Hypokalemic periodic paralysis with unusual responses to acetazolamide and sympathomimetics

Journal of the Neurological Sciences, 1987, 81: 159-172

159

Elsevier

JNS 02886

Hypokalemic periodic paralysis with unusual responses to acetazolamide and sympathomimetics Boils A. Vern, Moils J. Danon and Kathryn Hanlon Department of Neurology, College of Medicine, Universityof Illinois at Chicago, Chicago, IL (U.S.A.) (Received 12 December, 1986) (Revised, received 1 June, 1987) (Accepted 1 June, 1987)

SUMMARY

Five members in three generations of a family were affected by an illness that had many clinical features of the hypokalemic form of periodic paralysis (HPP). The serum potassium was either moderately reduced or normal during attacks, and there was no evidence of myotonia or cold-intolerance. All of the patients improved to a variable degree with oral potassium supplements, and 3 responded favorably to triamterene. The usually beneficial drug acetazolamide, however, invariably caused weakness in these patients, an effect previously described in only one other family with HPP. In addition, amphetamine-like sympathomimetic drugs effectively aborted or prevented paralysis in several members. Muscle biopsy in two patients revealed some unusual features, and electromyography showed myopathic potentials. There was no evidence of diabetes. The urine electrolyte concentrations during glucose tolerance tests, however, were different from those previously reported in HPP. This family may represent a variant form of HPP.

Key words: Hypokalemic periodic paralysis; Acetazolamide; Sympathomimetic drugs; Electromyography; Muscle biopsy; Muscle histochemistry

This work was presented in part at the American Academy of Neurology Meeting, New Orleans, April 29, 1986. Correspondence to: Boris A. Vern, M.D., Ph.D., Department of Neurology, University of Illinois at Chicago, 912 South Wood Street, Chicago, Illinois 60612, U.S.A. Telephone: 312-996-6496. 0022-510X/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)

160 INTRODUCTION

Familial hypokalemic periodic paralysis (HPP) is a disorder characterized by episodes of generalized skeletal muscle weakness of varying degree, accompanied by either low or normal serum potassium (K + ) levels (Aitken et al. 1938; Shy et al. 1961 ; Pearson 1964; Goulon et al. 1979; Johnsen 1981). Paretic spells may be induced by carbohydrate ingestion, corticosteroids, emotional stress, insulin/glucose administration, and rest after physical exercise. The mechanisms underlying these phenomena have yet to be clarified, although experimental evidence suggests several possibilities, including a functional defect in the sarcoplasmic reticulum (Shy et al. 1961; Pearson 1964; Porte et al. 1979; Johnsen 1981; Martin etal. 1984), abnormalities of specific ion conductances in muscle membrane (Troni et al. 1983; Rudel et al. 1984) and a disturbance of muscle carbohydrate metabolism (Otsuka and Ohtsuki 1970; Johnsen 1977b; Johnsen and Beck-Nielsen 1979; Hofmann 1983). The carbonic anhydrase inhibitor acetazolamide (ACTZ) is a beneficial prophylactic drug in many patients with HPP (Griggs et al. 1970; Vroom et al. 1975; Johnsen 1977b; Goulon et al. 1979). Torres and colleagues (1981), however, described a family with otherwise typical HPP in whom ACTZ actually precipitated muscle weakness, even in a previously asymptomatic individual. We now report a second family with HPP whose members were adversely affected by ACTZ. In addition, a previously not described beneficial response to several sympathomimetic drugs was also found. CASE REPORTS

Family summary We studied 5 members in 3 generations of a family affected by periodic paralysis (Fig. 1). Clinical features that were common to these patients are summarized in

|

2

III

2

I' 1

3

2

Fig. 1. The pedigree. Arrow indicates the propositus. Affected members are represented by filled symbols. Numbers within patient symbols indicate the number of siblings of the respective sex.

161 TABLE 1 SUMMARY OF CLINICAL CHARACTERISTICS OF ALL PATIENTS Patient

Age Sex Age at onset (years) Serum (K ÷] range (mequiv./I) Proximal muscle weakness Distal muscle hypertrophy Associated conditions

11-2

III-1

Ili-2

Ill-3

IV-1

61 F 4

29 F 6

38 M 11

36 M 11

14 F 6

2.9-4.6

3.4-4.3

3.7-4.5

3.6-4.2

3.6-4.0

mild

none

moderate

moderate

moderate

moderate

none

moderate

moderate

moderate

-

ovarian cysts; hypotonic bladder

congenital obesity; hip dysplasia polyeythemia

Table 1. Episodic weakness, which appeared by age 11, often occurred during early morning hours. It could be provoked by carbohydrate meals, emotional stress, alcohol, high fever, menses, or by rest after physical exercise. Typical attacks, lasting from 30 min to 72 h, usually began with symmetrical distallower limb weakness and often progressed to flaccid quadriplegia without respiratory compromise. These spells were accompanied by temporary muscle swelling; myalgia and muscle tenderness occurred during recovery. Interictally, all patients except Case III-1 showed mild to moderate proximal muscle weakness and hypertrophy of the gastrocnemius and forearm muscles. 5-h glucose tolerance tests (GTI') were normal in all patients. The serum [K ÷ ] was rarely correlated with episodes of weakness. The diagnosis of H P P was confirmed by an intraarterial epinephrine infusion test in Cases 11-2 and 111-3 (Engel et al. 1965), an exercise test in Case III-1 (Mc Manis et al. 1985), and by intravenous glucose/subcutaneous insulin provocation (Case 11-2). Prior to our study, all patients had experienced mild to moderate symptomatic improvement after beginning a daily r e , men of oral KCI (25 ~/o solution, 5-20 ml 3 times daily). Oral triamterene (100 mg daily) resulted in additional improvement in Cases III-1 and 111-2. Acetazolamide (ACTZ), on the other hand, caused prolonged quadriplegia after a single oral dose of 125-500 mg in Cases 11-2, III-1, and 111-3. Spironolactone had no significant effect. Clinical features that were unique to each patient are presented below and summarized in Table 1. Responses to various medications are summarized in Table 2.

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163 Patient 11-2

Serum electrolytes, creatine kinase (CK) and other hematologic tests were normal at age 36, except for hypokalemia during a spontaneous paretic episode ([ K + ] = 2.9 mequiv./l). At age 40, the serum [ K + ] was found to range between 3.0 and 4.6 mequiv./l during periods of normal motor function. The administration of oral glucose (2g) and subcutaneous insulin (15 U) at that time resulted in flaccid quadriplegia (during which the serum [K + ] was 3.4 mequiv./1); this weakness was rapidly reversed by oral KCI solution (5 g). Over the years, the severity of the illness has diminished, with the patient doing reasonably well on KC1 supplements. A 1-week trial of phentermine (15 mg daily) temporarily eliminated the usual requirement for KC1 supplementation. Patient III-1

During a recent hospitalization for the evaluation of urinary retention, this patient had two 5-h GTTs, with determinations of baseline (24-h), fasting, and post-glucose serum and urine electrolyte concentrations. The GTTs were normal, but an increase in the urinary excretion of K +, CI-, Mg 2 +, and phosphate occurred after glucose loading, relative to Na ÷ and Ca 2÷ . A decline in serum [K ÷ ] from 4.3 to 3.6 mequiv./1 at 1 h during the first GTT was unaccompanied by weakness. On the other hand, the [K ÷ ] was 3.7 during a spontaneous early-morning episode of moderately severe quadriparesis. After a period of normal motor function, a physical stress test (walking up 8 flights of stairs) was followed by moderate paraparesis after 90 rain, at which time the serum [K + ] was 3.6 mequiv./l, down from a pre-exercise value of 3.8. A single oral dose of ACTZ (125 mg), administered when muscle strength was normal, caused marked quadriparesis within 30min (the serum [K + ] was 3.4mequiv./l while the other electrolytes and glucose level remained unchanged). Outpatient trials of oral NH4C1 (6 g twice daily) and benzamphetamine (25 mg daily) were terminated after 48 and 24 h, respectively, because of side effects unrelated to motor function. Patient 111-2

As part of a weight reduction program 1 year prior to our assessment, benzamphetamine (25 mg) or phentermine (15 mg) was prescribed on a daily basis at different times. The patient reported that the ingestion of either drug during a spell of generalized weakness would usually abort the episode within 30 min, whereas weakness of varying degree would otherwise persist for several hours, responding only gradually to additional KC1 supplementation. We found that his ingestion of either drug once or twice weekly also "prophylactically" diminished the requirement for daily KC1 supplements by 50-75 ~o for 2-3 days, with normal muscle strength being noted after moderate physical exertion that would otherwise invariably produce weakness. Oral albuterol (2 mg) taken on 2 occasions (once during a paretic spell) caused no unusual reactions, although the paresis may have been slightly exacerbated. Propranolol, 20 mg 3 times daily, was without effect over 3 days, during which no drugs other than triamterene and KC1 were ingested. Electrophysiological studies showed the peripheral motor and sensory nerve functions to be normal. There was no evidence of a myoneural junction

164 disorder. Needle EMG of the extensor digitorum brevis, tibialis anterior and gastrocnemius muscles showed no active denervation at rest, nor were there any high frequency discharges. On volition, intermingled with normal size motor unit potentials of normal configuration, numerous short-duration, low-amplitude (at times highly polyphasic) myopathic motor units were seen. Recruitment was easily obtainable. Both quadriceps muscles showed similar abnormalities but they were mild. The most severe abnormalities were seen over both biceps, deltoid and wrist extensor muscles. Patient 111-3

Physical exertion in this man has been limited and symptomatic control with KC1 has been less than optimal because of his considerable appetite for carbohydrates. Treatment with dexamethasone for cerebral edema following head trauma at age 29 caused quadriplegia for several days. Laboratory studies have been significant for persistent polycythemia (Hb: 16-19 g/dl), type IV hyperlipidemia, normal GTTs, and a mild elevation of serum CK (236 IU/I). Serum electrolytes have always been normal, as in his brother (Case III-2). A brief trial of oral ( + )-amphetamine (5-10 mg daily) at age 32 produced a profound increase in muscle strength and prevented episodic weakness over a period of several days, during which time no oral KC1 supplements were required. A marked increase in exercise tolerance and decrease (75 ~o) in daily KC1 requirement occurred over 7 days during outpatient trials of either benzamphetamine (25 mg daily) or NH4CI (6 g twice daily). The f'n-st drug was discontinued because of nervousness, hyperactivity and insomnia, and the second because of nausea and abdominal cramps. This patient also ingested a single dose of diethylpropion (25 mg) on 3 separate occasions when he had no access to oral KC1 supplements during an evolving paretic episode. In each case, he reported a complete and rapid reversal of the weakness, with no recurrence for 12-24 h. Dichlorophenamide (50 mg orally twice daily), a carbonic anhydrase inhibitor more potent than ACTZ (Dalakas and Engel 1983), was without effect over 48 h, but was discontinued on the third day because of generalized weakness (although sustained physical exertion occurred on that day). A recent cardiologic evaluation, performed because of chest discomfort and dyspnea, revealed no evidence of heart disease. Nevertheless, a calcium channel blocker (nifedipine, 10 mg daily in divided doses) was prescribed for several months because of suspected angina; this caused no change in his muscular symptoms. Patient IV-I

At age 6, the intensity of paretic spells, lasting up to several days, was diminished by oral KC1 supplements. At age 12, however, the paretic episodes markedly increased in frequency, severity and duration, being easily triggered by even mild physical exercise, menses or emotional stress. A recent in-patient 5-h GTT revealed normal serum glucose and insulin responses, although the maximal insulin level inexplicably preceded the maximal glucose level by 30 min and the minimal K + level by 90 min. Moderate quadriparesis occurred 2 h after beginning the GTT. The serum [K + ] at that time fell from a baseline of 4.0 mequiv./1 to 3.6, whereas the other electrolytes remained normal. Urine electrolyte concentrations following the glucose load indicated an increased

165 excrection of K + and phosphate but not of CI- or Mg 2 + relative to Na + or Ca 2 +, as compared with the fasting sample values. No major difference in relative ionic excretion was apparent, however, when the post-glucose values were compared with a pre-GTT baseline 24-h urine collection, a result in contrast to Case III-1. A trial of oral ACTZ (125 mg 3 times daily) was initiated, and she was discharged from hospital after the t'n'st 2 doses, with no immediate response being observed. Profound quadriplegia occurred 6 h after the third dose of ACTZ, however, and the drug was discontinued. On 2 of 3 occasions, a spontaneous paretic spell was aborted within 30-60 min by a single oral dose of benzamphetamine (12.5 mg). Triamterene (100 mg daily) was added to the KC1 supplements, resulting in marked, sustained improvement in muscle strength and exercise tolerance, except during menses. Muscle biopsy

The biceps muscle was biopsied in Patients 111-2 and 111-3. The tissue from both patients was prepared for histochemical study, and electronmicroscopic analysis was subsequently performed in patient 111-3 (Carpenter and Karpati 1984). Patient 111-2

Fresh-frozen cryostat sections stained with hematoxylin-eosin and trichrome showed numerous small angulated fibers forming small groups (Fig. 2A). Many fibers were hypertrophic, some of them up to 300 #m in diameter. Numerous internal nuclei were also present. There was no necrosis or inflammation. In some sections, small angulated fibers contained red clusters with trichrome stain typical of ragged-red fibers. No vacuoles were seen. Few ringed fibers were noted, but numerous hypertrophic fibers appeared to be snake-coiled. Although most of this biopsy suggested a denervating process, there were some areas in which clusters of small rounded fibers of variable size were seen, suggestive of a myopathy (Fig. 2B). With histochemical stains, NADHtetrazolium reductase stain revealed many small angulated fibers which stained dark with formazan. Large hypertrophic fibers, especially of the Type I variety, appeared to be moth-eaten and some targetoid fibers were also present. There was a significant paucity of Type I fibers, especially apparent with myofibrillary ATPase (Fig. 2C) and menadione linked ~-glycerophosphate reactions. About 90~o of the fibers were of the Type II variety. Patient 111-3

In contrast to Patient 111-2, cryostat sections of his muscle showed a few small angulated fibers, occasionally forming small groups (Fig. 3A). The main abnormality, however, was that 2 0 - 3 0 ~ of the fibers contained subsarcolemmal accumulations of material which stained red with trichrome stain (Fig. 3A), stained heavily with NADH tetrazolium reductase, and remained unstained with myofibrillary ATPase and succinic dehydrogenase, thus suggestive of tubular aggregates. Numerous intramuscular nerves and blood vessels appeared normal. No type-grouping was seen. With epoxy resin histology, subsarcolemmal bluish accumulations in about one-half of the fibers con-

166

Fig. 2A.

Fig. 2B.

167

Fig. 2. (A) Cryostat section from the biceps muscle of patient 111-2 shows atrophic angulated fibers, and hypertrophic muscle fibers with numerous internal nuclei. HE, x 160. (B) Other areas from the same section show small-rounded fibers of varying diameters, hypertrophic fibers and a ring fiber. HE, x 160. (C)This cryostat section shows severe Type I fiber deficiency. Myofibrillar ATPase (pH 9.4), × 80.

stituted the major abnormality. On longitudinal sections, these accumulations at times covered 30-40 sarcomeres in distance. Electronmicroscopy (Fig. 3B) revealed typical tubular aggregates. DISCUSSION

The usually favorable effect of A C T Z in H P P (Griggs et al. 1970; Vroom et al. 1975; Johnsen 1977b; Goulon et al. 1979) was once considered to be mediated by metabolic acidosis (Vroom ct al. 1975; Jarrcll et al. 1976; Johnsen 1977b). In fact, one of our patients (III-3) derived significant benefit from N H 4 C I administration; he nevertheless experienced marked weakness after A C T Z , as did other members of his family. It has been suggested that A C T Z causes reliefand prophylaxis in H P P by an interaction with a carbonic anhydrase that may bc present in muscle membrane (Moynihan 1977; Riggs ct al. 1984), or by dissociating the transport of K + and glucose across muscle membrane (Riggs et al. 1984). Torres et al. (1981) proposed that the adverse response of their family with H P P to A C T Z may have bccn related to latent or overt diabetes, or to an ACTZ-induced hypokalemia. Our patients, however, showed no evidence of diabetes. In addition, their levels of serum K +wcrc not consistently

168

A

B Fig. 3. (A) Cryostat section from the biceps muscle (patient 111-3)shows a small group of atrophic-angulated fibers (arrow) and darkly staining subsarcolemmal accumulations (arrow heads). Modified Gomori trichrome, × 160. (B) This electronmicrograph shows typical tubular aggregates. × 52000.

169 correlated with episodes of weakness, an observation also reported in other cases of HPP (Shy et al. 1961; Pearson, 1964; Griggs et al. 1970; Johnsen 1981). Our results therefore support the concept of a direct action of ACTZ at the level of the muscle membrane. The adrenergic mediation of the anticonvulsant action of ACTZ in the central nervous system of rats (Mennear and Rudzik 1966; Rudzik and Mennear 1966) suggests that ACTZ may also interact with adrenergic systems in the periphery. The beneficial effect of the sympathomimetic, amphetamine-like drugs in 4 of our patients may reflect such an interaction. When fl2-adrenoceptors in normal skeletal muscle membranes are activated by epinephrine or more specific fl-agonists, they stimulate the ATPase-dependent membrane Na + + K + pump via the adenylate cyclase system (Clausen and Flatman 1974; Lockwood and Lum 1974; Reddy et al. 1978). This mechanism has been related to the favorable effect of fl2-adrenergic stimulation in familial hyperkalemic periodic paralysis (Clausen et al. 1980; Bendheim et al. 1985), in contrast to the induction of paralysis in HPP by fl-agonists (Engel et al. 1965; Johnsen 1981). The muscle weakness following intraarterial epinephrine infusion or emotional stress in our patients therefore strengthens our opinion that this family manifests a form of HPP. The paradoxically favorable response of our patients to other sympathomimetic drugs may be related to the report of cq-adrenoceptors that are either unmasked or induced by dietary-induced hypokalemia in the soleus, a slow-twitch Type I muscle in rats (Akaike 1981 ; Akaike et al. 1983). Specific activation of these receptors, which are modulated by a direct noradrenergic innervation, inhibits the Na + + K + muscle membrane pump; fl2-adrenoceptor stimulation in the same preparations exerts an opposite effect. Although ~-adrenoceptors have not yet been studied in human skeletal muscle membrane, we suggest that the amphetamine-like drugs effective in our patients may act by stimulating possibly abnormal or deficient ~-adrenoceptors by releasing norepinephrine from presynaptic terminals. Possible interactions of these adrenergic mechanisms with the Ca 2 + -conducting system in muscle membrane (Porte et al. 1979) may also be important. The muscle biopsies from the two brothers (Ill-2 and 111-3) were interesting for several reasons. Whereas they were similar in that central vacuoles were absent, an uncommon result (Shy et al. 1961; Pearson 1964; Gerard et al. 1978; Johnsen 1981; Martin et al. 1984) but occasionally reported (Olivarius and Christensen 1965; Dyken et al. 1969) in HPP, significant differences between the 2 cases were also found. The tissue from Patient II1-2 was compatible with a denervating disease (Fig. 2A), although less prominent areas of "myopathic" changes were also seen (Fig. 2B). Such marked denervation-like histopathological patterns have been infrequently reported in HPP (Shy et al. 1961; Pearson 1964; Martin et al. 1984), but have been observed in several purely "myopathic" conditions, e.g., Becker muscular dystrophy, inclusion body myositis, and Emery-Dreyfuss type scapular-peroneal muscular dystrophy (Carpenter and Karpati 1984). Riggs et al. (1977) described a patient with combined paramyotonia congenita and non-hyperkalemic periodic paralysis, from whom a muscle biopsy result similar to our patient 111-2was obtained. Of possible significance to our family (without myotonia) is their observation that ACTZ caused generalized muscle weakness but

170 improved the myotonia, while oral KC1 loading resulted in the opposite effect. Their additional finding of Type II muscle fiber predominance also corresponds to our Patient Ili-2 (Fig. 2C), in whom the remaining Type I fibers were mostly hypertrophic and had a "moth-eaten" appearance. In contrast, Type I, rather than II, fiber predominance has been the pattern usually reported in "classical" H P P (see Johnsen 1981, for review), although no fiber predominance has also been observed (Martin et al. 1981). Paradoxically, the muscle biopsy from our Patient 111-3 showed only mild denervation-like changes, while prominent tubular aggregates were present (Fig. 3A,B), mostly in Type II fibers. The latter finding has been often reported in cases of H P P (Johnsen 1981; Niakan et al. 1985; Porte et al. 1979) and, significantly, in the case of Riggs et al. (1977). In addition, no fiber type predominance was seen. The disparity between the two muscle biopsies remains unexplained, although the fact that Patient 111-3 was obese, excessively consumed carbohydrates, was hyperlipidemic, was not ingesting triamterene, and was not frequently using sympathomimetic drugs should be considered. It may be significant that the peak of serum glucose elevation occurred after the maximal increase in serum insulin during the G T T in Patient IV- 1 (Hofmann et al. 1983; Johnsen 1977a; Johnsen and Beck-Nielsen 1979). In addition, the urinary excretion of K + and phosphates was increased relative to N a + and C1- after glucose loading in patients III-1 and IV-l, in contrast to the response usually observed in H P P (Johnsen 1981). These anecdotal observations clearly require further investigation. Although this family's illness is characterized by many of the clinical features common to HPP, the adverse response to ACTZ, the muscle biopsy results, and the unusual urine electrolyte changes after glucose loading suggest that it represents a distinct variant of periodic paralysis. In addition, the favorable clinical response to amphetamine-like drugs may be unique to this condition, but we could find no other reports of the use of these agents in H P P for comparison. A careful analysis of possible adrenerglc mechanisms in skeletal muscle membranes is suggested. REFERENCES Aitken, R.S., E.N. Allott, L.I.M. Castleden and M. Walker (1938) Observations on a case of familial periodic paralysis. Clin. Sci., 3: 47-57. Akaike, N. (1981) Sodium pump in skeletal muscle: central nervous system-induced suppression by ~-adrenoceptors. Science, 213: 1252-1254. Akaike, N., A. Hirata, T. Kiyohara and Y. Oyama (1983) Neural regulation on the active sodium-potassium transport in hypokalemicrat skeletal muscles. J. Physiol. 341: 245-255. Bendheim, P.E., E.O. Reale and B.O. Berg (1985) /~-Adrenergic treatment of hyperkalemic periodic paralysis. Neurology, 35: 746-749. Carpenter, S. and G. Karpati (1984) Pathology of skeletal muscle. Churchill Livingstone, New York, 1984. Clausen, T. and J.A. Flatman (1977) The effect of catecholamines on Na-K transport and membrane potential in rat soleus muscle. J. Physiol., 270: 383-414. Clausen, T., P. Wang, H. Orskov and O. Kristensen (1980) Hyperkalemicperiodic paralysis. Relationships between changes in plasma water, electrolytes,insulin and catecholamines during attacks. Scand. J. Clin. Lab. Invest., 40: 211-220. Dalakas, M. C. and W. K. Engel (1983) Treatment of "permanent" muscleweakness in familialhypokalemic periodic paralysis. Muscle Nerve, 6: 182-186.

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172 Torres, C.F., R.C. Griggs, R.T. Moxley and A.N. Bender (1981) Hypokalemic periodic paralysis exacerbated by acetazolamide. Neurology, 31: 1423-1428. Troni, W., C. Doriguzzi and T. Mongini (1983) Interictal conduction slowing in muscle fibers in hypokalemic periodic paralysis. Neurology, 33: 1522-1525. Vroom, F.Q., M.A. Jarrell and T.H. Maren (1975) Acetazolamide treatment of hypokalemic periodic paralysis. Probable mechanism of action. Arch. Neurol., 32: 385-392.