SEMINARS IN NEUROLOGY-VOLUME
1 1 , NO. 3 SEPTEMBER 1991
Paramyotonia Congenita
Every clinician concerned with the evaluation of patients with myotonic disorders has seen individual patients and families who do not fit easily into the framework of a classification, and, new, seemingly distinct myotonic syndromes continue to be described.l This clinical heterogeneity of the myotonias has best been documented by the detailed clinical-genetic studies of Becker in Germany.'," There is less clinical variability in the nondystrophic myotonias. In paramyotonia congenita (PC), diagnostic problems usually arise in regard to the variable severity and the nature of transient weakness and its distinction from or association with adynamia episodica hereditaria (AE), also called hyperkalemic periodic paralysis (HPP). In this article I shall try to provide a clinically oriented picture of PC based on recent advances and my own experience in studying and treating many members of several families with PC. AEIHPP will be presented in the context of the differential diagnosis and its possible relationship or association with PC.
HISTORICAL BACKGROUND Eulenburg4 described a new myotonic illness in 1886 and coined the name paramyotonia congenita. He had studied a family living in the Baltic Sea area. Detailed medical information of six generations had been recorded by a family member who was a physician. T h e propositus was a woman born in Rome to a "Roman mother," transporting the illness to the northeastern part of Germany. Eulenburg recognized all the essential features of PC, including its dominant inheritance, onset in infancy, and cold-induced muscle stiffness with predilection for the muscles of face, hands, and tongue. He described the occurrence of prolonged
muscle weakness after exercise in moderate or severely cold temperatures and recognized that the disease was essentially unchanged throughout life. He noted in passing rhythmic oscillations in the thigh muscles, occurring during the state of transient leg weakness. This sign could be interpreted as "hyperexcitability" of peripheral nerve fibers as described in HPP,5 but Eulenburg did not describe spontaneous attacks of paralysis. This initial description of PC has withstood time well and firmly differentiates PC from other dystrophic and nondystrophic myotonic disorders. In certain families, however, affected members were described as having prominent myotonia at normal temperature relieved with exercise, in contrast to the typically encountered paradoxical myotonia."' In 1956, Ingrid Gamstorp-elineated clinical and laboratory features of AEIHPP in distinction to hypokalemic periodic paralysis. Shortly thereafter, families were described with affected members who seemed to fulfill diagnostic criteria for both PC and AE/HPP.'0-13Some of these had atypical features such as muscle wasting in later years and permanent w e a k n e s ~ ,findings ' ~ ~ ~ ~ common in AEIHPP but not in patients with true PC. Since the 1950s, there have been numerous publications and studies to support either the lumping or splitting of these two diseases (see Engel14 and Kicker et all5 for reviews). Hyperkalemic attacks have been described without clinical with or electromyographic (EMG) myotonia,Y.16,17 myotonia,17-"'and with p a r a m y o t ~ n i a . ~ ~ -con~Vo fuse the situation further, patients with PC were observed to have hypokalemic attack^^,^' or both hypokalemic and hyperkalemic attacks of paralyis.'^-'^ A recent article suggested clinical and electrophysiologic evidence of both entities existing in one family.25Becker2,"n his own extensive writings has long recognized that PC presents in two different forms. Those patients with PC who developed
Copyright O 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 100 16. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
Erich W. Streib, M.D., F.A.C.P.
SEMINARS I N NEUKOI.OC;Y
THE CLINICAL SYNDROMES PARAMYOTONZA CONGENZTA
PC is a rare, autosomal-dominantly inherited disorder with strong gene penetrance. Recent linkage studies in several large families from Germany have not resulted in identifiable chromosomal loci."' Signs of the disease occur in infancy. Parents familiar with the disorder can often determine if their children are affected by observing prolonged eye closure and stiffness of the child's face after crying and grimacing or after washing its face with cold water. This cold-induced muscle stiffness affects predominantly the facial muscles, the tongue, the throat, and hand muscles. The muscle stiffness or myotonia is "paradoxical." In the typical patient repeated muscle contraction of the cooled muscle leads to increasing stiffness; delayed muscle relaxation; and, eventually, prolonged flaccid paralysis. These are the most conspicuous and specific features of PC and are not found in related disorders (see later). This cold- or exercise-induced paralysis is brief if the facial and pharyngeal muscles are affected, but may often last many hours beyond the time of rewarming in the hand-and occasionally the leg-muscles. Episodic weakness unrelated to the time of cold exposure is common in the legs and is triggered by rest following exercise, hunger, or both (see case reports). Between attacks, neurologic examination of patients with PC reveals well-built, usually "muscular" individuals with normal or superior muscle strength. Tendon reflexes and muscle tone are normal and there are no involuntary muscle contractions. Hand-grip myotonia and percussion myotonia are inconspicuous. Delayed eye opening after repetitive forced eye closure, however, is present almost invariably. Muscle atrophy is not part of the disease and should point to other diagnostic considerations. PC is restricted to muscular symptoms and signs; there is no clinical evidence of other organ involvement. Recent studies of erythrocyte membranes in patients with PC, however, have raised the question of a more generalized 250 membrane d e f e ~ t . ~ '
SE1'7F;MHEK I991
Although symptonis of paramyotonia are stereotyped, the severity and frequency of' symptoms vary in individual patients. Some paticnts devttlop exercise-induced muscle weakness at warm arnbient temperatures or when the hands and other body parts are exposed to a gentle draft."-" 0 t h ers complain about stiffness only during extremely cold weather. Individual variability is also present in families; in our families episodic weakness and severe muscle stif'fness are much more common in nlen."Vt is our hypothesis that more powerful muscle bulk in men causes stronger muscle contractions and therefore greater exerc-ise-induced muscle weakness."Vn women severely affected with PC, symptoms may be worse during pregnancy. A recent case report suggested that cold-induced abdominal wall contraction led to an a1)ortion in such a patient.'" ADYNAMZA EPZSODZCA HEREDZTARZA
lnheritance of AEIHPP is autosomal dorninant with strong penetrance. The disease begins in late childhood. Attacks of weakness are variable and may be brief, with asymmetrical weakness ("brief" attacks), or prolonged with generalized weakness ("long" attacks). Either or both may occur in individual patients. Paralytic attacks are usually provoked by rest after exercise. They may be preceded by sensations of tiredness, aching, or heaviness in the legs. At times, the patient may be able to "walk his weakness off," but this is not invariably so. Cold, hunger, and sleep are additional provocative factors. Many patients with AEIHPP have cold-sensitive stiffness of the face, tongue, and hands and clinical evidence of' lid lag, eye closure myotonia, or mild percussion myotorlia,!'.14.1~'.l~'."'
During the paralytic attacks mild to moderate elevation of serum potassium may occur, but this is not invariably present."' Generalized paralysis can be precipitated by potassium loading, but the loading dose varies from patient to patient.?"
CASE HISTORIES CASE I
A 26-year-old man experienced lifelong intermittent muscle stiffness and weakness when he was exposed to cold temperatures or cool drafts; his eye movements would stiffen and become "slow," his eyelids drooped, and his speech became slurred. Drinking cold beverages or eating ice cream would briefly "paralyze" his tongue and throat and talking would be difficult. Most dis-
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prolonged weakness only in association with coldinduced stiffness and exercise, he called "pure" PC. For the far smaller numbers of patients who suffered from PC and "spontaneous" paralytic attacks, he coined the term "paralysis periodica paramyotonica".:' Becker also observed that paralytic attacks were more severe in adolescence and improved with advancing age in this group.
VOLUME 11, N U M B E R 3
Comment
This young man was o u r most severely affected patient with PC. ' I h e salient feature was the occurrence of muscle stilfness and severe weakriess even at warm summer temperatures. CASE 2
A 2 1-year-old man experienced cold-induced muscle stiffness since infancy. O n cold exposure,
his hands became stiff, would cramp, and then would be almost paralyzed for several hours. At age 17, he developed intermittent episodes of generalized weakness, triggered by heavy exercise such as fi)otball playing o r weightlifting. Weakness occurred while he was resting after the exercise. Symptoms began with an aching, cramping pain in his legs, sometimes associated with a tingling sensation in both legs and hands. Sometimes he was able to ward off impending weakness by gentle exercises such as bicycling. Weakness and aching were most pronounced in his legs, less in his arms. 'The right arm was always more affected than the left arm. During most of these attacks, he could walk but was unable to participate in sports. Complete recovery required several hours and occasionally several days. O n two occasions, he developed such severe leg weakness after long nonstop car trips that he could not walk for several hours. Susceptibility to episodes of' generalized weakness was variable; they were most likely to occur when he was under mental stress. Serum potassium level was measured during several paretic episodes and was always between 3.6 and 4.0 mEq/l. Treatment with hydrochlorothiazide 50 mglday for 2 months lowered the serum potassium to 3.0 to 3.3 mEqIl, but there was no change in his symptomatology. 'Ii-eatment with albuterol inhaler did not prevent attacks of' exercise-induced weakness. Examination revealed a muscular, athletic man. Paradoxical eye closure myotonia was prominent. 1 here was no hand-grip myotonia. Percussion myotonia was present in both calf and hamstring muscles but not in the thenar muscles. Muscle stretch reflexes and sensation were normal. Motor nerve conduction velocities were normal and the evoked CMAP amplitudes were of' normal size. At room temperature, short arid prolonged exercise tests revealed no abnormalities. Exercising the hand fbr short periods with hand and forearm in cold water (surface hand temperature 25°C) led to a marked decrease of the area and amplitude of the CMAP. Several hours were required for complete clinical and CMAP recovery. Potassium loading with 8 gm potassium chloride given orally resulted in an increase in the serum potassium from 3.5 to 5.9 mEqll within 90 minutes. There was generalized muscle aching and minimal weakness. Prolonged exercise at the higher potassium level resulted in a delayed, progressive decline of the CMAP for both the abductor digiti quinti and the anterior tibia1 muscles (the two muscles exercised). Recovery was delayed for several hours. 'Treatment with tocainide in doses of' 800 to 1200 mglday resulted in marked improvement of the patient's paramyotonic symptoms and inter?
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abling, however, was the presence of intermittent severe muscle weakness. Although of normal build and strongly muscled, he could never participate in athletics. Even in warm weather he could run only 100 yards before developing leg stiffness. Forcing himself' beyond that limit resulted in achy muscles and was followed by prolonged weakness. Night watch on a navy ship would "paralyze" his hands and he would be unable to undress himself. In a cool office, he would experience hand weakness when writing. He kept his thermostat at home at 78" F and used an electric blanket throughout the year to avoid morning stiffness arid leg weakness. He did not have periodic attacks of' paralysis. If leg weakness was present in the morning on awakening, it was accompanied by stiffness. Symptoms improved when he moved from the Great 1,akes region to Florida. Examination revealed a well-built but not excessively muscular man. Ptosis was not present, but, with forceful repetitive eye closure, delayed eye opening occurred. Eye movements were normal. Hand-grip myotonia was absent but repetitive hand gripping led to hand stiffness. Percussion myotonia of tongue and thenar muscle was present. Tendon reflexes were brisk; strength and coordination were normal. Serum creatinirie kinase (CK) level was slightly elevated. A right deltoid muscle biopsy revealed central nuclei in 10% of the muscle fibers, and there was mild type 1 fiber atrophy. A glucoselinsulin challenge did not produce weakness. Potassium loading without prior o r subsequent exercise caused generalized muscle stiffness but no weakness and no changes in the evoked compound muscle action potential (CMAP). Normal nerve conduction velocities and evoked CMAPs were obtained at rest. Needle electrode exarriiriatiori revealed widespread myotonic discharges in all proximal and distal muscles. 'l'he motor- unit potential (MUP) pattern was normal. Short periods of' exercise before and particularly after cooling led to a marked reduction of the CMAP with recovery delayed for several hours.
7
251
SEMINAKS IN NEUROLOGY
Comment This man with clinically typical PC developed episodic weakness reminiscent of AEIHPP. Results of exercise or potassium challenge and pharmacologic responses were incompatible with the diagnosis of AEIHPP.
CASE 3
A 28-year-old woman had stiffness of the face, tongue, and hands on exposure to cold. T h e family history revealed that two of her three children and her brother, father, and paternal grandfather were affected, with similar symptoms. Except for intermittent hand weakness, she never had paralytic symptoms. She was concerned about lack of finger dexterity, which interfered with her daily work. Examination revealed a muscular young wornan with superior muscle strength. Both paradoxical eye closure and mild hand-grip myotonia, as well as prominent percussion myotonia of her calf muscles, were evident. Tendon reflexes and sensation were normal. Nerve conduction studies were normal. Initially tested when her hands were cold, her evoked CMAPs were of small amplitude. Repeat studies with warm hands resulted in evoked CMAPs of large, normal amplitude. There was no change with short exercise at room temperature; exercise after cooling the hand muscles resulted in a marked drop of the CMAP. Recovery was delayed for several hours. Needle electrode examination revealed widespread myotonic discharges in all examined muscles; there were no other abnormalities. Treatment with tocainide abolished all her symptoms and signs. She takes 200 mg daily in the summer, 200 to 600 mg daily in the winter; she occasionally adds 200 mg when she anticipates unusual physical or cold-induced stress. She tolerates the medication well.
SEPTEMBER 1991
CLINICAL ELECTROMYOGRAPHIC STUDIES 'I'he motor nerve conduction studies in patients with PC reveal normal-sized CMAPs unless the patient is experiencing a paralytic attack. Conduction velocities and sensory nerve action potentials are always normal. A decremental response on repetitive nerve stimulation at room temperature is an unusual finding in PC. Needle electrode examination reveals widespread myotonic discharges in all proximal and distal muscles, even if clinical nlyotonia is absent. T h e MUP pattern is normal.
PATHOPHYSIOLOGIC CONSIDERATIONS
As the arm is cooled, a patient with PC initially complains of stiffness in the hand. Muscle contractions become weak and labored, and relaxation of the muscle contraction becomes prolonged. When the hand is almost paralyzed, it assumes a claw position. When the electromyogram is recorded with needle electrodes from the small hand muscles during cooling, fibrillation potential-like responses appear and then become intense; they disappear during the stage of paralysis.J"4" Mechanographic registration of isometric forearm muscle contraction during cooling initially reveals a relatively well-preserved amplitude of the response with a progressively increasing relaxation time. Further exercise leads to smaller amplitudes of the contraction. With rewarming of the extremity, the relaxation time returns to normal, but the amplitude and tbrce of the contraction remain small until complete recovery occurs several hours later.n,3n3y.4' This delayed cooling- or exercise-induced muscle relaxation has not been recorded in either AE or the other myotonic ~ ~ n d r o m e s . ~ , " " ~ ' Lehmann-Horn and associate^^',"^ studied intercostal muscle biopsies of six unrelated patients with PC. In vitro studies using voltage clamp techniques revealed a normal resting membrane potential at 37°C.42,4Wowever,at 27"C, sodium conductance was abnormally high, resulting in long-lasting membrane depolarization to about - 40 mV with subsequent inexcitability of the nluscle fibers. Tetrodotoxin prevented depolarization of the muscle membrane induced by cooling and stimulation. In solutions with high potassium concentrations, PC muscle fibers behaved "normally" Comment in contrast to muscle fibers from patients with This patient has had typical paramyotonic AE.1"'7.4',4"This easily explains the exercise- or cooling-induced weakness, but not the delayed symptoms without any paralytic attacks.
252
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mittent paralysis. This dosage did not totally abolish the exercise-induced weakness, and prior to football and baseball games the patient benefited from an additional dose of tocainide.
VOLUME 11, N U M B E R 3
EXERCISE TESTING We have found CMAP monitoring practical, since special equipment is not required and the test can be done in any clinical EMG laboratory.'"'I7 T h e CMAP reflects the electrical properties of muscle fibers well. Single supraniaximal nerve stimuli are well tolerated and the evoked CMAP is reproducible and independent of the patient's cooperation. Its only drawback is the temperaturedependence of the potential s i ~ e . " ~ " ~ Protocols using either short periods (short exercise test)""."" o r longer periods (long exercise)" of isometric muscle coritraction can be used. This is best performed with CMAP recording from the hypothenar eminence with stimulation of the ulnar nerve at the wrist. We have also used the anterior compartment muscles as recording site and stimulated the peroneal nerve at the knee level. Using the prolonged exercise test, McManis et demonstrated an abnorrnal response in all patients with any form of periodic paralysis; there was a greater than normal increase in CMAP size during the exercise period, followed by progressive decline in amplitude over the following 20 to 40 minutes. Subramony and Wee"" obtained identical results in
their patients with hyperkalemic periodic paralysis. All patients with PC"'."' had a normal prolonged exercise test at room temperature except for the particularly severely affected young man, Case 1. Weakness and decreasing CMAPs could be demonstrated, however, in every patient with PC who exercised at lowered muscle tenlperature." T h e variability of response, o r individual sensitivity, to the cold o r exercise challenge was striking. Patients with more severe clinical symptoms and signs required less cooling and less to obtain an abnormal test than less severely affected individuals. Recognition of this "individual threshold" is necessary to ensure that the test challenge is sufficient before assuming results are normal.
POTASSIUM CHALLENGE A potassium challenge is used to determine whether patients are "potassium-sensitive." With adequate potassium concentration, patients with AEIHPP develop quadriparesis and often a much higher serum potassium level than unaffected persons given the same amount of potassium.'"20."" T h e evoked CMAP should be monitored during such testing, since clinical weakness may not be evident at a time when the CMAP has decreased by about 50%.'" During potassium loading, o u r three patients with PC developed generalized muscle aching and stiffness without generalized weakness." Generalized muscle stiffness is not unexpected with potassium loading. It occurs in other forms of myotonia as well." Wegmuller et alj2 exposed patients with PC to cold temperatures in a refrigeration chamber. This led to stif'fness and mild weakness of the face and hand muscles, which improved immediately after rewarming. Exercise was not performed. When the same patients were challenged with increasing amounts of potassium on subsequent days to obtain serum potassium levels of more than 6.0 mEqIl, stiffness and mild weakness were similar to that seen after cold exposure. None of these patients had more generalized weakness. When PC patients were exercised after potassium loading, we observed focal muscle weakness that was not present when these patients were exercised without a potassium challenge."' Potassium loading must thus "sensitize" the muscles of patients with PC in some way to cause exercise-induced muscle stiffness and paralysis similar to that of cold expo-
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muscle relaxation, which Ricker et all' investigated further by con~biningthe results from recordings of isometric muscle force and EMG activity with intramuscular needle electrodes with the findings from in vitro studies of biopsied intercostal muscle. 'They concluded that the stiffness in PC could not be caused by continued electrical discharges (after discharges). They suggested that delayed muscle relaxation was instead related somehow to prolonged muscle fiber depolarization but did not know its exact mechanism.'" In vitro studies of intercostal muscle biopsies from patients with defined AEIHPP revealed less specific result^."^"^'^' Moreover, among patients with AEIHPP, the findings differed in those with and without clinical myotonia. It was concluded that patients with AEIHPP have abnormal sodium currents across the nluscle membrane, leading to depolarization and paralysis. This paralysis occurred at a much higher membrane potential in patients with AEIHPP, compared with both normal controls and patients with PC:. Muscle fibers from patierits with AEIHPP became paralyzed when the potassium concentration in the bathing solution was increased. Delayed muscle fiber relaxation did not occur in muscle fibers from patients with AEIHPP."
SEMINAKS I N NEUROI,O
1 1 , NO. 3 SEPTEMBER 1991
Paramyotonia Congenita
Every clinician concerned with the evaluation of patients with myotonic disorders has seen individual patients and families who do not fit easily into the framework of a classification, and, new, seemingly distinct myotonic syndromes continue to be described.l This clinical heterogeneity of the myotonias has best been documented by the detailed clinical-genetic studies of Becker in Germany.'," There is less clinical variability in the nondystrophic myotonias. In paramyotonia congenita (PC), diagnostic problems usually arise in regard to the variable severity and the nature of transient weakness and its distinction from or association with adynamia episodica hereditaria (AE), also called hyperkalemic periodic paralysis (HPP). In this article I shall try to provide a clinically oriented picture of PC based on recent advances and my own experience in studying and treating many members of several families with PC. AEIHPP will be presented in the context of the differential diagnosis and its possible relationship or association with PC.
HISTORICAL BACKGROUND Eulenburg4 described a new myotonic illness in 1886 and coined the name paramyotonia congenita. He had studied a family living in the Baltic Sea area. Detailed medical information of six generations had been recorded by a family member who was a physician. T h e propositus was a woman born in Rome to a "Roman mother," transporting the illness to the northeastern part of Germany. Eulenburg recognized all the essential features of PC, including its dominant inheritance, onset in infancy, and cold-induced muscle stiffness with predilection for the muscles of face, hands, and tongue. He described the occurrence of prolonged
muscle weakness after exercise in moderate or severely cold temperatures and recognized that the disease was essentially unchanged throughout life. He noted in passing rhythmic oscillations in the thigh muscles, occurring during the state of transient leg weakness. This sign could be interpreted as "hyperexcitability" of peripheral nerve fibers as described in HPP,5 but Eulenburg did not describe spontaneous attacks of paralysis. This initial description of PC has withstood time well and firmly differentiates PC from other dystrophic and nondystrophic myotonic disorders. In certain families, however, affected members were described as having prominent myotonia at normal temperature relieved with exercise, in contrast to the typically encountered paradoxical myotonia."' In 1956, Ingrid Gamstorp-elineated clinical and laboratory features of AEIHPP in distinction to hypokalemic periodic paralysis. Shortly thereafter, families were described with affected members who seemed to fulfill diagnostic criteria for both PC and AE/HPP.'0-13Some of these had atypical features such as muscle wasting in later years and permanent w e a k n e s ~ ,findings ' ~ ~ ~ ~ common in AEIHPP but not in patients with true PC. Since the 1950s, there have been numerous publications and studies to support either the lumping or splitting of these two diseases (see Engel14 and Kicker et all5 for reviews). Hyperkalemic attacks have been described without clinical with or electromyographic (EMG) myotonia,Y.16,17 myotonia,17-"'and with p a r a m y o t ~ n i a . ~ ~ -con~Vo fuse the situation further, patients with PC were observed to have hypokalemic attack^^,^' or both hypokalemic and hyperkalemic attacks of paralyis.'^-'^ A recent article suggested clinical and electrophysiologic evidence of both entities existing in one family.25Becker2,"n his own extensive writings has long recognized that PC presents in two different forms. Those patients with PC who developed
Copyright O 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 100 16. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
Erich W. Streib, M.D., F.A.C.P.
SEMINARS I N NEUKOI.OC;Y
THE CLINICAL SYNDROMES PARAMYOTONZA CONGENZTA
PC is a rare, autosomal-dominantly inherited disorder with strong gene penetrance. Recent linkage studies in several large families from Germany have not resulted in identifiable chromosomal loci."' Signs of the disease occur in infancy. Parents familiar with the disorder can often determine if their children are affected by observing prolonged eye closure and stiffness of the child's face after crying and grimacing or after washing its face with cold water. This cold-induced muscle stiffness affects predominantly the facial muscles, the tongue, the throat, and hand muscles. The muscle stiffness or myotonia is "paradoxical." In the typical patient repeated muscle contraction of the cooled muscle leads to increasing stiffness; delayed muscle relaxation; and, eventually, prolonged flaccid paralysis. These are the most conspicuous and specific features of PC and are not found in related disorders (see later). This cold- or exercise-induced paralysis is brief if the facial and pharyngeal muscles are affected, but may often last many hours beyond the time of rewarming in the hand-and occasionally the leg-muscles. Episodic weakness unrelated to the time of cold exposure is common in the legs and is triggered by rest following exercise, hunger, or both (see case reports). Between attacks, neurologic examination of patients with PC reveals well-built, usually "muscular" individuals with normal or superior muscle strength. Tendon reflexes and muscle tone are normal and there are no involuntary muscle contractions. Hand-grip myotonia and percussion myotonia are inconspicuous. Delayed eye opening after repetitive forced eye closure, however, is present almost invariably. Muscle atrophy is not part of the disease and should point to other diagnostic considerations. PC is restricted to muscular symptoms and signs; there is no clinical evidence of other organ involvement. Recent studies of erythrocyte membranes in patients with PC, however, have raised the question of a more generalized 250 membrane d e f e ~ t . ~ '
SE1'7F;MHEK I991
Although symptonis of paramyotonia are stereotyped, the severity and frequency of' symptoms vary in individual patients. Some paticnts devttlop exercise-induced muscle weakness at warm arnbient temperatures or when the hands and other body parts are exposed to a gentle draft."-" 0 t h ers complain about stiffness only during extremely cold weather. Individual variability is also present in families; in our families episodic weakness and severe muscle stif'fness are much more common in nlen."Vt is our hypothesis that more powerful muscle bulk in men causes stronger muscle contractions and therefore greater exerc-ise-induced muscle weakness."Vn women severely affected with PC, symptoms may be worse during pregnancy. A recent case report suggested that cold-induced abdominal wall contraction led to an a1)ortion in such a patient.'" ADYNAMZA EPZSODZCA HEREDZTARZA
lnheritance of AEIHPP is autosomal dorninant with strong penetrance. The disease begins in late childhood. Attacks of weakness are variable and may be brief, with asymmetrical weakness ("brief" attacks), or prolonged with generalized weakness ("long" attacks). Either or both may occur in individual patients. Paralytic attacks are usually provoked by rest after exercise. They may be preceded by sensations of tiredness, aching, or heaviness in the legs. At times, the patient may be able to "walk his weakness off," but this is not invariably so. Cold, hunger, and sleep are additional provocative factors. Many patients with AEIHPP have cold-sensitive stiffness of the face, tongue, and hands and clinical evidence of' lid lag, eye closure myotonia, or mild percussion myotorlia,!'.14.1~'.l~'."'
During the paralytic attacks mild to moderate elevation of serum potassium may occur, but this is not invariably present."' Generalized paralysis can be precipitated by potassium loading, but the loading dose varies from patient to patient.?"
CASE HISTORIES CASE I
A 26-year-old man experienced lifelong intermittent muscle stiffness and weakness when he was exposed to cold temperatures or cool drafts; his eye movements would stiffen and become "slow," his eyelids drooped, and his speech became slurred. Drinking cold beverages or eating ice cream would briefly "paralyze" his tongue and throat and talking would be difficult. Most dis-
Downloaded by: Universite Laval. Copyrighted material.
prolonged weakness only in association with coldinduced stiffness and exercise, he called "pure" PC. For the far smaller numbers of patients who suffered from PC and "spontaneous" paralytic attacks, he coined the term "paralysis periodica paramyotonica".:' Becker also observed that paralytic attacks were more severe in adolescence and improved with advancing age in this group.
VOLUME 11, N U M B E R 3
Comment
This young man was o u r most severely affected patient with PC. ' I h e salient feature was the occurrence of muscle stilfness and severe weakriess even at warm summer temperatures. CASE 2
A 2 1-year-old man experienced cold-induced muscle stiffness since infancy. O n cold exposure,
his hands became stiff, would cramp, and then would be almost paralyzed for several hours. At age 17, he developed intermittent episodes of generalized weakness, triggered by heavy exercise such as fi)otball playing o r weightlifting. Weakness occurred while he was resting after the exercise. Symptoms began with an aching, cramping pain in his legs, sometimes associated with a tingling sensation in both legs and hands. Sometimes he was able to ward off impending weakness by gentle exercises such as bicycling. Weakness and aching were most pronounced in his legs, less in his arms. 'The right arm was always more affected than the left arm. During most of these attacks, he could walk but was unable to participate in sports. Complete recovery required several hours and occasionally several days. O n two occasions, he developed such severe leg weakness after long nonstop car trips that he could not walk for several hours. Susceptibility to episodes of' generalized weakness was variable; they were most likely to occur when he was under mental stress. Serum potassium level was measured during several paretic episodes and was always between 3.6 and 4.0 mEq/l. Treatment with hydrochlorothiazide 50 mglday for 2 months lowered the serum potassium to 3.0 to 3.3 mEqIl, but there was no change in his symptomatology. 'Ii-eatment with albuterol inhaler did not prevent attacks of' exercise-induced weakness. Examination revealed a muscular, athletic man. Paradoxical eye closure myotonia was prominent. 1 here was no hand-grip myotonia. Percussion myotonia was present in both calf and hamstring muscles but not in the thenar muscles. Muscle stretch reflexes and sensation were normal. Motor nerve conduction velocities were normal and the evoked CMAP amplitudes were of' normal size. At room temperature, short arid prolonged exercise tests revealed no abnormalities. Exercising the hand fbr short periods with hand and forearm in cold water (surface hand temperature 25°C) led to a marked decrease of the area and amplitude of the CMAP. Several hours were required for complete clinical and CMAP recovery. Potassium loading with 8 gm potassium chloride given orally resulted in an increase in the serum potassium from 3.5 to 5.9 mEqll within 90 minutes. There was generalized muscle aching and minimal weakness. Prolonged exercise at the higher potassium level resulted in a delayed, progressive decline of the CMAP for both the abductor digiti quinti and the anterior tibia1 muscles (the two muscles exercised). Recovery was delayed for several hours. 'Treatment with tocainide in doses of' 800 to 1200 mglday resulted in marked improvement of the patient's paramyotonic symptoms and inter?
Downloaded by: Universite Laval. Copyrighted material.
abling, however, was the presence of intermittent severe muscle weakness. Although of normal build and strongly muscled, he could never participate in athletics. Even in warm weather he could run only 100 yards before developing leg stiffness. Forcing himself' beyond that limit resulted in achy muscles and was followed by prolonged weakness. Night watch on a navy ship would "paralyze" his hands and he would be unable to undress himself. In a cool office, he would experience hand weakness when writing. He kept his thermostat at home at 78" F and used an electric blanket throughout the year to avoid morning stiffness arid leg weakness. He did not have periodic attacks of' paralysis. If leg weakness was present in the morning on awakening, it was accompanied by stiffness. Symptoms improved when he moved from the Great 1,akes region to Florida. Examination revealed a well-built but not excessively muscular man. Ptosis was not present, but, with forceful repetitive eye closure, delayed eye opening occurred. Eye movements were normal. Hand-grip myotonia was absent but repetitive hand gripping led to hand stiffness. Percussion myotonia of tongue and thenar muscle was present. Tendon reflexes were brisk; strength and coordination were normal. Serum creatinirie kinase (CK) level was slightly elevated. A right deltoid muscle biopsy revealed central nuclei in 10% of the muscle fibers, and there was mild type 1 fiber atrophy. A glucoselinsulin challenge did not produce weakness. Potassium loading without prior o r subsequent exercise caused generalized muscle stiffness but no weakness and no changes in the evoked compound muscle action potential (CMAP). Normal nerve conduction velocities and evoked CMAPs were obtained at rest. Needle electrode exarriiriatiori revealed widespread myotonic discharges in all proximal and distal muscles. 'l'he motor- unit potential (MUP) pattern was normal. Short periods of' exercise before and particularly after cooling led to a marked reduction of the CMAP with recovery delayed for several hours.
7
251
SEMINAKS IN NEUROLOGY
Comment This man with clinically typical PC developed episodic weakness reminiscent of AEIHPP. Results of exercise or potassium challenge and pharmacologic responses were incompatible with the diagnosis of AEIHPP.
CASE 3
A 28-year-old woman had stiffness of the face, tongue, and hands on exposure to cold. T h e family history revealed that two of her three children and her brother, father, and paternal grandfather were affected, with similar symptoms. Except for intermittent hand weakness, she never had paralytic symptoms. She was concerned about lack of finger dexterity, which interfered with her daily work. Examination revealed a muscular young wornan with superior muscle strength. Both paradoxical eye closure and mild hand-grip myotonia, as well as prominent percussion myotonia of her calf muscles, were evident. Tendon reflexes and sensation were normal. Nerve conduction studies were normal. Initially tested when her hands were cold, her evoked CMAPs were of small amplitude. Repeat studies with warm hands resulted in evoked CMAPs of large, normal amplitude. There was no change with short exercise at room temperature; exercise after cooling the hand muscles resulted in a marked drop of the CMAP. Recovery was delayed for several hours. Needle electrode examination revealed widespread myotonic discharges in all examined muscles; there were no other abnormalities. Treatment with tocainide abolished all her symptoms and signs. She takes 200 mg daily in the summer, 200 to 600 mg daily in the winter; she occasionally adds 200 mg when she anticipates unusual physical or cold-induced stress. She tolerates the medication well.
SEPTEMBER 1991
CLINICAL ELECTROMYOGRAPHIC STUDIES 'I'he motor nerve conduction studies in patients with PC reveal normal-sized CMAPs unless the patient is experiencing a paralytic attack. Conduction velocities and sensory nerve action potentials are always normal. A decremental response on repetitive nerve stimulation at room temperature is an unusual finding in PC. Needle electrode examination reveals widespread myotonic discharges in all proximal and distal muscles, even if clinical nlyotonia is absent. T h e MUP pattern is normal.
PATHOPHYSIOLOGIC CONSIDERATIONS
As the arm is cooled, a patient with PC initially complains of stiffness in the hand. Muscle contractions become weak and labored, and relaxation of the muscle contraction becomes prolonged. When the hand is almost paralyzed, it assumes a claw position. When the electromyogram is recorded with needle electrodes from the small hand muscles during cooling, fibrillation potential-like responses appear and then become intense; they disappear during the stage of paralysis.J"4" Mechanographic registration of isometric forearm muscle contraction during cooling initially reveals a relatively well-preserved amplitude of the response with a progressively increasing relaxation time. Further exercise leads to smaller amplitudes of the contraction. With rewarming of the extremity, the relaxation time returns to normal, but the amplitude and tbrce of the contraction remain small until complete recovery occurs several hours later.n,3n3y.4' This delayed cooling- or exercise-induced muscle relaxation has not been recorded in either AE or the other myotonic ~ ~ n d r o m e s . ~ , " " ~ ' Lehmann-Horn and associate^^',"^ studied intercostal muscle biopsies of six unrelated patients with PC. In vitro studies using voltage clamp techniques revealed a normal resting membrane potential at 37°C.42,4Wowever,at 27"C, sodium conductance was abnormally high, resulting in long-lasting membrane depolarization to about - 40 mV with subsequent inexcitability of the nluscle fibers. Tetrodotoxin prevented depolarization of the muscle membrane induced by cooling and stimulation. In solutions with high potassium concentrations, PC muscle fibers behaved "normally" Comment in contrast to muscle fibers from patients with This patient has had typical paramyotonic AE.1"'7.4',4"This easily explains the exercise- or cooling-induced weakness, but not the delayed symptoms without any paralytic attacks.
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mittent paralysis. This dosage did not totally abolish the exercise-induced weakness, and prior to football and baseball games the patient benefited from an additional dose of tocainide.
VOLUME 11, N U M B E R 3
EXERCISE TESTING We have found CMAP monitoring practical, since special equipment is not required and the test can be done in any clinical EMG laboratory.'"'I7 T h e CMAP reflects the electrical properties of muscle fibers well. Single supraniaximal nerve stimuli are well tolerated and the evoked CMAP is reproducible and independent of the patient's cooperation. Its only drawback is the temperaturedependence of the potential s i ~ e . " ~ " ~ Protocols using either short periods (short exercise test)""."" o r longer periods (long exercise)" of isometric muscle coritraction can be used. This is best performed with CMAP recording from the hypothenar eminence with stimulation of the ulnar nerve at the wrist. We have also used the anterior compartment muscles as recording site and stimulated the peroneal nerve at the knee level. Using the prolonged exercise test, McManis et demonstrated an abnorrnal response in all patients with any form of periodic paralysis; there was a greater than normal increase in CMAP size during the exercise period, followed by progressive decline in amplitude over the following 20 to 40 minutes. Subramony and Wee"" obtained identical results in
their patients with hyperkalemic periodic paralysis. All patients with PC"'."' had a normal prolonged exercise test at room temperature except for the particularly severely affected young man, Case 1. Weakness and decreasing CMAPs could be demonstrated, however, in every patient with PC who exercised at lowered muscle tenlperature." T h e variability of response, o r individual sensitivity, to the cold o r exercise challenge was striking. Patients with more severe clinical symptoms and signs required less cooling and less to obtain an abnormal test than less severely affected individuals. Recognition of this "individual threshold" is necessary to ensure that the test challenge is sufficient before assuming results are normal.
POTASSIUM CHALLENGE A potassium challenge is used to determine whether patients are "potassium-sensitive." With adequate potassium concentration, patients with AEIHPP develop quadriparesis and often a much higher serum potassium level than unaffected persons given the same amount of potassium.'"20."" T h e evoked CMAP should be monitored during such testing, since clinical weakness may not be evident at a time when the CMAP has decreased by about 50%.'" During potassium loading, o u r three patients with PC developed generalized muscle aching and stiffness without generalized weakness." Generalized muscle stiffness is not unexpected with potassium loading. It occurs in other forms of myotonia as well." Wegmuller et alj2 exposed patients with PC to cold temperatures in a refrigeration chamber. This led to stif'fness and mild weakness of the face and hand muscles, which improved immediately after rewarming. Exercise was not performed. When the same patients were challenged with increasing amounts of potassium on subsequent days to obtain serum potassium levels of more than 6.0 mEqIl, stiffness and mild weakness were similar to that seen after cold exposure. None of these patients had more generalized weakness. When PC patients were exercised after potassium loading, we observed focal muscle weakness that was not present when these patients were exercised without a potassium challenge."' Potassium loading must thus "sensitize" the muscles of patients with PC in some way to cause exercise-induced muscle stiffness and paralysis similar to that of cold expo-
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muscle relaxation, which Ricker et all' investigated further by con~biningthe results from recordings of isometric muscle force and EMG activity with intramuscular needle electrodes with the findings from in vitro studies of biopsied intercostal muscle. 'They concluded that the stiffness in PC could not be caused by continued electrical discharges (after discharges). They suggested that delayed muscle relaxation was instead related somehow to prolonged muscle fiber depolarization but did not know its exact mechanism.'" In vitro studies of intercostal muscle biopsies from patients with defined AEIHPP revealed less specific result^."^"^'^' Moreover, among patients with AEIHPP, the findings differed in those with and without clinical myotonia. It was concluded that patients with AEIHPP have abnormal sodium currents across the nluscle membrane, leading to depolarization and paralysis. This paralysis occurred at a much higher membrane potential in patients with AEIHPP, compared with both normal controls and patients with PC:. Muscle fibers from patierits with AEIHPP became paralyzed when the potassium concentration in the bathing solution was increased. Delayed muscle fiber relaxation did not occur in muscle fibers from patients with AEIHPP."
SEMINAKS I N NEUROI,O
