The nosological distinction between paramyotonia congenita (PC) and hyperkalemic periodic paralysis (HPP) continues to generate debate. Recently, electrophysiologicalsigns thought to be specific for each entity have been described and have been used to bolster the argument that the two disorders are distinct. We report a particularly instructive family wherein individual members had clinical features of either PC or HPP and electrophysiological features of both. We suggest that PC and HPP represent part of the spectrum of a single genetic disorder. Evoked response testing, with exercise and cold provocation, may be useful in determining the physiologic pattern that predominates in any one individual. Key words: paramyotonia congenita hyperkalemic periodic paralysis electrodiagnosis myotonia MUSCLE & NERVE 13~21-26 1990
PARAMYOTONIA CONGENITA OR HYPERKALEMIC PERIODIC PARALYSIS? CLINICAL AND ELECTROPHYSIOLOGICAL FEATURES OF EACH ENTITY IN ONE FAMILY SHARI M. DE SILVA, MD, RALPH W. KUNCL, MD, PhD, JOHN-W. GRIFFIN, MD, DAVID R. CORNBLATH, MD, and STEVEN CHAVOUSTIE, M D
I n 1886, Von Eulenberg described a previously unknown form of familial muscle disease characterized by episodic weakness, muscle stiffness, and myotonia precipiated by cold which he named "paramyotonia congenita" (PC)." Seventy years later, Gamstorp described a similar disease that was associated with an eIevated serum potassium, which she named "adynamia episodica hereditaria," or as it came to be called, hyperkalemic periodic paralysis (HPP).',' Since that time considerable debate has taken place as to whether the two entities are in fact distinct, based on the following:
From the Neuromuscular Division, Department of Neurology Johns Hopkns University School of Medicine Baltimore, MD (Drs de Silva, Kuncl, Griffin, and Cornblath) and the Department of Obstetrics and Gynecology, Dover Air Force Base Hospital, Dover, DE (Dr Chavoustie)
Or de Silva is currently at the Neuroimmunoiogy Branch, NINCDS, NIH, Building 10, Room 58-16, Bethesda, MD 20893 Acknowledgments The authors acknowledge the excellent technical assistance of C DiPietro and secretarial support of B Ertel This work was supported in part by a NINCDS Teacher Investigator Development Award (5-KO7-NS00734) (RWK) and by the Jay Slotkin Fund for Neuromuscular Research Address reprint requests and correspondence to Dr Kuncl at the Department of Neurology, Johns Hopkins Hospital, Meyer 5-119, 600 N Wolfe Street, Baltimore, MD 21205 Accepted for publication October 21, 1988 CCC 0148-639X190101021-06 $04 00 0 1990 John Wiley & Sons, Inc
Pararnyotonia & Periodic Paralysis
(1) HPP may be associated with my~tonia,"'".'~(2) attacks of paresis unrelated to cold may occur in pc,6,13.19 (3) focal paralysis may occur with cold exposure in patients with HPP,"14,20(4)potassium may provoke paralysis in patients with paramyotonia,6,22 and ( 5 ) both disorders are thought to be associated with abnormal Naf channel function.1°-12 In patients with the two disorders, distinct electrophysiological changes upon exercise and cold testing have been observed and proposed as specific for each entity.'s,2'326We report an informative family wherein members had clinical features of either PC, HPP, or both but individuals had electrophysiological features characteristic of both syndromes. CASE REPORTS Patient A. The proband is a 22-year-old pregnant woman who presented to her obstetrician with episodes of paralysis which increased in frequency and severity during the course of each of three pregnancies. Episodic weakness began at age 11 and occurred once every 1 - 2 years, usually when resting after exercise. Her father (patient C), brother (patient B), paternal grandfather, and uncle all had similar episodes (see Fig. 1).
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January 1990
21
AFFECTED HISTORICALLY :&ELECTROMMNOSTIC
0
AFFECTED HISTORICALLY
00 HISTORICALLY UNAFFECTED
I
63% mlscarriop.
FIGURE 1. Family pedigree. See case reports for details.
In her last trimester, the woman’s spells occurred daily and lasted 1 or 2 hours at a time. Between attacks her hands felt stiff. She thought she could abort some attacks by performing mild exercise when she felt a spell coming on. There was an increase in the severity of the attacks when she used a potassium-containing salt substitute, with improvement when this was discontinued. She denied nocturnal weakness or any cold-induced symptoms. Examination revealed only grip and percussion myotonia of the thenar muscles. Serum creatine kinase during these frequent attacks was elevated at 1647 IU/L (normal 0- 136 IU/L). Electromyography (EMG)of limb muscles during an attack showed frequent myotonic discharges. Voluntary motor unit potentials and recruitment were normal. Approximately 2 hours after delivery of her baby, while monitored, she had a spontaneous attack of weakness during which time her serum K + rose to 5.6 mEq/L, and she developed peaked T waves. Examination revealed severe quadriparesis sparing speech, respirations, and uterine and vaginal tone. The weakness, EKG changes, and serum K+ all esponded to the intravenous administration of glucose and insulin. Since that time she has been asymptomatic on acetazolamide. This 23-year-old man, the brother of patient A, recalled spells of leg weakness since his early childhood. The episodes were precipitated by rest following exercise and could be aborted by mild exercise. He had nocturnal paralysis twice monthly. He denied symptoms of any kind during cold exposure (including muscle stiffness or any exacerbation of the periodic paralysis) and in fact had worked in a cold locker for extended periods and had been an avid snow skier, with no symptoms. He reported the peculiar tendency of his eyes to move slowly (myotonia), such that head movement was required to change the line of viPatient B.
22
Pararnyotonia & Periodic Paralysis
sion. The neurological examination was normal, without percussion myotonia. Serum creatine kinase level was slightly elevated at 279 IU/L (normal 5 160 IU/L). EMG of the tibialis anterior showed frequent repetitive discharges at multiple needle sites, with normalappearing motor unit potentials. Five other tested muscles were normal. As a bedside test, a paralytic attack was induced by 10 minutes of continuous aerobic exercises followed by 40 minutes of bed rest. During the attack he lost all deep tendon reflexes, had mild weakness of his arms, and was completely unable to move his legs. Serum Kf immediately postexercise was 3.6 mEq/L. At the onset of weakness it rose to 5.6 mEq/L, and at the height of weakness was 6.0 mEq/L. N o EKG changes were noted, and the patient “walked off’ both the rise in serum K+ and the weakness within 20 minutes. The patient was given a trial of acetazolamide but felt that he became generally stiff on the drug and discontinued taking it. Patient c. This 46-year-old man had the onset in his early teens of nocturnal paralysis and episodic weakness that was most likely to occur in cold weather. Even between paralytic attacks he had cold-induced generalized stiffness and trouble releasing his grip. He, too, complained of intermittent myotonic eye movements. His spells were also precipitable by rest following exercise but over the years have diminished in frequency. The neurological examination was normal, without percussion myotonia. The serum creatine kinase was normal. EMG of both the abductor pollicus brevis (APB) and the 1st dorsal interosseous showed frequent insertional positive sharp waves, present at nearly every needle site. High-frequency repetitive discharges were present with morphology of normal motor units o r positive sharp waves. Voluntary motor unit potentials were normal. This patient reported increased stiffness when taking acetazolamide, but he found that the rest-induced paralysis that he was accustomed to experiencing with long crosscountry drives was entirely prevented by the drug.
MATERIALS AND METHODS
Electromyography and exercise testing were performed with a Nicolet Viking electromyograph using the protocol of McManis et al.15 Surfacerecording electrodes were placed over the belly of the abductor digiti minimi (ADM) and adjusted so that the amplitude of the compound muscle action
MUSCLE & NERVE
January 1990
potential (CMAP) evoked by supramaximal ulnar nerve stimulation at the wrist was maximized. CMAPs were elicited with the hand warmed to a skin temperature of 33-34°C. The ulnar nerve was stimulated at a rate of once/minute. A baseline tracing of 4-8 CMAPs was obtained, after which the ADM was exercised isometrically for 3-4 minutes, with 3-second rests every 15 seconds. The CMAP amplitude and area were recorded after each minute of exercise. At the completion of exercise the patient was instructed to relax completely, and CMAP responses to single shocks were recorded every 1-2 minutes for either 30 minutes or until no further decrease in amplitude or area could be elicited. In every case changes in CMAP amplitude exactly reflected CMAP area; thus we report results as amplitudes. Modifications of this procedure are reported separately for the individual study involved. In the three studies reported, whenever significant changes in the CMAP were noted, blood was obtained from a forearm vein above the site of stimulation and was stored on ice until the end of the study, at which time serum K+ determinations were rapidly made for all samples. RESULTS
Patient A (see Fig. 2) had no immediate changes in CMAP during exercise. Following exercise, however, a steep 91% decline in CMAP amplitude occurred over 45 minutes until stabilization. When the amplitude fell below 2 mV, generalized weakness and areflexia were apparent. The patient was quadriparetic; the legs were severely weak,
PATIENT A
EXEIX
10
II PATIENT RECOVERED X'.S.B rnEO/L
0 5 10 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 M )
,, 180
TIME IN MINUTES
FIGURE 2. Exercise testing in patient A with the syndrome of both hyperkalemic periodic paralysis and myotonia. No change in CMAP amplitude occurred during exercise, but a delayed fall ensued.
whereas proximal arm muscles were less involved. Cranial and respiratory muscles were spared. Serum K+ drawn during the height of weakness was 4.4 mEq/L, and EKG revealed peaked T waves. After the patient was permitted to exercise her arms mildly, she slowly regained function, returning to normal over the course of approximately 90 minutes. Serum K+ at this time was 3.8 mEq/L. Patient B was studied three times. On the first occasion during and following exercise the CMAP amplitude increased to 150% of baseline, peaking 8 minutes after exercise. It then declined over 45 minutes to a nadir of 7% of baseline, at which time leg weakness was present. At the second EMG study (Fig. 3A), CMAP amplitude increased 23% during exercise. After
EXERCISE
":ii
10
PATIENT B I
30 40 50 60 70 TIME IN MINUTES
20
B A FIGURE 3. Exercise testing and cold provocation in patient B with the syndrome of hyperkalemic periodic paralysis. (A) Reciprocal changes in serum K+ and CMAP amplitude during exercise testing. An increase in CMAP amplitude occurred during exercise, followed by a delayed fall. (B)Cold provoked an immediate sustained fall in CMAP amplitude, again with reciprocal changes in serum K*.
Paramyotonia & Periodic Paralysis
MUSCLE & NERVE
January 1990
23
reaching its peak, the evoked amplitude then fell 56% to its nadir 40 minutes following the end of the exercise period. Furthermore, serum K+ was inversely related to changes in CMAP, so that the decline in CMAP was accompanied by a rise in K+. The third EMG study (Fig. 3B) included provocative cold testing in addition to execise testing and serial K+ measurement. The patient began this study with a CMAP that was approximately 70% of that obtained for him during previous studies (despite all attempts to ensure accurate lead placement and supramaximal stimulation). After a stable baseline was obtained, a cold towel was applied to the hand, reducing skin temperature to between 27 and 29°C. This resulted in a decline in CMAP amplitude to a nadir of 18% of baseline. There was a rapid rise to 80% of baseline with hand rewarming alone. Exercise testing, performed after the skin temperature had returned to normal, again resulted in a prompt increase to 170% of baseline. The CMAP then declined and stabilized to 147% of the initial value, essentially identical to the values obtained for him at rest during previous studies. Once more, serum K+ was inversely related to all changes in CMAP, with the cold-induced decline in amplitude being accompanied by a rise in local serum K+. Patient C was studied on two occasions. During the first examination, there was an abrupt fall in CMAP amplitude beginning immediately after exercise and reaching a nadir of 44% of the baseline
EXERCISE
EXERClSE
H
H
I
3t
Y
I 0
PATIENT C
5
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
TIME IN MINUTES
FIGURE 4. Exercise testing in patient C with the syndrome of paramyotonia congenita. A prompt and transient fall in CMAP amplitude occurred during exercise: a sustained fall in CMAP amplitude was provoked by cold. There was no change in serum Kf.
24
Pararnyotonia & Periodic Paralysis
amplitude. CMAP amplitude returned within 2 minutes to baseline values and then remained stable. A second exercise study (Fig. 4) included serum K+ measurements and provocative cold testing. There was a prompt 51% decline in CMAP amplitude immediately after the beginning of exercise, with rapid recovery to baseline within 2 minutes of rest. After recovery, the CMAP amplitude remained stable for more than 30 minutes. A cold towel applied to the hand reduced skin temperature to 26-28°C and resulted in a slow and sustained decline in CMAP amplitude of >60%. At this time, focal weakness of the right ADM became apparent. Rewarming the hand to 34°C resulted in only minimal improvement in the CMAP. Repeat exercise for 2 minutes again produced a prompt and brief 38% decline. No significant changes in serum K+ occurred during the course of the examination. N o weakness could be elicited by exercise followed by 3 hours rest. DISCUSSION
These results illsutrate the presence of distinctive clinical and electrophysiological features of either paramyotonia congenita o r hyperkalemic periodic paralysis within a single family. T h e nosologic distinction between the two entities has been debated for almost 30 years. During that time numerous clinical subtypes of thidthese disorders have been described and given various names, includin familial hyperkalemic paralysis with myotnia?' familial myotonic periodic paralysis,28 and paralysis periodica paramyot~nica'~~~'~,'~~~~ among others."17 Multiple other observations raise questions about the separate identities of HPP and PC, as discussed aboVe.4-6.Y,1~,14,19,20.22,27 By contrast, proponents for the separation of the two diseases point to the homogeneity of symptoms within fa mi lie^^,^^^^ and challenge the experiments involving the production of focal weakness with cold in patients with HPP on a number of grounds. It has been suggested that immobility owing to prolonged rest may be a contributing factor in these patient^^^"^ or that the patients were tested when in the rocess of developing a generalized attack. 14,2' Also, excessively cold temperatures (13- 15°C) were used, and even normal persons may develop focal weakness with prolonged cooling at extremely low temperatures.6726Reports that patients with HPP respond to thiazide diuretic^'^ or to beta adrenergic drugs,3 whereas patients with PC respond to t ~ c a i n i d e ' ~ and ' ~ ~ may be made worse with
MUSCLE & NERVE
January 1990
diuretics, l 9 also bolster the impression that the two disorders may be distinct. However, it should be noted that in one reported patient who had both hyperkalemic attacks as well as cold-induced muscle stiffness, the hyperkalemic spells were successfully treated with a diuretic, whereas the paramyotonic symptoms responded to tocainide. l 7 To add to this debate, a number of electrophysiological changes have been observed in patients with the two disorders and have been used to separate the two entities. 16,26 Most recently, distinct changes in the evoked CMAP during either exercise or cold provocation have been described. Streib and his coworkers, in studies of patients with a variety of myotonic disorders including myotonia congenita, myotonic dystrophy, and PC, reported a transient but marked decline in evoked CMAP amplitude immediately following exercise .2 -23 Such declines were not seen in controls. The authors noted that in PC there was an immediate and prolonged exercise-induced decline in CMAP amplitude. They felt that this change could be distinguished from exercise testing in HPP where CMAP decline is delayed for at least 10- 15 minutes. 23 These observations were extended and confirmed in a large number of patients with periodic paralysis.15 In that study patients with HPP tended to have large increases in amplitude after exercise, followed by large decreases. The one patient with PC included in the study was found to have a 56% decrease in amplitude immediately after exercise, which was maximal in the first 3 minutes and then gradually returned to baseline similar to Streibs description for PC.23 Cold temperature-induced changes in CMAP amplitude have also been described as specifically separating HPP and PC.24,26In two members of a family with PC, cold temperature provoked decreases in both CMAP area and amplitude.24 By contrast, in a family with HPP there was only a mild temperature-related decrease in CMAP amplitude which was offset by a concomitant increase in CMAP area, similar to results reported for normal individuals.26 Because of the distinctly different responses which ran true within each family, it was suggested that HPP and PC were two distinct disorders. In our study we carried out exercise testing in three members of a family with autosomal domi-
Paramyotonia & Periodic Paralysis
nant transmission (see Fig. 1). Two of the members (A and B) had witnessed attacks, unrelated to cold exposure but associated with an elevated serum K + consistent with the diagnosis of HPP. Neither of these patients reported paramyotonia. Both experienced paralytic attacks during electrophysiological testing, and in both cases weakness became apparent when CMAP amplitude dropped below 2 mV. Patient B had increased serum K+ linked to the fall in CMAP amplitude even when not experiencing any clinical weakness. On all occasions studied, he had large exercise-induced immediate increases in CMAP amplitude. Both A and B, with symptomatic HPP, had large, delayed decreases in CMAP. These distinctive findings are similar to those reported for HPP in previous studies. 1592223 By contrast, patient C reported exacerbation of attacks during cold and, on the two occasions that exercise testing was performed ave results “characteristic” of the my~tonias~’-’~’ i.e., large immediate decreases in CMAP amplitude that rapidly reverse. Exposure to mild cold (26-28°C) resulted in profound decrease in both CMAP area and amplitude with no change in serum K+ in a fashion thought to be specific for PC.‘6 His son (Patient B), who clinically had HPP, also had a large, coldprovoked decrease in CMAP amplitude (a typical param yotonic response), which however was accompanied by a rise in serum K + . We suggest that the presence within a single family of members each having the clinical and electrophysiological features of either hyperkalemic periodic paralysis or of paramyotonia congenita suggests that the two disorders represent two extremes of the spectrum of a single genetic entity. In two of our patients, acetazolamide prevented spontaneous paralytic attacks but produced myotonia. This pattern of exacerbation of myotonia and alleviation of paralytic attacks with diuretics has been reported previously in a patient who had both PC and hyperkalemic paralytic attacks. l 7 The myotonia, by contrast, is alleviated by lidocaine derivatives which may worsen HPP. 17,22 Standard electromyographic testing with exercise and cold provocation, and measurement of local K+ during stimulation, may be useful to help determine which physiological pattern predominates for any particular individual and may help direct therapy.
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25
REFERENCES 1. Becker PE: Genetic approaches to the nosology of muscle
disease: myotonia and similar diseases. Birth Defects 1971;7:52-62. 2. Becker PE: Syndromes associated with myotonia: clinicalgenetic classification, in Rowland LP (ed): Pathogenesis of Human Muscular Dystrophies. Amsterdam, Exercepta Medica 1977, pp 609-703. 3. Bendheim PE, Reale EO, Berg BO: Beta-adrenergic treatment of hyperkalemic periodic paralysis. Neurology (NY) 1985;35:746-749. 4. Drager GA, Hammill JF, Shy GM: Paramyotonia congenita. Arch Neurol Psychiatry 1958;80: 1-9. 5. Engel AG, Lambert EH, Rosevear JW, Taure WN: Clinical and electromyographic studies in a patient with primary hyperkalemic periodic paralysis. Am J Med 1965;38:626646. 6. French EB. Kibatrick R: A varietv of Daramvotonia congenita. J Neurol Neurosurg Pqchiatry 1957;20:40-46. 7. Gamstorp I: Adynamia episodica hereditaria. Acta Paediatr Scand (suppl) 1956;108:1- 126. 8. Gamstorp I, Hauge M, Heuweg-Larsen F, Mjones H, Saghd U: Adynamia episodica hereditaria: a disease clinically resembling familial periodic paralysis but characterized by increasing serum potassium during paralytic attacks. Am J hfed 1957;23:385-390. 9. Layzer RB, Lovelace RE, Rowland LP: Hyperkalemic periodic paralysis. Arch Neurol 1967; 16:455-472. 10. Lehmann-Horn F, Kiither G, Ricker K, Grafe P, Ballanyi K, Riidel R: Adynamia episodica hereditaria: a noninactivating sodium current and the effect of intracellular pH. Muscle Nerve 1987; 10:363-374. 11. Lehmann-Horn F, Riidel R, Dengler R, Lorkovic H, Haass A, Ricker K: Membrane defects in paramyotonia congenita with and without myotonia in a warm environment. Muscle Nerve 1981;4:396-406. 12. Lehmann-Horn F, Riidel R, Ricker K, Lorkovic F, Dengler R, Hopf HC: Two cases of adynamia episodica hereditaria: in vitro investigation of muscle cell membrane and contraction parameters. Muscle Nerve 1983;6:113-121. 13. Lundberg PO, Stglberg E, Thiele B: Paralysis periodica paramyotonica. J Neurol Sci 1974;2 1:309- 32 1. 14. McArdle B: Adynamia episodica hereditaria and its treatment. Brain 1962;85:121- 148. ,
26
I
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15. McManis PG, Lambert EH, Daube JR: The exercise test in periodic paralysis. Muscle Nerve 1986;9:704-710. 16. Nielson VK, Frus ML, Johnsen F: Electromyographic distinction between paramyotonia congenita and myotonia congenita: Effect of cold. Neurology (NY) 1982;32:827832. 17. Ricker K, Bohlen R, Rohkamm R: Different effectiveness of tocainide and hydrochlorothiazide in paramyotonia congenita with hyperkalemic episodic paralysis. Neurology (NY) 1983;33:1615- 1618. 18. Ricker K, Meinck HM: Paramyotonia congenita (Eulenberg). Neurophysiologic studies of a case. 2 NeuroZ 1972; 203113-22. 19. Riggs JE, Griggs RC, Moxley RT 111: Acetazolamideinduced weakness in paramyotonia congenita. Ann Intern Med 1977;86: 169- 173. 20. Samaha FJ: Hyperkalemic periodic paralysis. Arch Neurol 1965; 12: 145- 154. 21. Streib EW: Evoked response testing in myotonic syndromes. Mwcle Nerve 1984;7:590-592. 22. Streib EW: Paramyotonia congenita: successful treatment with tocainide. Clinical and electrophysiologic findings in seven patients. Muscle Nerve 1987;10:155- 162. 23. Streib EW, Sun SF, Yaskowsky T: Transient paresis in myotonic syndromes: a simplified electrophysiologic approach. Muscle Nerve 1982;5:719-723. 24. Subramony SH, Malhotra CP, Mishra SK: Distinguishing paramyotonia congenita and myotonia congenita by electromyography. Mwcle Nerve 1983;6:374-379. 25. Subramony SH, Wee AS: Exercise and rest in hyperkalemic periodic paralysis. Neurology (NY) 1986;36: 173- 177. 26. Subramony SH, Wee AS, Mishra SK: Lack of cold sensitivity in hyperkalemic periodic paralysis. Muscle Nerve 1986;9:700- 703. 27. Van Der Muelen JP, Gilbert GJ, Kane CA: Familial hyperkalemic paralysis with myotonia. N Engl J Med 1961;264: 1- 10. 28. Van’t Hoff W: Familial myotonic periodic paralysis. Quart J Med 1962;31:385-402. 29. Von Eulenberg: Ueber eine familiare, durch 6 generations verfolghare form congenitaler paramyotonie. Neurol Centralblatt 1886;12:265-272.
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January 1990
PARAMYOTONIA CONGENITA OR HYPERKALEMIC PERIODIC PARALYSIS? CLINICAL AND ELECTROPHYSIOLOGICAL FEATURES OF EACH ENTITY IN ONE FAMILY SHARI M. DE SILVA, MD, RALPH W. KUNCL, MD, PhD, JOHN-W. GRIFFIN, MD, DAVID R. CORNBLATH, MD, and STEVEN CHAVOUSTIE, M D
I n 1886, Von Eulenberg described a previously unknown form of familial muscle disease characterized by episodic weakness, muscle stiffness, and myotonia precipiated by cold which he named "paramyotonia congenita" (PC)." Seventy years later, Gamstorp described a similar disease that was associated with an eIevated serum potassium, which she named "adynamia episodica hereditaria," or as it came to be called, hyperkalemic periodic paralysis (HPP).',' Since that time considerable debate has taken place as to whether the two entities are in fact distinct, based on the following:
From the Neuromuscular Division, Department of Neurology Johns Hopkns University School of Medicine Baltimore, MD (Drs de Silva, Kuncl, Griffin, and Cornblath) and the Department of Obstetrics and Gynecology, Dover Air Force Base Hospital, Dover, DE (Dr Chavoustie)
Or de Silva is currently at the Neuroimmunoiogy Branch, NINCDS, NIH, Building 10, Room 58-16, Bethesda, MD 20893 Acknowledgments The authors acknowledge the excellent technical assistance of C DiPietro and secretarial support of B Ertel This work was supported in part by a NINCDS Teacher Investigator Development Award (5-KO7-NS00734) (RWK) and by the Jay Slotkin Fund for Neuromuscular Research Address reprint requests and correspondence to Dr Kuncl at the Department of Neurology, Johns Hopkins Hospital, Meyer 5-119, 600 N Wolfe Street, Baltimore, MD 21205 Accepted for publication October 21, 1988 CCC 0148-639X190101021-06 $04 00 0 1990 John Wiley & Sons, Inc
Pararnyotonia & Periodic Paralysis
(1) HPP may be associated with my~tonia,"'".'~(2) attacks of paresis unrelated to cold may occur in pc,6,13.19 (3) focal paralysis may occur with cold exposure in patients with HPP,"14,20(4)potassium may provoke paralysis in patients with paramyotonia,6,22 and ( 5 ) both disorders are thought to be associated with abnormal Naf channel function.1°-12 In patients with the two disorders, distinct electrophysiological changes upon exercise and cold testing have been observed and proposed as specific for each entity.'s,2'326We report an informative family wherein members had clinical features of either PC, HPP, or both but individuals had electrophysiological features characteristic of both syndromes. CASE REPORTS Patient A. The proband is a 22-year-old pregnant woman who presented to her obstetrician with episodes of paralysis which increased in frequency and severity during the course of each of three pregnancies. Episodic weakness began at age 11 and occurred once every 1 - 2 years, usually when resting after exercise. Her father (patient C), brother (patient B), paternal grandfather, and uncle all had similar episodes (see Fig. 1).
MUSCLE & NERVE
January 1990
21
AFFECTED HISTORICALLY :&ELECTROMMNOSTIC
0
AFFECTED HISTORICALLY
00 HISTORICALLY UNAFFECTED
I
63% mlscarriop.
FIGURE 1. Family pedigree. See case reports for details.
In her last trimester, the woman’s spells occurred daily and lasted 1 or 2 hours at a time. Between attacks her hands felt stiff. She thought she could abort some attacks by performing mild exercise when she felt a spell coming on. There was an increase in the severity of the attacks when she used a potassium-containing salt substitute, with improvement when this was discontinued. She denied nocturnal weakness or any cold-induced symptoms. Examination revealed only grip and percussion myotonia of the thenar muscles. Serum creatine kinase during these frequent attacks was elevated at 1647 IU/L (normal 0- 136 IU/L). Electromyography (EMG)of limb muscles during an attack showed frequent myotonic discharges. Voluntary motor unit potentials and recruitment were normal. Approximately 2 hours after delivery of her baby, while monitored, she had a spontaneous attack of weakness during which time her serum K + rose to 5.6 mEq/L, and she developed peaked T waves. Examination revealed severe quadriparesis sparing speech, respirations, and uterine and vaginal tone. The weakness, EKG changes, and serum K+ all esponded to the intravenous administration of glucose and insulin. Since that time she has been asymptomatic on acetazolamide. This 23-year-old man, the brother of patient A, recalled spells of leg weakness since his early childhood. The episodes were precipitated by rest following exercise and could be aborted by mild exercise. He had nocturnal paralysis twice monthly. He denied symptoms of any kind during cold exposure (including muscle stiffness or any exacerbation of the periodic paralysis) and in fact had worked in a cold locker for extended periods and had been an avid snow skier, with no symptoms. He reported the peculiar tendency of his eyes to move slowly (myotonia), such that head movement was required to change the line of viPatient B.
22
Pararnyotonia & Periodic Paralysis
sion. The neurological examination was normal, without percussion myotonia. Serum creatine kinase level was slightly elevated at 279 IU/L (normal 5 160 IU/L). EMG of the tibialis anterior showed frequent repetitive discharges at multiple needle sites, with normalappearing motor unit potentials. Five other tested muscles were normal. As a bedside test, a paralytic attack was induced by 10 minutes of continuous aerobic exercises followed by 40 minutes of bed rest. During the attack he lost all deep tendon reflexes, had mild weakness of his arms, and was completely unable to move his legs. Serum Kf immediately postexercise was 3.6 mEq/L. At the onset of weakness it rose to 5.6 mEq/L, and at the height of weakness was 6.0 mEq/L. N o EKG changes were noted, and the patient “walked off’ both the rise in serum K+ and the weakness within 20 minutes. The patient was given a trial of acetazolamide but felt that he became generally stiff on the drug and discontinued taking it. Patient c. This 46-year-old man had the onset in his early teens of nocturnal paralysis and episodic weakness that was most likely to occur in cold weather. Even between paralytic attacks he had cold-induced generalized stiffness and trouble releasing his grip. He, too, complained of intermittent myotonic eye movements. His spells were also precipitable by rest following exercise but over the years have diminished in frequency. The neurological examination was normal, without percussion myotonia. The serum creatine kinase was normal. EMG of both the abductor pollicus brevis (APB) and the 1st dorsal interosseous showed frequent insertional positive sharp waves, present at nearly every needle site. High-frequency repetitive discharges were present with morphology of normal motor units o r positive sharp waves. Voluntary motor unit potentials were normal. This patient reported increased stiffness when taking acetazolamide, but he found that the rest-induced paralysis that he was accustomed to experiencing with long crosscountry drives was entirely prevented by the drug.
MATERIALS AND METHODS
Electromyography and exercise testing were performed with a Nicolet Viking electromyograph using the protocol of McManis et al.15 Surfacerecording electrodes were placed over the belly of the abductor digiti minimi (ADM) and adjusted so that the amplitude of the compound muscle action
MUSCLE & NERVE
January 1990
potential (CMAP) evoked by supramaximal ulnar nerve stimulation at the wrist was maximized. CMAPs were elicited with the hand warmed to a skin temperature of 33-34°C. The ulnar nerve was stimulated at a rate of once/minute. A baseline tracing of 4-8 CMAPs was obtained, after which the ADM was exercised isometrically for 3-4 minutes, with 3-second rests every 15 seconds. The CMAP amplitude and area were recorded after each minute of exercise. At the completion of exercise the patient was instructed to relax completely, and CMAP responses to single shocks were recorded every 1-2 minutes for either 30 minutes or until no further decrease in amplitude or area could be elicited. In every case changes in CMAP amplitude exactly reflected CMAP area; thus we report results as amplitudes. Modifications of this procedure are reported separately for the individual study involved. In the three studies reported, whenever significant changes in the CMAP were noted, blood was obtained from a forearm vein above the site of stimulation and was stored on ice until the end of the study, at which time serum K+ determinations were rapidly made for all samples. RESULTS
Patient A (see Fig. 2) had no immediate changes in CMAP during exercise. Following exercise, however, a steep 91% decline in CMAP amplitude occurred over 45 minutes until stabilization. When the amplitude fell below 2 mV, generalized weakness and areflexia were apparent. The patient was quadriparetic; the legs were severely weak,
PATIENT A
EXEIX
10
II PATIENT RECOVERED X'.S.B rnEO/L
0 5 10 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 M )
,, 180
TIME IN MINUTES
FIGURE 2. Exercise testing in patient A with the syndrome of both hyperkalemic periodic paralysis and myotonia. No change in CMAP amplitude occurred during exercise, but a delayed fall ensued.
whereas proximal arm muscles were less involved. Cranial and respiratory muscles were spared. Serum K+ drawn during the height of weakness was 4.4 mEq/L, and EKG revealed peaked T waves. After the patient was permitted to exercise her arms mildly, she slowly regained function, returning to normal over the course of approximately 90 minutes. Serum K+ at this time was 3.8 mEq/L. Patient B was studied three times. On the first occasion during and following exercise the CMAP amplitude increased to 150% of baseline, peaking 8 minutes after exercise. It then declined over 45 minutes to a nadir of 7% of baseline, at which time leg weakness was present. At the second EMG study (Fig. 3A), CMAP amplitude increased 23% during exercise. After
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PATIENT B I
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B A FIGURE 3. Exercise testing and cold provocation in patient B with the syndrome of hyperkalemic periodic paralysis. (A) Reciprocal changes in serum K+ and CMAP amplitude during exercise testing. An increase in CMAP amplitude occurred during exercise, followed by a delayed fall. (B)Cold provoked an immediate sustained fall in CMAP amplitude, again with reciprocal changes in serum K*.
Paramyotonia & Periodic Paralysis
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January 1990
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reaching its peak, the evoked amplitude then fell 56% to its nadir 40 minutes following the end of the exercise period. Furthermore, serum K+ was inversely related to changes in CMAP, so that the decline in CMAP was accompanied by a rise in K+. The third EMG study (Fig. 3B) included provocative cold testing in addition to execise testing and serial K+ measurement. The patient began this study with a CMAP that was approximately 70% of that obtained for him during previous studies (despite all attempts to ensure accurate lead placement and supramaximal stimulation). After a stable baseline was obtained, a cold towel was applied to the hand, reducing skin temperature to between 27 and 29°C. This resulted in a decline in CMAP amplitude to a nadir of 18% of baseline. There was a rapid rise to 80% of baseline with hand rewarming alone. Exercise testing, performed after the skin temperature had returned to normal, again resulted in a prompt increase to 170% of baseline. The CMAP then declined and stabilized to 147% of the initial value, essentially identical to the values obtained for him at rest during previous studies. Once more, serum K+ was inversely related to all changes in CMAP, with the cold-induced decline in amplitude being accompanied by a rise in local serum K+. Patient C was studied on two occasions. During the first examination, there was an abrupt fall in CMAP amplitude beginning immediately after exercise and reaching a nadir of 44% of the baseline
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PATIENT C
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10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
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FIGURE 4. Exercise testing in patient C with the syndrome of paramyotonia congenita. A prompt and transient fall in CMAP amplitude occurred during exercise: a sustained fall in CMAP amplitude was provoked by cold. There was no change in serum Kf.
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Pararnyotonia & Periodic Paralysis
amplitude. CMAP amplitude returned within 2 minutes to baseline values and then remained stable. A second exercise study (Fig. 4) included serum K+ measurements and provocative cold testing. There was a prompt 51% decline in CMAP amplitude immediately after the beginning of exercise, with rapid recovery to baseline within 2 minutes of rest. After recovery, the CMAP amplitude remained stable for more than 30 minutes. A cold towel applied to the hand reduced skin temperature to 26-28°C and resulted in a slow and sustained decline in CMAP amplitude of >60%. At this time, focal weakness of the right ADM became apparent. Rewarming the hand to 34°C resulted in only minimal improvement in the CMAP. Repeat exercise for 2 minutes again produced a prompt and brief 38% decline. No significant changes in serum K+ occurred during the course of the examination. N o weakness could be elicited by exercise followed by 3 hours rest. DISCUSSION
These results illsutrate the presence of distinctive clinical and electrophysiological features of either paramyotonia congenita o r hyperkalemic periodic paralysis within a single family. T h e nosologic distinction between the two entities has been debated for almost 30 years. During that time numerous clinical subtypes of thidthese disorders have been described and given various names, includin familial hyperkalemic paralysis with myotnia?' familial myotonic periodic paralysis,28 and paralysis periodica paramyot~nica'~~~'~,'~~~~ among others."17 Multiple other observations raise questions about the separate identities of HPP and PC, as discussed aboVe.4-6.Y,1~,14,19,20.22,27 By contrast, proponents for the separation of the two diseases point to the homogeneity of symptoms within fa mi lie^^,^^^^ and challenge the experiments involving the production of focal weakness with cold in patients with HPP on a number of grounds. It has been suggested that immobility owing to prolonged rest may be a contributing factor in these patient^^^"^ or that the patients were tested when in the rocess of developing a generalized attack. 14,2' Also, excessively cold temperatures (13- 15°C) were used, and even normal persons may develop focal weakness with prolonged cooling at extremely low temperatures.6726Reports that patients with HPP respond to thiazide diuretic^'^ or to beta adrenergic drugs,3 whereas patients with PC respond to t ~ c a i n i d e ' ~ and ' ~ ~ may be made worse with
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January 1990
diuretics, l 9 also bolster the impression that the two disorders may be distinct. However, it should be noted that in one reported patient who had both hyperkalemic attacks as well as cold-induced muscle stiffness, the hyperkalemic spells were successfully treated with a diuretic, whereas the paramyotonic symptoms responded to tocainide. l 7 To add to this debate, a number of electrophysiological changes have been observed in patients with the two disorders and have been used to separate the two entities. 16,26 Most recently, distinct changes in the evoked CMAP during either exercise or cold provocation have been described. Streib and his coworkers, in studies of patients with a variety of myotonic disorders including myotonia congenita, myotonic dystrophy, and PC, reported a transient but marked decline in evoked CMAP amplitude immediately following exercise .2 -23 Such declines were not seen in controls. The authors noted that in PC there was an immediate and prolonged exercise-induced decline in CMAP amplitude. They felt that this change could be distinguished from exercise testing in HPP where CMAP decline is delayed for at least 10- 15 minutes. 23 These observations were extended and confirmed in a large number of patients with periodic paralysis.15 In that study patients with HPP tended to have large increases in amplitude after exercise, followed by large decreases. The one patient with PC included in the study was found to have a 56% decrease in amplitude immediately after exercise, which was maximal in the first 3 minutes and then gradually returned to baseline similar to Streibs description for PC.23 Cold temperature-induced changes in CMAP amplitude have also been described as specifically separating HPP and PC.24,26In two members of a family with PC, cold temperature provoked decreases in both CMAP area and amplitude.24 By contrast, in a family with HPP there was only a mild temperature-related decrease in CMAP amplitude which was offset by a concomitant increase in CMAP area, similar to results reported for normal individuals.26 Because of the distinctly different responses which ran true within each family, it was suggested that HPP and PC were two distinct disorders. In our study we carried out exercise testing in three members of a family with autosomal domi-
Paramyotonia & Periodic Paralysis
nant transmission (see Fig. 1). Two of the members (A and B) had witnessed attacks, unrelated to cold exposure but associated with an elevated serum K + consistent with the diagnosis of HPP. Neither of these patients reported paramyotonia. Both experienced paralytic attacks during electrophysiological testing, and in both cases weakness became apparent when CMAP amplitude dropped below 2 mV. Patient B had increased serum K+ linked to the fall in CMAP amplitude even when not experiencing any clinical weakness. On all occasions studied, he had large exercise-induced immediate increases in CMAP amplitude. Both A and B, with symptomatic HPP, had large, delayed decreases in CMAP. These distinctive findings are similar to those reported for HPP in previous studies. 1592223 By contrast, patient C reported exacerbation of attacks during cold and, on the two occasions that exercise testing was performed ave results “characteristic” of the my~tonias~’-’~’ i.e., large immediate decreases in CMAP amplitude that rapidly reverse. Exposure to mild cold (26-28°C) resulted in profound decrease in both CMAP area and amplitude with no change in serum K+ in a fashion thought to be specific for PC.‘6 His son (Patient B), who clinically had HPP, also had a large, coldprovoked decrease in CMAP amplitude (a typical param yotonic response), which however was accompanied by a rise in serum K + . We suggest that the presence within a single family of members each having the clinical and electrophysiological features of either hyperkalemic periodic paralysis or of paramyotonia congenita suggests that the two disorders represent two extremes of the spectrum of a single genetic entity. In two of our patients, acetazolamide prevented spontaneous paralytic attacks but produced myotonia. This pattern of exacerbation of myotonia and alleviation of paralytic attacks with diuretics has been reported previously in a patient who had both PC and hyperkalemic paralytic attacks. l 7 The myotonia, by contrast, is alleviated by lidocaine derivatives which may worsen HPP. 17,22 Standard electromyographic testing with exercise and cold provocation, and measurement of local K+ during stimulation, may be useful to help determine which physiological pattern predominates for any particular individual and may help direct therapy.
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January 1990
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REFERENCES 1. Becker PE: Genetic approaches to the nosology of muscle
disease: myotonia and similar diseases. Birth Defects 1971;7:52-62. 2. Becker PE: Syndromes associated with myotonia: clinicalgenetic classification, in Rowland LP (ed): Pathogenesis of Human Muscular Dystrophies. Amsterdam, Exercepta Medica 1977, pp 609-703. 3. Bendheim PE, Reale EO, Berg BO: Beta-adrenergic treatment of hyperkalemic periodic paralysis. Neurology (NY) 1985;35:746-749. 4. Drager GA, Hammill JF, Shy GM: Paramyotonia congenita. Arch Neurol Psychiatry 1958;80: 1-9. 5. Engel AG, Lambert EH, Rosevear JW, Taure WN: Clinical and electromyographic studies in a patient with primary hyperkalemic periodic paralysis. Am J Med 1965;38:626646. 6. French EB. Kibatrick R: A varietv of Daramvotonia congenita. J Neurol Neurosurg Pqchiatry 1957;20:40-46. 7. Gamstorp I: Adynamia episodica hereditaria. Acta Paediatr Scand (suppl) 1956;108:1- 126. 8. Gamstorp I, Hauge M, Heuweg-Larsen F, Mjones H, Saghd U: Adynamia episodica hereditaria: a disease clinically resembling familial periodic paralysis but characterized by increasing serum potassium during paralytic attacks. Am J hfed 1957;23:385-390. 9. Layzer RB, Lovelace RE, Rowland LP: Hyperkalemic periodic paralysis. Arch Neurol 1967; 16:455-472. 10. Lehmann-Horn F, Kiither G, Ricker K, Grafe P, Ballanyi K, Riidel R: Adynamia episodica hereditaria: a noninactivating sodium current and the effect of intracellular pH. Muscle Nerve 1987; 10:363-374. 11. Lehmann-Horn F, Riidel R, Dengler R, Lorkovic H, Haass A, Ricker K: Membrane defects in paramyotonia congenita with and without myotonia in a warm environment. Muscle Nerve 1981;4:396-406. 12. Lehmann-Horn F, Riidel R, Ricker K, Lorkovic F, Dengler R, Hopf HC: Two cases of adynamia episodica hereditaria: in vitro investigation of muscle cell membrane and contraction parameters. Muscle Nerve 1983;6:113-121. 13. Lundberg PO, Stglberg E, Thiele B: Paralysis periodica paramyotonica. J Neurol Sci 1974;2 1:309- 32 1. 14. McArdle B: Adynamia episodica hereditaria and its treatment. Brain 1962;85:121- 148. ,
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15. McManis PG, Lambert EH, Daube JR: The exercise test in periodic paralysis. Muscle Nerve 1986;9:704-710. 16. Nielson VK, Frus ML, Johnsen F: Electromyographic distinction between paramyotonia congenita and myotonia congenita: Effect of cold. Neurology (NY) 1982;32:827832. 17. Ricker K, Bohlen R, Rohkamm R: Different effectiveness of tocainide and hydrochlorothiazide in paramyotonia congenita with hyperkalemic episodic paralysis. Neurology (NY) 1983;33:1615- 1618. 18. Ricker K, Meinck HM: Paramyotonia congenita (Eulenberg). Neurophysiologic studies of a case. 2 NeuroZ 1972; 203113-22. 19. Riggs JE, Griggs RC, Moxley RT 111: Acetazolamideinduced weakness in paramyotonia congenita. Ann Intern Med 1977;86: 169- 173. 20. Samaha FJ: Hyperkalemic periodic paralysis. Arch Neurol 1965; 12: 145- 154. 21. Streib EW: Evoked response testing in myotonic syndromes. Mwcle Nerve 1984;7:590-592. 22. Streib EW: Paramyotonia congenita: successful treatment with tocainide. Clinical and electrophysiologic findings in seven patients. Muscle Nerve 1987;10:155- 162. 23. Streib EW, Sun SF, Yaskowsky T: Transient paresis in myotonic syndromes: a simplified electrophysiologic approach. Muscle Nerve 1982;5:719-723. 24. Subramony SH, Malhotra CP, Mishra SK: Distinguishing paramyotonia congenita and myotonia congenita by electromyography. Mwcle Nerve 1983;6:374-379. 25. Subramony SH, Wee AS: Exercise and rest in hyperkalemic periodic paralysis. Neurology (NY) 1986;36: 173- 177. 26. Subramony SH, Wee AS, Mishra SK: Lack of cold sensitivity in hyperkalemic periodic paralysis. Muscle Nerve 1986;9:700- 703. 27. Van Der Muelen JP, Gilbert GJ, Kane CA: Familial hyperkalemic paralysis with myotonia. N Engl J Med 1961;264: 1- 10. 28. Van’t Hoff W: Familial myotonic periodic paralysis. Quart J Med 1962;31:385-402. 29. Von Eulenberg: Ueber eine familiare, durch 6 generations verfolghare form congenitaler paramyotonie. Neurol Centralblatt 1886;12:265-272.
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