Acta Neuropathol (1992) 84:202 - 206
Acta
_
.
.
Neuropa|hoKa (~) Springer-Verlag1992
Muscle pathology correlates with permanent weakness in hypokalemic periodic paralysis: a case report* R. Gold and H. Reichmann Department of Neurology, University of Wtirzburg, Josef-Schneider-Strage 11, W-8700 Wfirzburg, Federal Republic of Germany Received October 21, 1991/Revised, accepted February 21, 1992
Summary. We present a morphological follow-up in a case of familial h y p o k a l e m i c periodic paralysis with progressive weakness. A t age 12 years muscle biopsy revealed mild vacuolar changes. Seventeen years later, after the patient had developed p e r m a n e n t weakness, light and electron microscopy disclosed tubular aggregates in a b o u t 15 % of the fibers and m e d i u m - g r a d e m y o p a t h i c alterations.We describe correlation of muscle p a t h o l o g y with p e r m a n e n t weakness in h y p o k a l e m i c periodic paralysis. Key words: Familial h y p o k a l e m i c periodic paralysis Tubular aggregates - Muscle p a t h o l o g y - Follow-up study
Periodic paralysis is a h e t e r o g e n o u s s y n d r o m e classified into p r i m a r y and secondary types. P r i m a r y periodic paralysis is a hereditary group of diseases typically associated with an a b n o r m a l i t y of circulating p o t a s s i u m during attacks. Most of the patients with p r i m a r y forms have a positive family history. A muscle biopsy is usually done to exclude o t h e r n e u r o m u s c u l a r diseases. T h e morphological h a l l m a r k of periodic paralysis is a vacuolar m y o p a t h y the origin of which is still a subject of debate. Engel [2] has classified the vacuoles into various forms according to their evolution and their content. A t t a c k frequency in h y p o k a l e m i c periodic paralysis m a y initially be very low and usually increases during the following years but in the fourth and fifth decade it m a y b e c o m e less frequent or even disappear completely. Some patients m a y develop p e r m a n e n t weakness in the later stages of the disease [2, 8]. T h e r e are reports on kinships with developing m y o p a t h y even without attacks of paralysis [2, 121. In the cases with p e r m a n e n t weakness muscle biopsy has revealed various m y o p a t h i c * Part of these results were presented at the "Neuromuskul~ffe Diskussionsrunde", Aachen, 1989 Correspondence to: R. Gold (address see above)
changes [4, 7, 8]. We describe a 12-year-old patient with a re-biopsy 17 years later because of familial hypokalemic paralysis.
Case report In 1972 the 12-year-old son of an affected father with hypokalemic periodic paralysis was evaluated. He had had paralytic attacks since the age of 11 years with initially one nocturnal attack per week and later usually two per night. During symptom-free intervals examination was normal. Serum potassium was 2 mmol/1 during the attacks. A muscle biopsy of the right quadriceps muscle taken at the age of 12 years was normal except for some scattered vacuoles (Fig. la) of which up to a maximum of 15 was found in a tissue sample of 3-mm diameter. Electron microscopy (Fig. 2a) revealed slight dilatation of the sarcotubular system, few intermyofibrillar accumulations of morphologically normal-appearing mitochondria and some focal increase of granular material indicative of glycogen. In the following years attack frequency and severeness increased. Paralytic periods lasting up to 24 hours occurred. The patient increased his potassium consumption to sometimes more than 40 g/day. Seventeen years later physical examination showed marked proximal weakness and no atrophy. During a bicycle ergometer test serum lactate rose to 6.6 mmol]l (normal upto 2.25 mmol/1). Treatment with azetazolamide and spironolactone was commenced and his condition improved. Because of gynecomastia he stopped intake of spironolactone and again consumed increasing amounts of potassium. Seventeen years later a repeated biopsy of the left biceps muscle was taken. The specimens were processed for histological examinations as described above. Informed consent of the patient was obtained.
Methods Open muscle biopsies were performed under local anesthesia. Specimens were frozen, sectioned at 10-9m thickness and the following histochemical reactions were carried out as described in [1]: hematoxylin-eosin (H&E), modified Gomori trichrome 1, oil-red O, nicotinamide adenine dinucleotide (NADH), periodic acid-Schiff (PAS), acid phosphatase, myofibrillar adenosine triphosphatase (pH 4.3, 4.6, 9.4), succinic dehydrogenase (SDH), lactate dehydrogenase 1 (LDH), myoadenylate deaminase 1 1not performed on the muscle from the first biopsy
2 (MADA), cytochrome c oxidase 1, phosphorylase1, and phosphofruktokinase (PFK) 1. Another specimen was fixed in buffered glutaraldehyde and processed for electron microscopy by standard methods [1]. Muscle strength was assessed following the MRC classification as described in [1], with intermediate stages rated as 0.5. A total score was obtained by summing up the individual scores for flexion at the elbow and hip joint and extension at the elbow and knee joint.
Results T h e outstanding histological features were subsarcolemreal, often crescent-shaped, masses that stained basotnot performed on the muscle from the first biopsy
203 philic with H & E (Fig. lb). T h e r e was a m a r k e d interfascicular variation of the n u m b e r of affected fibers, ranging f r o m 1.2 % to 33 % with an average of 17.6 %. Focal cytoplasmatic destructions were evident, some fibers had small vacuoles. Fiber-splitting and a slight increase in connective tissue was detected. Fiber size varied f r o m 15 to 95 btm. The subsarcolemmal masses showed intense staining for N A D H (Fig. 3a) and L D H . T h e y were negative for myofibrillar ATPase at p H 9.4 and were confined to type 2 fibers (Fig. 3b). Less c o m m o n l y these areas a p p e a r e d as single, p r o m i n e n t deposits within a fiber (Fig. 3b). T h e histochemical presentation is s u m m a r i z e d in Table 1. By electron microscopy the subsarcolemmal masses could be identified as accumulations of tubular aggreagates (Fig. 2b). The tubules
Fig. 1. a Four fibers with vacuolar changes, b Basophilic subsarcolemmaly located masses, a,b H&E, a • 170, b • 180; bars = 50 b~m
204 Table 1. Histochemical findings in our patient with tubular aggregates
Histochemical reaction
Tubular aggregates
Hematoxylin-eosin Modified trichrome Periodic acid-Schiff NADH Myofibrillar ATPase Phosphorylase Succinic dehydrogenase Lactate dehydrogenase
+ + + O +
contained a fine granular material. Structures with a double lumen or an intervening clear space could not be found. In addition areas with differential contraction, Z-disc streaming and smearing and vacuolation were seen. Figure 4 compares the histological and clinical findings from 1972 and 1989. The n u m b e r of muscle fibers disclosing vacuoles or tubular aggregates increased from 1.5 % to 17.6 %. A t the same time there was a decrease in the overall strength score of proximal limb muscles from 20 to 17.
+, Strong reaction; - , weak or absent reaction; O, normal reaction
Fig. 2. a Electron micrograph showing focal intermyofibrillar accumulation of vacuoles, mitochondria and glycogen, b Electron micrograph showing subsarcolemmal accumulation of tubular aggregates, a x 16400, b x 7100; bars = 0.5 b~m
205 2s
i
!i
25
20
16
Is
5
1972
1989
i,/
~972
1989
...........................................
% pathological fibres
i //'
2/
sum s c o r e o f proximal limb muscles
Fig. 4. Histogramcomparingpathologicalmusclefiber alterations and muscle strength in 1972 and 1989
Fig. 3. a Stainingfor NADH depictingintense staining of subsarcolemmal masses along edge of fibers and a ring fiber (arrowheads), b Staining for myofibrillarATPase at pH 4.6. Negative staining of subsarcolemmal and centrally located (star) areas, exclusively occurring in type2 fibers, a x 125, b • 175; bars = 50 ~m
Discussion
Here we describe the progression of histological abnormalities over 17 years in a case with autosomal dominant hereditary hypokalemic periodic paralysis at a time when weakness had developed. Similar myopathic changes have been reported [4, 6-8] but no comparable individual follow-up is available. The abnormalities described in those reports consisted of vacuolation, focal fiber degeneration, atrophy and interstitial fibrosis. Tubular aggregates are a typical, but unspecific, sign of periodic paralysis [2, 5]. They can also be seen in a wide variety of other neuromuscular disorders [10]. Aggregates may emerge from proliferation of the tubular sarcoplasmatic reticulum [2]. Intermittent electrical inexcitability of fibers and disturbances of the intracellular electrolyte milieu are said to favor the induction of tubular aggregates and development of vacuolation [2]. The pathophysiological basis for hypokalemic periodic paralysis seems to be an abnormal ratio in the relative conductances of Na + and K +, leading to depo-
larization of the muscle fiber membrane [11]. Membrane repolarization can be induced by K + channel openers, which enhance membrane K + conductance and restore fiber strength of diseased muscle in vitro [3]. The effect of oral potassium administration could be based on a similar mechanism, in that transient increase of extracellular K + concentration favors membrane repolariziation. Excessive potassium therapy over 17 years, however, may have contributed to adaptation and failure of further prophylactic potassium administration [9]. Although pathophysiological mechanisms are not fully understood, this may be partially based upon counterregulatory changes in adrenal steroid hormones. By potassium adaptation an increase of attack frequency, even higher than without any treatment, could be explained. Subsequently extensive proliferation of tubular aggregates and other reactive changes of muscle might arise. It could be speculated that acetazolamide, the prophylactic drug of choice in primary hypokalemic periodic paralysis, could have halted this process by preventing paralytic attacks. Based on this long-term morphological follow-up we suggest that the emerging permanent weakness of our patient could be best explained by the histological abnormalities. Alterations of muscle fiber membranes, impulse conduction and excitation coupling could contribute to the resulting disability, but the outstanding features are marked structural changes which progressed along with the disease course and the evolving weakness. Although the second biopsy had been taken from a different muscle, the influence of the biopsy site is probably of minor importance as the patient didn't have any weakness at the time of the first biopsy. Furthermore, the frequency of type 2 fibers, which were exclusively affected, is higher in the quadriceps muscle (biopsy site 1972) than in the biceps muscle (biopsy site 1989).
Acknowledgements. We thank Dr. K. Toykafor helpful comments and Dr. K. Ricker for allowingus to publish data on his patient. Mrs. U. Walter provided technical assistance.
206
References 1. Dubowitz V (1985) Muscle biopsy. A practical approach, 2nd edn. Balliere Tindall, London 2. Engel AG (1986) Periodic paralysis. In: Engel AG, Banker BQ (eds) Myology, 1st edn. Mc Graw-Hill, New York, pp 1843-1870 3. Grafe P, Quasthoff S, Strupp M, Lehmann-Horn F (1990) Enhancement of K + conductance improves in vitro the contraction force of skeletal muscle in hypokalemic periodic paralysis. Muscle Nerve 13:451-57 4. Howes EL, Price HM~ Pearson CM, Blumberg JM (1966) Hypokalemic periodic paralysis. Electromicroscopic changes in the sarcoplasm. Neurology 16:242-256 5. Meyers KR, Gilden DH, Rinaldi CF, Hansen JL (1972) Periodic muscle weakness, normokalemia and tubular aggregates. Neurology 22:269-279 6. Odor DL, Patel AN, Pearce L A (1967) Familial hypokalemie periodic paralysis with permanent myopathy. J Neuropathol Exp Neurol 26:98-114
7. Olivarius BE Christensen E (1965) Histopathological muscular changes in familial, periodic paralysis. Acta Neurol Scand 41 : 1-18 8. Pearson CM (1964) The periodic paralyses: differential features and pathological observations in permanent myopathic weakness. Brain 87:341-354 9. Riggs JE (1988) The periodic paralyses. Neurol Clin 6: 485 -499 10. Rosenberg NL, Neville HE, Ringel SP (1985) Tubular aggregates. Their association with neuromuscular diseases, including the syndrome of myalgia/cramps. Arch Neurol 42:973-976 11. Rt~del R (1986) The pathophysiological basis of the myotonias and the periodic paralyses. In: Engel AG, Banker BQ (eds) Myology, 1st edn. Mc-Graw-Hill, New York, pp 1297-1311 12. Stevens JR (1954) Familial periodic paralysis, myotonia, progressive myopathy and pes cavus in members of a single family. Arch Neurol Psychiatry 72:726
Acta
_
.
.
Neuropa|hoKa (~) Springer-Verlag1992
Muscle pathology correlates with permanent weakness in hypokalemic periodic paralysis: a case report* R. Gold and H. Reichmann Department of Neurology, University of Wtirzburg, Josef-Schneider-Strage 11, W-8700 Wfirzburg, Federal Republic of Germany Received October 21, 1991/Revised, accepted February 21, 1992
Summary. We present a morphological follow-up in a case of familial h y p o k a l e m i c periodic paralysis with progressive weakness. A t age 12 years muscle biopsy revealed mild vacuolar changes. Seventeen years later, after the patient had developed p e r m a n e n t weakness, light and electron microscopy disclosed tubular aggregates in a b o u t 15 % of the fibers and m e d i u m - g r a d e m y o p a t h i c alterations.We describe correlation of muscle p a t h o l o g y with p e r m a n e n t weakness in h y p o k a l e m i c periodic paralysis. Key words: Familial h y p o k a l e m i c periodic paralysis Tubular aggregates - Muscle p a t h o l o g y - Follow-up study
Periodic paralysis is a h e t e r o g e n o u s s y n d r o m e classified into p r i m a r y and secondary types. P r i m a r y periodic paralysis is a hereditary group of diseases typically associated with an a b n o r m a l i t y of circulating p o t a s s i u m during attacks. Most of the patients with p r i m a r y forms have a positive family history. A muscle biopsy is usually done to exclude o t h e r n e u r o m u s c u l a r diseases. T h e morphological h a l l m a r k of periodic paralysis is a vacuolar m y o p a t h y the origin of which is still a subject of debate. Engel [2] has classified the vacuoles into various forms according to their evolution and their content. A t t a c k frequency in h y p o k a l e m i c periodic paralysis m a y initially be very low and usually increases during the following years but in the fourth and fifth decade it m a y b e c o m e less frequent or even disappear completely. Some patients m a y develop p e r m a n e n t weakness in the later stages of the disease [2, 8]. T h e r e are reports on kinships with developing m y o p a t h y even without attacks of paralysis [2, 121. In the cases with p e r m a n e n t weakness muscle biopsy has revealed various m y o p a t h i c * Part of these results were presented at the "Neuromuskul~ffe Diskussionsrunde", Aachen, 1989 Correspondence to: R. Gold (address see above)
changes [4, 7, 8]. We describe a 12-year-old patient with a re-biopsy 17 years later because of familial hypokalemic paralysis.
Case report In 1972 the 12-year-old son of an affected father with hypokalemic periodic paralysis was evaluated. He had had paralytic attacks since the age of 11 years with initially one nocturnal attack per week and later usually two per night. During symptom-free intervals examination was normal. Serum potassium was 2 mmol/1 during the attacks. A muscle biopsy of the right quadriceps muscle taken at the age of 12 years was normal except for some scattered vacuoles (Fig. la) of which up to a maximum of 15 was found in a tissue sample of 3-mm diameter. Electron microscopy (Fig. 2a) revealed slight dilatation of the sarcotubular system, few intermyofibrillar accumulations of morphologically normal-appearing mitochondria and some focal increase of granular material indicative of glycogen. In the following years attack frequency and severeness increased. Paralytic periods lasting up to 24 hours occurred. The patient increased his potassium consumption to sometimes more than 40 g/day. Seventeen years later physical examination showed marked proximal weakness and no atrophy. During a bicycle ergometer test serum lactate rose to 6.6 mmol]l (normal upto 2.25 mmol/1). Treatment with azetazolamide and spironolactone was commenced and his condition improved. Because of gynecomastia he stopped intake of spironolactone and again consumed increasing amounts of potassium. Seventeen years later a repeated biopsy of the left biceps muscle was taken. The specimens were processed for histological examinations as described above. Informed consent of the patient was obtained.
Methods Open muscle biopsies were performed under local anesthesia. Specimens were frozen, sectioned at 10-9m thickness and the following histochemical reactions were carried out as described in [1]: hematoxylin-eosin (H&E), modified Gomori trichrome 1, oil-red O, nicotinamide adenine dinucleotide (NADH), periodic acid-Schiff (PAS), acid phosphatase, myofibrillar adenosine triphosphatase (pH 4.3, 4.6, 9.4), succinic dehydrogenase (SDH), lactate dehydrogenase 1 (LDH), myoadenylate deaminase 1 1not performed on the muscle from the first biopsy
2 (MADA), cytochrome c oxidase 1, phosphorylase1, and phosphofruktokinase (PFK) 1. Another specimen was fixed in buffered glutaraldehyde and processed for electron microscopy by standard methods [1]. Muscle strength was assessed following the MRC classification as described in [1], with intermediate stages rated as 0.5. A total score was obtained by summing up the individual scores for flexion at the elbow and hip joint and extension at the elbow and knee joint.
Results T h e outstanding histological features were subsarcolemreal, often crescent-shaped, masses that stained basotnot performed on the muscle from the first biopsy
203 philic with H & E (Fig. lb). T h e r e was a m a r k e d interfascicular variation of the n u m b e r of affected fibers, ranging f r o m 1.2 % to 33 % with an average of 17.6 %. Focal cytoplasmatic destructions were evident, some fibers had small vacuoles. Fiber-splitting and a slight increase in connective tissue was detected. Fiber size varied f r o m 15 to 95 btm. The subsarcolemmal masses showed intense staining for N A D H (Fig. 3a) and L D H . T h e y were negative for myofibrillar ATPase at p H 9.4 and were confined to type 2 fibers (Fig. 3b). Less c o m m o n l y these areas a p p e a r e d as single, p r o m i n e n t deposits within a fiber (Fig. 3b). T h e histochemical presentation is s u m m a r i z e d in Table 1. By electron microscopy the subsarcolemmal masses could be identified as accumulations of tubular aggreagates (Fig. 2b). The tubules
Fig. 1. a Four fibers with vacuolar changes, b Basophilic subsarcolemmaly located masses, a,b H&E, a • 170, b • 180; bars = 50 b~m
204 Table 1. Histochemical findings in our patient with tubular aggregates
Histochemical reaction
Tubular aggregates
Hematoxylin-eosin Modified trichrome Periodic acid-Schiff NADH Myofibrillar ATPase Phosphorylase Succinic dehydrogenase Lactate dehydrogenase
+ + + O +
contained a fine granular material. Structures with a double lumen or an intervening clear space could not be found. In addition areas with differential contraction, Z-disc streaming and smearing and vacuolation were seen. Figure 4 compares the histological and clinical findings from 1972 and 1989. The n u m b e r of muscle fibers disclosing vacuoles or tubular aggregates increased from 1.5 % to 17.6 %. A t the same time there was a decrease in the overall strength score of proximal limb muscles from 20 to 17.
+, Strong reaction; - , weak or absent reaction; O, normal reaction
Fig. 2. a Electron micrograph showing focal intermyofibrillar accumulation of vacuoles, mitochondria and glycogen, b Electron micrograph showing subsarcolemmal accumulation of tubular aggregates, a x 16400, b x 7100; bars = 0.5 b~m
205 2s
i
!i
25
20
16
Is
5
1972
1989
i,/
~972
1989
...........................................
% pathological fibres
i //'
2/
sum s c o r e o f proximal limb muscles
Fig. 4. Histogramcomparingpathologicalmusclefiber alterations and muscle strength in 1972 and 1989
Fig. 3. a Stainingfor NADH depictingintense staining of subsarcolemmal masses along edge of fibers and a ring fiber (arrowheads), b Staining for myofibrillarATPase at pH 4.6. Negative staining of subsarcolemmal and centrally located (star) areas, exclusively occurring in type2 fibers, a x 125, b • 175; bars = 50 ~m
Discussion
Here we describe the progression of histological abnormalities over 17 years in a case with autosomal dominant hereditary hypokalemic periodic paralysis at a time when weakness had developed. Similar myopathic changes have been reported [4, 6-8] but no comparable individual follow-up is available. The abnormalities described in those reports consisted of vacuolation, focal fiber degeneration, atrophy and interstitial fibrosis. Tubular aggregates are a typical, but unspecific, sign of periodic paralysis [2, 5]. They can also be seen in a wide variety of other neuromuscular disorders [10]. Aggregates may emerge from proliferation of the tubular sarcoplasmatic reticulum [2]. Intermittent electrical inexcitability of fibers and disturbances of the intracellular electrolyte milieu are said to favor the induction of tubular aggregates and development of vacuolation [2]. The pathophysiological basis for hypokalemic periodic paralysis seems to be an abnormal ratio in the relative conductances of Na + and K +, leading to depo-
larization of the muscle fiber membrane [11]. Membrane repolarization can be induced by K + channel openers, which enhance membrane K + conductance and restore fiber strength of diseased muscle in vitro [3]. The effect of oral potassium administration could be based on a similar mechanism, in that transient increase of extracellular K + concentration favors membrane repolariziation. Excessive potassium therapy over 17 years, however, may have contributed to adaptation and failure of further prophylactic potassium administration [9]. Although pathophysiological mechanisms are not fully understood, this may be partially based upon counterregulatory changes in adrenal steroid hormones. By potassium adaptation an increase of attack frequency, even higher than without any treatment, could be explained. Subsequently extensive proliferation of tubular aggregates and other reactive changes of muscle might arise. It could be speculated that acetazolamide, the prophylactic drug of choice in primary hypokalemic periodic paralysis, could have halted this process by preventing paralytic attacks. Based on this long-term morphological follow-up we suggest that the emerging permanent weakness of our patient could be best explained by the histological abnormalities. Alterations of muscle fiber membranes, impulse conduction and excitation coupling could contribute to the resulting disability, but the outstanding features are marked structural changes which progressed along with the disease course and the evolving weakness. Although the second biopsy had been taken from a different muscle, the influence of the biopsy site is probably of minor importance as the patient didn't have any weakness at the time of the first biopsy. Furthermore, the frequency of type 2 fibers, which were exclusively affected, is higher in the quadriceps muscle (biopsy site 1972) than in the biceps muscle (biopsy site 1989).
Acknowledgements. We thank Dr. K. Toykafor helpful comments and Dr. K. Ricker for allowingus to publish data on his patient. Mrs. U. Walter provided technical assistance.
206
References 1. Dubowitz V (1985) Muscle biopsy. A practical approach, 2nd edn. Balliere Tindall, London 2. Engel AG (1986) Periodic paralysis. In: Engel AG, Banker BQ (eds) Myology, 1st edn. Mc Graw-Hill, New York, pp 1843-1870 3. Grafe P, Quasthoff S, Strupp M, Lehmann-Horn F (1990) Enhancement of K + conductance improves in vitro the contraction force of skeletal muscle in hypokalemic periodic paralysis. Muscle Nerve 13:451-57 4. Howes EL, Price HM~ Pearson CM, Blumberg JM (1966) Hypokalemic periodic paralysis. Electromicroscopic changes in the sarcoplasm. Neurology 16:242-256 5. Meyers KR, Gilden DH, Rinaldi CF, Hansen JL (1972) Periodic muscle weakness, normokalemia and tubular aggregates. Neurology 22:269-279 6. Odor DL, Patel AN, Pearce L A (1967) Familial hypokalemie periodic paralysis with permanent myopathy. J Neuropathol Exp Neurol 26:98-114
7. Olivarius BE Christensen E (1965) Histopathological muscular changes in familial, periodic paralysis. Acta Neurol Scand 41 : 1-18 8. Pearson CM (1964) The periodic paralyses: differential features and pathological observations in permanent myopathic weakness. Brain 87:341-354 9. Riggs JE (1988) The periodic paralyses. Neurol Clin 6: 485 -499 10. Rosenberg NL, Neville HE, Ringel SP (1985) Tubular aggregates. Their association with neuromuscular diseases, including the syndrome of myalgia/cramps. Arch Neurol 42:973-976 11. Rt~del R (1986) The pathophysiological basis of the myotonias and the periodic paralyses. In: Engel AG, Banker BQ (eds) Myology, 1st edn. Mc-Graw-Hill, New York, pp 1297-1311 12. Stevens JR (1954) Familial periodic paralysis, myotonia, progressive myopathy and pes cavus in members of a single family. Arch Neurol Psychiatry 72:726
![[Hypokalemic periodic paralysis. A case report].](/assets/img/hold.png)
