS then shows a decrease in CMAP amplitude. With isometric testing after cooling, there is decreased force with maximal voluntary contraction in most patients and prolongation to relaxation time of muscles in all patients with paramyotonia congenita. Isometric testing after cooling is done by testing finger flexor muscles before and after immersion in a cool water bath (15°Cfor 30 minutes).IoThe changes may be marked. With cooling, spontaneous activity in the cooled muscles that is more like fibrillation potentials than myotonic discharges can be seen on EMG. The changes seen in these muscles occur in all skeletal muscle, although diaphragm is spared, as is cardiac muscle. The basis of the weakness is the prolonged inactivation of sodium channels, resulting in membrane inexcitability.
Treatment
Most patients with paramyotonia congenita do not require treatment. Most learn quickly how to cope with their disease. Some antiarrhythmic drugs (e.g., mexilitene) have been shown to help prevent stiffness and weakness occurring in cold and with exercise. The combination of one of these drugs plus a thiazide diuretic can help prevent the paramyotonic symptoms and the spontaneous episodic weakness that occurs in some patients with paramyotonia and the more typical symptoms of KPP.1,2,10
SUMMARY
The periodic paralyses are an interesting group of disorders with unusual clinical presentations. The genetics of these disorders have become better understood and they are now recognized as muscle channelopathies.Understanding the channel defects has led to further research, but the full mechanism of action to produce weakness in each disease still is not completely understood. Further research for more specific understanding and treatment for these diseases is necessary.
References 1. Cannon SC: Sodium channel defects in myotonia and periodic paralysis. Annu Rev Neurosci 19:141-164,1996 2. Cummins TR, Sigworth FJ: Impaired slow inactivation in mutant sodium channels. Biophys 71:227-236,1996 3. Eulenberg A: Ueber eine familiare, durch 6 generationen verfolgbare form congenitaler paramyotonie. Neurol Central 5:265-272,1886 4. Fardeau M, Tome FMS: Congenital myopathies. In Engel AG, Franzini-Armstrong C (eds): Myology, Vol. 2. McGraw-Hill, 1994, pp 1516-1519 5. Feero WG, Wang J, Barany F, et al: Hyperkalemic periodic paralysis: Rapid molecular diagnosis and relationship of genotype to phenotype in 12 families. Neurology 43:668673,1993 6. Fontaine 8, Vale Santos JM, Jurkat-Rott K, et al: Mapping of hypokalemic periodic paralysis (HypoPP) to chromosome lq31-q32 by a genome-wide search in three European families. Nat Genet 6:267-272, 1994 7. Greenberg DA: Calcium channels in neurological disease. Ann Neuro 42:275-282,1997 8. Hanna MG, Stewart J, Schapira AH, et a1 Salbutamol treatment in a patient with hyperkalaemic periodic paralysis due to a mutation in the skeletal muscle sodium channel gene (SCN4A).J Neurol Neurosurg Psvchiatr 65:248-250, 1998 9. Hayward LJ, Brown RH, Cannon SC: Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis. Biophys J 72:1204-1219, 1997 10. Lehmann-Horn F, Rudel R Channelopathies: The nondystrophic myotonias and periodic paralyses. Sem Ped Neurol, 3:122-139, 1996 11. Lehmann-Horn F, Rudel R, Ricker K, et al: Two cases of adynamia episodica hereditaria: In vitro investigation of muscle membrane and contractile parameters. Muscle Nerve 6:113-121,1983 12. Ptacek LJ, Trimmer JS, Agnew WS, et al: Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium channel gene locus. Am J Hum Genet 492351854,1991 13. Ptacek LJ: Channelopathies: Ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system. Neuromuscul Disord 7250-255,1997 14. Riggs JR: The periodic paralyses. Neurologic Clinics 6:485-498, 1988 15. Rudel R, Lehmann-Horn F, Ricker K, et al: Hypokalemic periodic paralysis: In vitro investigation of muscle fiber membrane parameters. Muscle Nerve 7110-120, 1984 16. Sansone V, Griggs RC, Meola G, et al: Andersen's syndrome: A distinct periodic paralysis. Ann Neurol42:305-312,1997 17. Talbott JH: Periodic paralysis. Medicine 20:85-143, 1941
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