PERMANENT MUSCLE WEAKNESS IN FAMILIAL HYPOKALAEMIC PERIODIC PARALYSIS

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1 Bran (99),, PERMANENT MUSCLE WEAKNESS IN FAMILIAL HYPOKALAEMIC PERIODIC PARALYSIS CLINICAL, RADIOLOGICAL AND PATHOLOGICAL ASPECTS by THERA P. LINKS, MACHIEL J. ZWARTS, JAN T. WILMINK, WILLEMINA M. MOLENAAR and HANS J. G. H. OOSTERHUIS (From the Departments of 'Neurology, Dagnostc Radology and ^Pathology, Unversty Hosptal of Gronngen, Gronngen, The Netherlands) SUMMARY Myopathy accompanyng famlal hypokalaemc perodc paralyss (HPP) s much less well documented than the paralytc attacks from whch the dsease derves ts name. Eleven affected members of a large knshp wth HPP were studed clncally and radologcally for the presence of myopathy. In patents muscle bopses were also performed and n of them the hstologcal fndngs obtaned at autopsy were compared wth the CT scans of varous muscles. In another patent not prevously bopsed, the specmens of both amputated legs were examned hstologcally. The age of the studed ndvduals ranged from to 7 yrs. The youngest patents showed no clncal sgns of myopathy. However, n of them CT scans demonstrated dscrete hypodense lesons n the leg muscles, whereas n the other, muscle bopses showed a vacuolar myopathy. The other 7 patents, all older than 5 yrs, presented both clncal and CT evdence of myopathy of proxmal and dstal muscles rangng from very mld to very severe, males beng slghtly more affected than females. In all patents a mean CT gradng was made that was based on the abnormaltes found n the dfferent muscle groups. The myopathy appeared to be unrelated to the hstory of paralytc attacks, but a strong correlaton was found between age and mean CT gradng. It was concluded that HPP s a myopathy wth permanent muscle weakness of late onset n all the patents. The expresson of the paralytc attacks s varable. INTRODUCTION Famlal hypokalaemc perodc paralyss (HPP) s an autosomal domnant dsease characterzed by transent attacks of muscle weakness of varyng duraton and severty. These paralytc attacks are amply descrbed n the lterature (Engel, 986), but less attenton has been pad to the myopathy whch also may occur. In partcular, the extent and the prevalence of the myopathy and ts relatonshp wth prevous attacks are not well known (Engel, 986). Although Buruma and Bots (978) dened a relatonshp between the myopathy and the occurrence of paralytc attacks, both earler (Pearson, 96) and more recent reports (Rdel and Rcker, 985; Grggs, 986) favoured such a relatonshp. In addton to well-defned paralytc attacks, 'abortve attacks' may occur, that s, long-lastng epsodes wth fluctuatng weakness. In contrast to the myopathy, but smlar to the paralytc attacks, ths weakness can be reversed by acetazolamde (Lnks et al., 988). Hstopathologcally, HPP s characterzed by vacuolaton of the Downloaded from by guest on May, 6 Correspondence to: Dr T. P. Lnks, Department of Internal Medcne, Unversty Hosptal Gronngen, PO Box,., 97 RB Gronngen, The Netherlands. Oxford Unversty Press 99

2 87 T. P. LINKS AND OTHERS muscle fbres (Engel, 986), but lttle s known about the relatonshp between these changes and permanent muscle weakness. No radologcal reports on HPP are known. The current study focuses on myopathy n HPP and descrbes the clncal and radologcal fndngs n members of a large knshp wth HPP lvng n the northeast of the Netherlands and the hstologcal fndngs n 5 of them, ncludng an autopsy and leg amputaton specmens. PATIENTS AND METHODS Patents A survey of a large prevously descrbed knshp (Zwarts et al., 988) revealed 55 patents wth HPP among the 77 members (fg. ) n the last 5 generatons. It may be assumed that addtonal patents were present among the famly members who could not be nduced to partcpate n the study or were dead by the tme of the study. Of the 55 patents, 5 had typcal attacks. In the other patents a typcal hstory of paralytc attacks could not be elcted. Of the 5 patents stll alve, were studed personally by one of the authors (T.P.L.). Of these, 9 were affected, wth typcal attacks, and had never suffered from paralytc attacks but had slght or more severe complants of muscle weakness. In the remanng cases and n the deceased patents a clncal hstory was obtaned from famly members, whch was confrmed n some cases by data from other hosptals. The dagnoss HPP was based on a reduced muscle fbre conducton velocty (MFCV; Zwarts et al., 988), measured n a nonparalytc state. Ths was measured n all patents studed, wth or wthout a hstory of paralytc attacks. Muscle strength was evaluated by dynamometry (Ploeg et al., 98) The crtera for ncluson n the study were () a reduced MFCV and () agreement to have CT scannng. Eleven patents wth a reduced MFCV, 5 wth and 6 wthout attacks, gave permsson for CT scannng of ther muscles n a nonparalytc state. These form the subject of ths report and a summary of ther clncal features s gven n Table. Representatve case hstores The case numbers correspond to the numbers n fg. and Table. Case. An otherwse healthy, -yr-old woman had experenced fatgue and muscle pan snce her thrteenth year, whch curtaled her actvtes by the end of the day. Her symptoms were exacerbated by her menses and exercse and had steadly ncreased over the years. She felt that her muscle strength had decreased, but she had not experenced paralytc attacks. Neurologcal examnaton revealed no abnormaltes except slght muscle weakness, partcularly of the proxmal lmb muscles. Routne electromyographc (EMG) examnaton demonstrated manly neuropathc changes. Concentrc needle examnaton of several muscles showed some spontaneous actvty (fbrllatons and postve sharp waves). The motor unt acton potentals were mostly normal, although some were of a slghtly ncreased duraton. She mproved subjectvely wth acetazolamde treatment (5 mg tmes daly) and her strength returned to normal as measured by dynamometry. Downloaded from by guest on May, 6 Case. Ths 5-yr-old man had had daly paralytc attacks snce hs thrteenth year. Intally he became totally paralysed durng these attacks for 6 h, but by usng potassum salts ( 5 g daly) the attacks were lmted to slght weakness of the legs each mornng. Once a month he suffered from moderate or severe weakness n the mornng, despte the use of potassum salts, lastng -6 h. When he was aged yrs old he was evaluated clncally and provocaton wth ntravenously admnstered glucose caused a tetraplega durng whch the serum potassum concentraton decreased to.7 mmol/. Three years ago he started takng acetazolamde (5 mg tmes daly). The paralytc attacks dsappeared and hs requrement for potassum salts was reduced to - g daly. He also notced an ncrease of hs strength between attacks, whch was confrmed wth dynamometry. When not takng acetazolamde, routne neurologcal examnaton revealed no abnormaltes except moderate muscle weakness, partcularly of the proxmal muscles of hs legs measured wth dynamometry.

3 Fo.. Pedgree of the famly wth perodc paralyss. The numbers - correspond to the patents descrbed n ths artcle. = males; O = females; = personally studed, affected; = not studed, reported affected; = affected, no attacks, only myopathc changes; = dead; A ~ number of chldren, nothng known about them. r < Downloaded from by guest on May, 6 > < O m n

4 876 T. P. LINKS AND OTHERS TABLE. CLINICAL DATA Case Sex/age (yrs) F/ F/ M/5 F/9 F/5 F/5 F/6 F/7 M/7 F/7 M/7 Paralytc attacks. Age at onset/ at termnaton (yrs) - /* 7/** 5/8 8/5 8/5 7/*** Frequency of attacks at onset/at present - Daly /mo. -/mo. -/mo. Weekly /mo. /yr MFCV (m-s-') Muscle weakness Fluctuatng Fluctuatng Fluctuatng Fluctuatng Slght proxmal weakness legs Slght proxmal weakness legs Slght proxmal weakness legs Severe problems wth walkng Severely dsabled Severe problems wth walkng Severely dsabled Serum CK myogl. (ng/i) CK = creatnne knase (normal: 5 /tg/); myogl. = myoglobn (normal: - /g/); MFCV = muscle fbre conducton velocty (normal:.9-5. ms~'); = absent; * On startng acetazolamde; ** Attacks reduced by potassum; * Attacks persst. Case 6. Ths 5-yr-old woman had suffered from paralytc attacks from the age of 8 to 5 yrs. The attacks occurred once or twce monthly and responded to potassum salts n varyng doses ( g). She had no more attacks after the age of 5, but she stll notced stffness of the thghs after rest and on cold days. She also complaned of fluctuatons of her strength and of a permanent decrease n strength n her legs. Neurologcal examnaton revealed very slght weakness of the proxmal muscles of the lower lmbs. Treatment for months wth acetazolamde (5 mg tmes daly) dd not alter her symptoms and dd not mprove the muscle strength n her legs sgnfcantly. The patent's daughter has been hosptalzed on several occasons wth paralytc attacks and a serum potassum of.8. mmol/. 8 Downloaded from by guest on May, 6 Case 7. Ths 6-yr-old woman was healthy untl the age of 6 yrs, when she frst experenced stffness and muscle pans n her thghs on cold days and after sttng. She also notced dffculty n gong up and down stars and n rsng from a char, whle her arms also became weaker. These symptoms progressed slowly. Neurologcal examnaton revealed weakness of the proxmal muscles of both the upper and the lower lmbs. Acetazolamde (5 mg tmes daly) partly reduced her symptoms and mproved her strength, as verfed by dynamometry. Case 9. A 7-yr-old man had had dabetes melltus snce the age of yrs. From the age of 55 he had notced slowly progressve panless weakness of hs legs. He had been wheelchar-bound for yrs. Hs neurologst made a dagnoss of dabetc amyotrophy. The patent notced that the strength of hs arms

5 FAMILIAL HYPOKALAEMIC PARALYSIS 877 was also declnng. He had never had paralytc attacks and there was no hstory of sudden exacerbatons of the weakness assocated wth pan. Neurologcal examnaton revealed severe weakness of all proxmal and dstal muscles, slght dstal sensory mparment n the arms and legs and absent tendon reflexes. On EMG there was a mxture of neuropathc and myogenc changes n the motor unt acton potentals. Nerve conducton studes were compatble wth a mld dabetc poly neuropathy. Therapy wth acetazolamde (5 mg tmes daly), for wks, produced no beneft. Soon after dscharge the patent ded from an unrelated dsease. An autopsy was performed (see below). Case. A 7-yr-old man had had monthly paralytc attacks from the age of 7 yrs. Durng these attacks he had become totally paralysed for days. After yrs he had started usng potassum salts n varyng dosages ( g) and frequency, whch shortened the attacks to a maxmum of h. Although the frequency and the severty of these attacks had decreased wth age, they had not ceased. Permanent muscle weakness developed n hs 57th year, whch made hm wheelchar-bound over the next yrs. Neurologcal examnaton revealed tendon areflexa and severe weakness of all proxmal muscles of the upper and lower lmbs and the dstal muscles of the lower extremtes. Electromyography demonstrated a mxture of neuropathc and myogenc changes n the motor unt acton potentals. One year after ths nvestgaton the patent's legs were amputated above the knees, because of schaemc pan due to vascular nsuffcency. At present the strength n hs arms s stll decreasng. Serum studes Fourteen patents were observed durng attacks and serum potassum levels vared between. and mmol/. Of the patents who form the subject of ths report, blood samples were taken to measure the serum potassum and myoglobn concentratons and creatne knase actvty at the tme of a routne vst to the hosptal n a nonparalytc state. Patents were requested to avod physcal exercse on the day of the vst. Surface electromyography Muscle fbre conducton velocty (MFCV) was measured wth bpolar surface EMG electrodes placed parallel to drecton of the fbres of the bceps brach muscle between the motor pont and the dstal tendon. Average MFCV was estmated from the delay of the sgnals derved from the electrodes usng the cross correlaton method (for detals of the methods, see Zwarts et al., 988). For controls, MFCV s.9-5. m-s~'. Radology A seres of CT sectons was performed at predetermned levels n the neck, upper thorax, abdomen, pelvs, thgh and lower leg, accordng to the protocol descrbed by Bulcke and Baert (98). For every muscle group the CT abnormaltes were graded by one of us (J.T. W.) wthout knowledge of the clncal pcture. The classfcaton was made accordng to the extent of hypodense lesons n the muscle tssue, ndcatng replacement of muscle by fat, and not by CT densty measurements, whch have already proved to be no more relable than a qualtatve assessment (De Vsser and Verbeeten, 985). Crtera for scorng were (fg. ): = normal; = mnmal abnormalty; small hypodense areas wthn the muscle; = clear abnormalty; replacement of areas of muscle tssue by fat, but less than 5%; = severe abnormalty; replacement of more than 5% of area of muscle tssue by fat; = end stage; total or subtotal replacement of muscle tssue of fat. Downloaded from by guest on May, 6 Morphologcal studes Open muscle bopses n Cases, and 5 were performed on the vastus medal s muscle and n Case 9 on the rght bceps brach muscle. At autopsy n Case 9 care was taken to sample the muscles at the levels scanned by CT. The same was done wth the amputated legs of Case. All materal was embedded n paraffn and staned wth haematoxyln-eosn and PAS stans. The percentage of vacuolated fbres n the bopses was estmated by countng the vacuolated fbres among at least cross-sectoned fbres. In addton, the muscle bopses from Cases, and 9 were snap-frozen for hstochemcal studes, ncludng

6 878 T. P. LINKS AND OTHERS ' ^ ' Downloaded from by guest on May, 6 FIG.. Examples of varous grades of muscle nvolvement n CT scans, A, Case. Normal appearances wthout sgns of replacement of muscle tssue by fat (grade ). Normal fat planes and areas between muscle groups ndcated by arrows. B, Case 8. Mnmal nvolvement of sartorus and gracls (small arrows, grade ). Involvement of more than 5% n quadrceps (large arrows, grade ). Posteror groups show approxmately 5% nvolvement (open arrows). Note some dfferences n severty between left and rght; ths mpedes completely accurate and reproducble ratng, c, Case. Clear nvolvement of sartorus and gracls muscles but less than 5% affected (small arrows, grade ). Severe nvolvement of more than 5% n posteror groups (grade ), subtotal: only central areas at left are spared (large arrows). Vrtually total nvolvement of quadrceps at left (open arrows, grade ).

7 FAMILIAL HYPOKALAEMIC PARALYSIS 879 adenosne-trphosphatase (ATPase) reactons at ph 9.,.6 and., NADH-tetrazolum reductase reacton, succnate dehydrogenase reacton and PAS stans wth and wthout dastase pretreatment, Ol red O, sudan black B and Gomor trchrome stans. Four samples from each of the same muscle bopses were studed by electron mcroscopy. For each bopsy the pathologcal characterstcs were graded on a 5 pont scale by one of us (W.M.M.; fg. ): = normal muscle tssue; = vacuolaton typcal for HPP, slght fbrotc changes and replacement by fat; = vacuolaton, extensve fbrotc changes and/or replacement by fat; = almost total replacement by fat, sporadc muscle tssue; = no recognzable muscle tssue but assumed to be muscle tssue n vew of the macroscopcal appearance and localzaton. RESULTS Clncal profle The age of the patents was 7 yrs. The frequency of paralytc attacks ranged from none to daly. Permanent muscle weakness (PMW) was present n the 7 oldest patents (Table ). The youngest patents complaned of fluctuatng weakness and fatgue of the legs. The patents n the ffth and sxth decades suffered manly from weakness of the thghs, frst detected durng star clmbng and rsng from a char. All patents over 7 yrs old were severely dsabled, especally the males. The female patents were stll able to walk wth assstance. Case 8 was thought to be dsabled from blateral hp arthross and Case 9 was dagnosed as dabetc amyotrophy. Case had vascular nsuffcency n both hs legs. The muscle weakness n the patents wth PMW was symmetrc wth a predomnance n the leg muscles. It was accompaned by tendon areflexa, but not by vsble atrophy. The proxmal and dstal muscle groups were equally affected. Serum potassum levels between attacks were normal. Serum creatne knase ranged from 5- (normal -5) /tg/ and serum myoglobn from - (normal -) /tg/ (Table ). Radologcal fndngs Gradng of the CT scans of all patents (Table ) revealed that the muscles of leg and pelvc grdle were more affected than the arm and shoulder grdle muscles and some dstal leg muscles were affected to the same extent as the proxmal muscles. Fg. shows a full CT study of a representatve patent (Case 7). The earlest vsble abnormalty appears to be a small hypodense leson n the centre of the muscle, whereas n later stages there s more extensve replacement of the central muscle tssue by fat. At the end stage only a thckened fasca seems to be vsble (see also fg. ). For all patents the sum of the CT stages of 8 muscle groups was related to age (fg. 5). It was found that the score of the patents wth a hstory of paralytc attacks was not clearly dfferent from the patents wthout attacks, but tat there was a correlaton wth age. The Spearman rank correlaton for age was.9 (z =., P <.5). Downloaded from by guest on May, 6 Morphologcal fndngs The open muscle bopses of the cases (,, 5, 9) all revealed the characterstc vacuoles n muscle fbres. Some of the vacuoles contaned PAS-postve granular materal. In Case 5 approxmately % of the fbres possessed vacuoles, n Case approxmately 5% and n Cases and 9 approxmately %. All bopses were classfed as stage.

8 ..... * ;. : * - FIG.. Hstologcal stages -, obtaned at autopsy n Case 9 (for defntons of the stages, see text), haematoxyln-eosn, X5. () Left peroneus muscle, stage I: many vacuolated fbres and ncreased varablty n fbre sze, but no substantal fbross or ncrease n fat; () left bceps brach, stage : vacuolated fbres, atrophc fbres and focal fbross; () rght gastrocnemus, stage : vacuolated fbres, atrophc fbres, advanced fbross and ncrease n fat; () rght soleus stage : complete replacement of muscle by adpose tssue. r z z o o H X m 5 "^ 7 «;. - f-rt&j Downloaded from by guest on May, 6 O -

9 FAMILIAL HYPOKALAEMIC PARALYSIS 88 Age (yrs) Level Neck Ventral group Dorsal group Thorax Pectoral group Perscapular group Paraspnal group Perhumoral group Abdomen Abdomnal wall Paraspnal group Psoas group Pelvs Abdomnal wall llopsoas group Gluteus group Thgh Quadrceps group Sartorus, gracls Posteror group Lower legs Anteror group Deep posteror group Superfcal group / TABLE. 5 GRADING OF CT Case 6 5 SCANS* Total * Crtera for scorng (see text), x = classfcaton not possble. An ncreased varablty n fbre sze and an ncreased number of central nucle were also observed, especally n Case 9, n whom pathologcal changes were most advanced. In the ATPase reactons n Cases, and 9 both type and fbres were found to be affected; type-groupng was not observed. The Gomor trchrome stan revealed fbres wth brght red deposts n Case 9 (fg. 6A), such fbre n Case and none n Case. Wth the NADH tetrazolum reductase reacton ntense focal reactvty was observed n several fbres n Case 9 (fg. 6B), but not n Cases and. Ultrastructurally, some tubular aggregates were found n Cases and (fg. 6c), but not n Case 9. Taken together, the enzyme hstochemcal and ultrastructural fndngs ndcate that tubular aggregates were present n all patents, but to a very lmted extent. Vacuoles, partly surrounded by membranes, were readly observed n all bopses that were studed electron mcroscopcally (fg. 6D). The autopsy of Case 9 showed the characterstc vacuoles n all skeletal muscle samples (fg. ). In addton, many atrophc fbres were observed scattered throughout the fbre bundles and not grouped together. The more affected muscles dsplayed extensve fbross and an ncrease n fat (fg. ; see next paragraph). The daphragm and ntercostal muscles also showed vacuoles. Lght mcroscopy of the heart revealed no abnormaltes; electron mcroscopy was not performed. Smooth muscle and perpheral nerves were not examned. 7 // 7 X X To Downloaded from by guest on May, 6

10 T. P. LINKS AND OTHERS Downloaded from by guest on May, 6 FIG.. Full CT study of a representatve patent (Case 7). A, neck: normal appearances of ventral muscles, grade nvolvement of dorsal paraspnal group (arrow), B, thorax: normal appearances for pectoral and perscapular muscles, grade nvolvement of paraspnal and perhumeral groups (arrows), c, abdomen: grade nvolvement of abdomnal wall muscles (arrows), grade of lopsoas and paraspnal groups (large arrows). D, pelvs: grade nvolvement of superfcal abdomnal muscles (arrow), grade of lopsoas and gluteal groups (large arrow), E, thgh: grade nvolvement of sartorus and gracls (arrows), grade nvolvement of the quadrceps group as a whole, but rather uneven dstrbuton wth more severe nvolvement n lateral areas (curved arrow), mnmal nvolvement anteror leg (open arrow); more dffuse grade nvolvement of posteror groups (Isgp arrows). F, lower legs: grade nvolvement n anteror groups (arrows), grade n deep posteror groups (black arrow), grade n superfcal groups (curved arrow).

11 FAMILIAL HYPOKALAEMIC PARALYSIS 88 - * o E o 5 6 Age (yrs) 7 8 FIG. 5. Sum of CT stages of 8 muscle groups, related toage (Spearman rank correlaton.9, z =., P <.5). X = male; closed crcle = female; open crcle = no attacks. Comparson between CT scan appearances and hstology In Cases 9 and the CT appearances could be compared wth the hstologcal fndngs n the autopsy and n the amputaton specmens of the legs, respectvely. In Case 9, muscle samples from the dfferent muscle groups were taken at the levels of the CT scans. There appeared to be a strkng relaton between CT gradng and the hstologcal gradng (fg. 7). All stages were found n the proxmal as well as n the dstal legs. There was no preference for the hgher stages n the proxmal muscles. In Case vrtually all muscle tssue was replaced by fat, but the macroscopc features of muscle bundles were stll apparent (fg. 8). The only vsble muscle tssue was found just below the fasca, whch presumably explans the CT fndng of a 'thckened fasca'. DISCUSSION Hypokalaemc perodc paralyss s transmtted as an autosomal domnant condton. In women the dsease tends to be less severe than n man (Engel, 986). Sometmes patents develop only a sngle attack or escape manfest attacks. The varable expresson of the attacks has led to a denal by some ndvduals of beng affected and has gven the mpresson that the gene can 'skp' generatons. Permanent muscle weakness (PMW) n HPP s a well-known phenomenon (Bemond and Polak Danels, 9; Dyken et al., 969), but the causal relatonshp between the perodc paralytc attacks and the myopathy has been a source of debate. Pearson (96), for example, stated that PMW does not appear untl at least 5 yrs after the onset of the attacks and he was supported recently by Rdel and Rcker (985) and Grggs (986). Buruma and Bots (978), on the other hand, presented a patent n a Dutch famly wth HPP, probably unrelated to our famly, n whom muscle weakness and vacuolar changes were found. Ths patent has remaned free of attacks untl the present (personal Downloaded from by guest on May, 6

12 88 T. P. LINKS AND OTHERS A: <k Downloaded from by guest on May, 6 FIG. 6. A, brght red deposts n the Gomor trchrome stan n the bopsy of Case 9 (x). B, NADH tetrazolum reductase reacton showng dense deposts (arrowheads) n the same bopsy as n A (X). C, electron mcrograph of Case I showng subsarcolemmal tubular aggregates (x.). D, electron mcrograph of Case showng several small membrane-bound vacuoles (arrowheads) and granular deposts (astersks) wth membranes presumably derved from a ruptured vacuole (X685). communcaton). Later, t was reported that all hs sbs wth HPP, dagnosed by the occurrence of paralytc attacks, suffered from PMW (Buruma et cd., 985). In the present famly, PMW wthout perodc paralytc attacks occurred n % of cases. Ths contrasts sharply wth the fndngs of Johnsen (98), who reported PMW n only of the 6

13 FAMILIAL HYPOKALAEMIC PARALYSIS llsi _ I CT stage _,, ',, Hstologcal stage Infraspnatus Bceps Ilopsoas Quadrceps (prox) Quadrceps/rectus femors Bceps femors Tbals anteror Peroneus Soleus Gastrocnemus VJ U*Jl-l ^^^*l l^/l \^+J FIG. 7. Relatonshp between the CT stages and the pathologcal stages of the varous muscle of Case 9, autopsed yr after obtanng the CT scan. Downloaded from by guest on May, 6 A FIG. 8. A, CT secton through rght lower leg demonstratng extensve nvolvement of all muscle groups (Case ). B, anatomcal secton of the same level n the same patent confrmng dsappearance of muscle tssue and replacement by fat. patents wth HPP from famles. Ths dfference can largely be explaned by our use of surface EMG measurement of MFCV, a new nonnvasve method to dagnose HPP (Zwarts et al., 988). In general, needle EMG fndngs were not specfc and neuropathc and myopathc changes could be found, as also prevously descrbed by us and by others (Krendler et al., 96; Zwarts et al., 988). However, the surface

14 886 T. P. LINKS AND OTHERS EMG measurement of the MFCV made t possble to nclude patents wthout paralytc attacks, and even wthout clncal sgns of myopathy. In all patents n whom myopathc changes were found on the CT scan and/or on hstologcal examnaton, MFCV was reduced. Further, PMW s probably only reported n the most serous cases, whereas cases wthout attacks tend to go undagnosed, despte a postve famly hstory of HPP. As may be expected n the older patent populaton some of the patents also suffered from other llnesses, and the muscle weakness was attrbuted to ther dseases, such as dabetes melltus n Case 9 and vascular nsuffcency n Case. It cannot be excluded that these concurrent dseases contrbuted to the muscle pathology. However, although both patents had other dagnoses n addton to ther HPP, the hstologcal changes were smlar. In Case 9 the muscle bopsy and especally the samples taken at autopsy showed extensve hstologcal changes,.e., wdespread vacuolaton, atrophc fbres, fbross, ncrease of the number of nternal nucle and ncrease n fat. Among these changes the vacuoles are characterstc for HPP and the other changes have also been descrbed n HPP (Tome', 98), and also n neurogenc dsorders. However, the atrophc fbres were scattered throughout the fbre bundles and not grouped, a pattern more compatble wth HPP than wth neurogenc changes. The EMG studes revealed a mxture of neuropathc and myopathc changes, whch was also seen n other patents wth HPP wthout concurrent dsease (Krendler etal., 96; Zwarts et al., 988). Moreover, n Case 9, nerve conducton studes ndcated only a mld neuropathy, whereas the muscle pathology was severe. Fnally, no grossly vsble atrophy was present. In Case vrtually no muscle fbres remaned n many of the muscles of the amputaton specmen and those that were present showed many vacuoles. These changes can hardly be attrbuted to vascular nsuffcency alone. It remans to be seen whether a myopathy wthout attacks s a fndng pecular to the current famly or a general feature of HPP, whch s as yet underdagnosed. PMW appeared to be unrelated to the number and severty of paralytc attacks, snce t occurred both n patents wth and wthout attacks. It may be assumed that the varous clncal features,.e. the less than average strength, occurrng n patents wth and wthout attacks, the nterctal muscle weakness and the perodc paralyss only occurrng n patents wth attacks (Lnks et al., 988) can all be explaned by the same structural muscle defects {see below). The fndng of a strong correlaton between PMW and age may be explaned by a progressve destructon of muscle tssue. Ths destructon seems to contnue nto old age. Measurng muscle enzymes alone s not a senstve method for detectng carrers of HPP, because many other factors can cause enzyme elevaton, such as prevous exercse. Therefore the fndng of slghtly elevated muscle enzyme levels n some famly members wthout symptoms, wth a normal MFCV, normal muscle strength and a normal bopsy s a nonspecfc fndng on whch no conclusons can be founded. Ths s n contrast wth the opnon of Wggers and Nerregaard Hansen (985) who supposed that serum myoglobn and serum creatne knase can be used to detect carrers of HPP. An alternatve approach could be to measure the muscle enzymes after provocaton (e.g., glucose stress, Hudson et al., 967). We are currently undertakng such studes. In paralytc attacks the muscles of the legs and pelvc grdle are affected more and for longer than the arm and shoulder grdle muscles and patents complan more about mnor attacks of the legs than n the arms. The severty of myopathc changes shown n the CT scans (Table ) and found at autopsy (fg. 7) parallels ths dstrbuton, Downloaded from by guest on May, 6

15 FAMILIAL HYPOKALAEMIC PARALYSIS 887 rrespectve of a hstory of attacks. It s remarkable that some muscles, for example, sartorus, gracls and rectus femors, were relatvely spared. Ths s also observed n other myopathes (Bulcke and Baert, 98, pp. -9), wthout a cogent explanaton. HPP s not a typcal proxmal weakness, because some dstal muscles as soleus and gastrocnemus were found to be affected to the same extent as the proxmal leg muscles. In the present patents, no muscle atrophy n the lmbs was vsble or measurable. Ths s n contrast to the fndngs of Bemond and Polak Danels (9), who descrbed atrophy so severe as to smulate a neurogenc dsorder. On CT scannng, as well as on gross and mcroscopc examnaton of the amputaton specmens and the autopsy, there appeared to be a progressve replacement of muscle by connectve tssue or fat, alterng the functon, but not the sze of the orgnal muscle. Ths process, when observed n muscular dystrophes (e.g., Becker dystrophy), s reported to start at the perphery of the muscle, just deep to the fasca, and s known as the 'fllng up process' (Bulcke and Baert, 98, p. 89). In contrast, the focal replacement of muscle tssue n HPP begns at the centre of the muscle, just as the vacuoles do {see below; Dubowtz, 985). Pseudohypertrophy, for nstance of the calves, s not seen clncally or on the CT scans. Although t s not possble to predct a patent's moblty or degree of ncapacty by studyng the CT scan, the smple vsual gradng of the CT scans proved very useful n judgng the severty of the dsease n a semquanttatve manner (De Vsser and Verbeeten, 985). Especally n the youngest patents, CT scannng was more senstve than the clncal examnaton n demonstratng the presence of myopathy. Hstologcally, vacuolaton of muscle fbres s the hallmark of HPP. It has been reported that the vacuoles are predomnantly located n type I fbres (Ionasescu et al., 97; Tome', 98), but they were found n both types by Engel (986) as well as n the present cases. The number of vacuoles vares from muscle to muscle and may ncrease reversbly durng attacks (Shy et al., 96; Ionasescu et al., 97). Ths ncrease (Shy et al., 96), though sometmes absent (Resnck et al., 969) may ndcate that the vacuoles are a manfestaton of muscle membrane dsturbance or destructon occurrng durng attacks. The reducton n MFCV s possbly caused by the membrane dsablty that underles HPP. Some hypotheses have been proposed to explan the membrane dsablty, such as an ncreased conductance of the muscle membrane to sodum, a decreased conductance to potassum or an ncreased actvty of the Na + K + pump. As early as 97, Hofmann and Smth hypotheszed an ncreased sodum conductance. Layzer (98) defended a decreased conducton of potassum by analysng the membrane potentals and on concentratons between and durng paralytc attacks. Hofmann (98) opposed the theores of Layzer. Rdel et al. (98a) shared the opnon of an ncreased sodum conductance and a reduced exctablty based on membrane voltage clamp experments and exctablty tests. More recent, Rdel et al. (986) suggested an ncreased actvty of the Na + K + pump. Ths latter theory has been consdered to be wrong on theoretcal grounds by Martn and Levnson (985). However, none of these theores has convncngly explaned the pathophysology of HPP. As already mentoned, the reduced MFCV can be the expresson of the membrane dsablty. In ths respect, t s of nterest that both vacuoles and a reduced MFCV found n all the currently reported cases, suggest that the membrane defect s present wthout manfest attacks. It s lkely that membrane dsturbance s present n all strated muscles, but t s unclear why some muscles are affected more severely than others. Downloaded from by guest on May, 6

16 888 T. P. LINKS AND OTHERS The second hstopathologcal characterstc of HPP s the presence of tubular aggregates, whch are presumably derved from the sarcoplasmc retculum. Such structures were observed ultrastructurally n of the studed patents and enzyme hstochemcally n the other. They were, however, very lmted n number. Snce none of these patents experenced from attacks, t may be wondered whether, n contrast to vacuoles, the presence of tubular aggregates correlates wth the occurrence of attacks. There s lttle known about the nvolvement of the cardac muscle n HPP, although acute dlataton and cardac arrhythma durng severe attacks has been descrbed (Kramer et al., 979). In the current Case 9, lght mcroscopy of the heart showed no abnormaltes, whereas electron mcroscopy was not performed. To our knowledge, the only prevous hstologcal report s that by Buruma et al. (98) who also descrbed normal lght mcroscopc as well as enzyme hstochemcal fndngs and observed no vacuoles on electron mcroscopy. Electron mcroscopcally they dd fnd rather abundant glycogen deposton between the myofbrls of some fbres and an ncrease n the number of mtochondra, but these fndngs are nonspecfc and ther sgnfcance s as yet unclear. We conclude that HPP, at least n the current famly, s a myopathy wth permanent muscle weakness of late onset n all patents. Perodc paralytc attacks are strkng, but ther expresson s varable. Wth surface EMG measurements of MFCV, whch s characterstcally reduced n HPP, t s possble to detect relatves who have nherted the dsease. Some of them have no complants, others are affected by fluctuatng muscle weakness due to slght perodc paralytc attacks, and some are handcapped because of reduced muscle strength. We assume that vacuolar changes, seen at a young age, are the frst hstologcal expresson of destructon of muscle tssue and are unrelated to paralytc attacks. In a later stage, at an older age, muscle tssue s destroyed to such an extent that t may cause severe dsablty. CT scannng s a senstve method of confrmng the presence and extent of the myopathy, not only n the proxmal, but also n the dstal muscles, at least n the legs. HPP can therefore be regarded as a myopathy featurng late onset destructon of proxmal and dstal muscles. Ths myopathy, as shown n ths study of members of a famly, s unrelated to the hstory of paralytc attacks. Based on the numbers n the whole famly studed, t s characterzed by paralytc attacks n only 6% of the cases. Downloaded from by guest on May, 6 REFERENCES BIEMOND A, POLAK DANIELS A (9) Famlal perodc paralyss and ts transton nto spnal muscular atrophy. Bran, 57, 9-8. BULCKE JAL, BAERT AL (98) Clncal and Radologcal Aspects of Myopathes: CT Scannng-EMG Radosotopes. Berln: Sprnger, pp. 5-78, -9, 89. BURUMA OJS, BOTS GTAM (978) Myopathy n famlal hypokalaemc perodc paralyss ndependent of paralytc attacks. Ada Neurologca Scandnavca, 57, BURUMA OJS, SCHIPPERHEYN JJ, BOTS GTAM (98) Heart muscle dsease n famlal hypokalaemc perodc paralyss. Acta Neurologca Scandnavca, 6, -. BURUMA OJS, BOTS GTAM, WENT LN (985) Famlal hypokalemc perodc paralyss: 5-year followup of a large famly. Archves of Neurology, Chcago,, 8. DE VISSER M, VERBEETEN B (985) Computed tomography of the skeletal musculature n Becker-type muscular dystrophy and bengn nfantle spnal muscular atrophy. Muscle and Nerve, 8, 5.

17 FAMILIAL HYPOKALAEMIC PARALYSIS 889 DUBOWITZ V (985) Muscle Bopsy: A Practcal Approach. Second edton. London: Ballere Tndall, pp DYKEN M, ZEMAN W, RUSCHE T (969) Hypokalemc perodc paralyss: chldren wth permanent myopathc weakness. Neurology, Cleveland, 9, ENGEL AG (986) Perodc paralyss. In: Myology: Basc and Clncal. Edted by A. G. Engel and B. Q. Banker. New York: McGraw-Hll, pp GRIGGS RC (986) Overvew of current therapes n myotonas and perodc paralyses: results and mechansms. Muscle and Nerve, 9, Supplement, 65. HOFMANN WW (98) Perodc paralyss. Annals of Neurology,, HOFMANN WW, SMITH RA (97) Hypokalaemc perodc paralyss studed n vtro. Bran, 9, 5-7. HUDSON AJ, STRICKLAND KP, WILENSKY AJ (967) Serum enzyme studes n famlal hyperkalemc perodc paralyss. Clnca Chmca Ada, 7, -7. IONASESCU V, SCHOCHET SS, POWERS JM, KOOB K, CONWAY TW (97) Hypokalemc perodc paralyss: low actvty of sarcoplasmc retculum and muscle rbosomes durng an nduced attack. Journal of the Neurologcal Scences,, 9-9. JOHNSEN T (98) Famlal perodc paralyss wth hypokalaema: expermental and clncal nvestgatons. Dansh Medcal Bulletn, 8, -7. KRAMER LD, COLE JP, MESSENGER JC, ELLESTAD MH (979) Cardac dysfuncton n a patent wth famlal hypokalemc perodc paralyss. Chest, 75, KREINDLER A, IONASESCO V, PETROVICI I, PETRESCO A, CALCAJANU G (96) Etudes clnques et de laboratore dans la paralyse p^rodque famlale avec hypokal6me. Revue Neurologque,, LAYZER RB (98) Perodc paralyss and the sodum-potassum pump. Annals of Neurology,, LINKS TP, ZWARTS MJ, OOSTERHUIS HJGH (988) Improvement of muscle strength n famlal hypokalaemc perodc paralyss wth acetazolamde. Journal of Neurology, Neurosurgery and Psychatry, 5, -5. MARTIN AR, LEVINSON SR (985) Contrbuton of the Na + -K + pump to membrane potental n famlal perodc paralyss. Muscle and Nerve, 8, PEARSON CM (96) The perodc paralyses: dfferental features and pathologcal observatons n permanent myopathc weakness. Bran, 87, 5. PLOEG RJO VAN DER, OOSTERHUIS HJGH, REUVEKAMP J (98) Measurng muscle strength. Journal of Neurology,, -. RESNICK JS, DORMAN JD, ENGEL WK (969) Thyrotoxc perodc paralyss. Amercan Journal of Medcne, 7, RODEL R, LEHMANN-HORN F, RICKER K, KOTHER G (98a) Hypokalemc perodc paralyss: n vtro nvestgaton of muscle fber membrane parameters. Muscle and Nerve, 7,,. RODEL R, RICKER K, LEHMANN-HORN F (98fc) Pathophysology of the perodc paralyses: new expermental data. In: Neuromuscular Dseases. Edted by G. Serratrce, D. Cros, C. Desnuelle, J.-L. Gastaut, J.-F. Pellsser, J. Pouget and A. Schano. New York: Raven Press, pp RODEL R, RICKER K (985) The prmary perodc paralyses. Trends n Neuroscences, 8, SHY GM, WANKO T, ROWLEY PT, ENGEL AG (96) Studes n famlal perodc paralyss. Expermental Neurology,, 5-. TOM FMS (98) Perodc paralyss and electrolyte dsorders. In: Skeletal Muscle Pathology. Edted by F. L. Mastagla and Sr John Walton. Ednburgh: Churchll Lvngstone, pp WIGGERS P, NBRREGAARD-HANSEN K (985) Myoglobn, creatne knase and creatne knase subunt-b n serum from patents and relatves wth hypokalaemc famlal perodc paralyss. Acta Neurologca Scandnavca, 7, ZWARTS MJ, WEERDEN TW VAN, LINKS TP, HAENEN HTM, OOSTERHUIS HJG (988) The muscle fber conducton velocty and power spectra n famlal hypokalemc perodc paralyss. Muscle and Nerve,, Downloaded from by guest on May, 6 {Receved March 7, 989. Revsed October, 989. Accepted January, 99)

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