Journal of Neurology, Neurosurgery, and Psychiatry, 1972, 35, 202-207

Myopathy in association with primaryhyperaldosteronism

M. A. SAMBROOK, J. R. HERON, AND G. M. ABER

From the Department of Neurology, North Staffordshire Royal Infirmary, Stoke-on-Trent

SUMMARY We report a patient presenting with a proximal myopathy in association with primaryhyperaldosteronism (Conn's syndrome). The possible factors concerned in the inter-relationship ofthese two conditions are discussed, with particular reference to the influence of potassium depletion.

Myopathies have been described in associationwith several endocrine disorders including thyro-toxicosis (Bathurst, 1895; Ramsay, 1965),myxoedema (Astrom, Kugelberg, and Muller,1961), hyperparathyroidism (Vicale, 1949), Cush-ing's syndrome (Muller and Kugelberg, 1959),and hypopituitarism (Shy, 1960; Walton, 1960).Although patients with primary hyperaldoster-onism often complain of muscular weakness weare not aware of the electrophysiological, histo-logical, and serum muscle enzyme changes of adegenerative myopathy having previously beendescribed in this condition. We wish therefore toreport a patient who presented with a proximalmyopathy, in whom further investigation re-vealed primary hyperaldosteronism. Treatmentof the endocrine disorder resulted in a fullrecovery of his myopathy.

CASE REPORT

Mr. S. B., a 47 year old plate-maker, was admittedto hospital in September 1970, with a five year historyof progressive muscular weakness. Previously as ascout-master he was accustomed to walking severalmiles at a time but now he was able to maintain anormal pace for only 200 to 300 yards. In particularhe noted restriction in climbing stairs and uphillgradients. Increasing weakness of his arms, parti-cularly when elevating them above his shoulders, hadcurtailed his home-decorating activities. His disabilityhad spontaneously fluctuated in severity and hefound that repetitive actions aggravated his weak-ness. An example of this was the loss of power in hishands which developed after handling large quan-tities of clay for a day in the course of his job. Also,when stock-taking, which demanded repeated crouch-ing to look at objects on the floor, he developedbilateral foot-drop. Such symptoms would last forseveral hours. Despite having a good appetite, there

202

had been a gradual wasting of his shoulder musclesand buttocks over the past two years, associatedwith a loss of two stones (13 kg) in weight. He hadnoticed increasing thirst, polyuria, and nocturia.Specific questioning revealed that his bowel habithad remained regular and he had not been takingany drugs or laxatives likely to influence potassiummetabolism.

Apart from the development of bilateral lenticularcataracts at approximately 20 years of age his pastmedical history had been free of any significant ill-ness. A right iridectomy had been performed in 1959.There was no family history of any significant neuro-logical disease.

PHYSICAL EXAMINATION He was of asthenic bodybuild. His pulse rate was 84 per minute and regular.The blood pressure in both arms was 150/100mm Hg.The apex beat of the heart was of normal characterand situated in the fifth left intercostal space in themid-clavicular line. Auscultation of the heart wasnormal. No abnormality was found in the chest orabdomen.

CENTRAL NERVOUS SYSTEM His intellect and memorywere unimpaired, and his speech was normal. Hehad a cataract of the left lens. Full examination of thecranial nerves revealed no abnormality and therewas no evidence of facial weakness. There wasproximal weakness of his arms and legs with par-ticular involvement of the deltoid, triceps, biceps,spinati, pelvic girdle, and thigh muscles. Wastingwas noted over the shoulder girdle muscles and thebuttocks. Muscular tone and tendon reflexes werenormal and the plantar responses were bilaterallyflexor. Sensory testing revealed no abnormality.At the time of admission the following investiga-

tions were made.

HAEMATOLOGICAL Haemoglobin was 14 g/100 ml.and the white blood cell count was 7,900 per cu.mm,

Protected by copyright.

on March 17, 2020 by guest.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.35.2.202 on 1 April 1972. D

ownloaded from

Myopathy in association with primary hyperaldosteronism

with a normal differential count; erythrocyte sedi-mentation rate was 5 mm in the first hour.

BIOCHEMICAL The following estimations were made:serum urea 45 mg/100 ml., potassium 2-0 m-equiv/l.,sodium 146 m-equiv/l., chloride 98 m-equiv/l.;calcium 9 3 mg/100 ml., phosphate 3 2 mg/100 ml.,blood pH 7-52; pCO2 48 mm Hg; standard bicar-bonate 34 m-equiv/l.; serum albumin 4-6 g/100 ml.;globulin 2-0 g/100 ml.; bilirubin 0-3 mg/100 ml.;serum creatinine 1-4 mg/100 ml.; with a creatinineclearance of 57 ml./min. Glucose tolerance test wasnormal. Protein bound iodine level was 7 5 ,ug/100ml.; serum T3-1311 resin uptake 26-7 %. Plasma cor-tisol at 0900 hours was 9 ,ug/100 ml.; at 2400 hours3 ,ug/100 ml.; plasma aldosterone was 69 mpg/100 ml.(normal up to 18 mtkg/100 ml.) and plasma renin 4-2u./l. (normal 4 to 20 u./l.). The plasma renin andaldosterone estimations were both made after thepatient had been in hospital for three weeks on aregulated dietary intake of sodium, 150 m-equiv perday, and potassium, 60 m-equiv per day. The bloodwas taken while the patient was in the supine positionand after 12 hours fasting.Enzyme levels relevant to neuromuscular disease

were: serum creatinine phosphokinase 882 i.u./l.;serum aldolase 6 5 u./ml.; serum glutamic-oxaloace-tic transaminase 45 u./ml.; serum glutamic-pyruvatetransaminase 20 u./ml.

ELECTROMYOGRAPHY Sensory nerve conductiontimes were determined in both median, ulnar, andlateral popliteal nerves. The resultant sensory nerveaction potentials were all of normal amplitude anddelay. Motor conduction velocities in both medianand ulnar nerves ranged between 45 and 50 m/sec.Motor conduction velocity in the right and leftlateral popliteal nerves was 43 and 45 m/sec respec-tively. Electromyographic (EMG) sampling wasperformed in the deltoid and vastus medialis musclesbilaterally. At all sampling sites there was no excessof post-insertional activity. No spontaneous fibril-lation or fasciculation potentials were noted at rest.On volition a full interference pattern was found atall sites but there was a reduction in the amplitudeand duration of many of the individual motor unitpotentials. Tetanic stimulation at 20 impulses persecond revealed a gradual but fluctuating decay in theresultant muscle action potential. This was not re-versed by intravenous edrophonium. With suitableexercise we were able to induce bilateral foot-drop.Further EMG sampling particularly from the tibialisanterior and extensor hallucis longus muscles showedabnormal individual motor unit action potentialsand a reduction in the interference pattern. Therewas no reduction in the motor conduction velocityof either lateral popliteal nerve at this time.

MUSCLE HISTOLOGY A muscle biopsy was taken fromthe left deltoid muscle. Staining with trichrome and

DPNH tetrazolium reductase showed some musclefibres in various stages of necrosis with centralizationof nuclei in other fibres (Figs 1 and 2). No mono-nuclear or macrophage infiltration into the involvedmuscle was seen.

..1

/'4

FIG. 1. Trichrome, x 125.t~~~~ ,

t-sPik-L .~~'..2kr.'d

-4 V,

FIG. 2. DPNH tetrazolium reductase, x 125.

FIGS 1 and 2. Transverse sections of left deltoidmuscle before treatment with spironolactone showingdegenerating fibres and centralization of nuclei.

ELECTROCARDIOGRAPHY There was evidence of leftventricular hypertrophy and strain with 'U' wavesin leads II, III, V3, V4, V5, and V6.

RADIOLOGY Radiographs of the chest showed acardiothoracic ratio of 50 °%. An intravenous pyelo-gram revealed normal concentration and excretionby both kidneys.

EFFECT OF TREATMENT WITH SPIRONOLACTONE Dur-ing the period of investigation the patient was main-

203

10,t

.1.. f

4 1i

Protected by copyright.

on March 17, 2020 by guest.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.35.2.202 on 1 April 1972. D

ownloaded from

M. A. Sambrook, J. R. Heron, and G. M. Aber

:= -Jr

4 PRNLATN 30mc-l0-110

l I , , I

1 2 3 4 5WEEKS

6 7 8 9 10 11 12

FIGS 3 and 4. Serum so-dium and potassium, bloodpH, and bicarbonate beforeand during treatment withspironolactone.

SPIRONOLACTONE 300 mng daily

^ -0

*., \\

\0***~~~~o

I 2 3 4 5 6. 7 8 9

WEEKS

204

I50o

D 140Q w) -

3 0zC- a,D 130uJ 130-U)

SO-

40

3,0I

nD

0:

U)

I17,0*uJe

2-0

1-0-

m

0u

I'

0w

0.aJ

40-

30

20-

7.5

74 -

7.3

10 11 12

Protected by copyright.

on March 17, 2020 by guest.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.35.2.202 on 1 April 1972. D

ownloaded from

Myopathy in association with primary hyperaldosteronism

a daily intake of 150 m-equiv of sodium his serum potassium increased to 3 m-equiv/l. andL-equiv of potassium. He was observed for his serum sodium decreased to 144 m-equiv/l. (FigsDks before treatment with spironolactone 3 and 4). At the end of this period he was still ac-ed and his serum electrolyte and acid-base cumulating 30 m-equiv potassium and losing 30 m-lities remained unchanged (Figs 3 and 4). equiv sodium daily. Only slight improvement in hisve balance studies of sodium and potassium muscle function was observed during this time.-ted 10 days before commencement with After four weeks of treatment his serum potassium,ctone. During this 'control' period he was sodium, and standard bicarbonate stabilized at 45,be in zero balance for potassium and in 138, and 22 m-equiv/l. respectively (Figs 3 and 4).)alance for sodium despite a serum potas- There was a marked improvement in his muscular1 of only 2 m-equiv/l. and a serum sodium power and repeat estimation of his muscle enzymes-equiv/l. (Figs 5 and 6). revealed that the serum creatinine phosphokinasehis observation period the patient received had fallen to 30 i.u./l. and the serum aldolase waspironolactone daily for three months. Dur- now 2-9 u./ml. Further electromyographic studiesirst 10 days of treatment he retained 350 were made and these showed a disappearance of theof potassium and developed a negative abnormal motor unit potentials which had originallyof 330 m-equiv sodium (Figs 5 and 6), while been observed.

Although balance studies were discontinued, hecontinued to receive spironolactone for another eightweeks as an outpatient. There was a further subjectiveimprovement in his muscular power and at the end

*SPIRONOLACTONE 300mg of this period he felt that he had made a completeda'ily

recovery. He was employed as a piece worker andnow that he had returned to work he was able toearn £5 per week extra compared with his perform-ance before hospital admission. On clinical examina-tion muscular power was now normal and the wast-ing of the shoulder muscules and buttocks was lessmarked. A second muscle biopsy was taken from theopposite deltoid muscle and this revealed no abnor-mality.

IS10 Is 20At this stage a laparotomy was performed at which

DAYS a tumour of the left adrenal gland was found (2 x 1cm), and a left adrenalectomy performed. Post-

FIG. 5 operatively the spironolactone was discontinued.During the six months postoperative follow-upperiod he has shown no evidence of deterioration of

SPIRONOLACTONE 300 mg muscular power or return of his original electrolyte_ derangement.

Histology of the left adrenal tumour showed awell-circumscribed adenoma consisting mainly ofzona fasciculata type cells with some 'hybrid' cellsas typically described in Conn's tumours. Histologi-cal examination of a renal biopsy taken at the timeof laparotomy showed arteriolar hypertrophy andrenal tubular dilatation and atrophy with a moderateamount of interstitial fibrosis and focal lymphocyticreaction. These findings were felt to be consistentwith long-standing hypertension.

DAYS

FIG. 6

FIGS 5 and 6. Daily urinary excretion of potassiumand sodium for 10 days before and duringfirst 10 daysof treatment with spironolactone.

DISCUSSION

In 1964 Conn, Knopf, and Nesbit discussed the

clinical presentation and findings in their series

of 145 cases of primary hyperaldosteronism. One

of the most common initial symptoms in their

patients was muscular weakness (730%) typicallyfluctuant in severity. Analysing their data, we

tained onand 60 mthree weewas start(abnormalCumulatiwere starspironolanoted topositive tsium leveof 146 m-

After ti300 mg SIing the fim-equivbalance o

80-

\4nN,

L&Jw

z E

60-

40-

20-

205P

rotected by copyright. on M

arch 17, 2020 by guest.http://jnnp.bm

j.com/

J Neurol N

eurosurg Psychiatry: first published as 10.1136/jnnp.35.2.202 on 1 A

pril 1972. Dow

nloaded from

M. A. Sambrook, J. R. Heron, and G. M. Aber

were unable to find criteria to suggest that anyof their patients had a degenerative myopathy,and they attributed the muscular weakness tohypokalaemia.We have studied a patient whose main com-

plaint was of longstanding muscular weakness.Neurological examination and investigations re-vealed that he had a proximal myopathy whichwas confirmed histologically, and biochemicalinvestigation showed that he had primary hyper-aldosteronism. During treatment with spirono-lactone for 12 weeks his biochemical disturbancewas corrected and there was a complete recoveryof his muscular power with disappearance of thebiochemical, electromyographic, and histologicalevidence upon which we had originally based ourdiagnosis of myopathy, suggesting that this wasdirectly related to his endocrine disorder.

Analysis of the biochemical changes which oc-curred during the period of spironolactone ther-apy showed a striking retention of potassium.The balance studies showed an elevation of hisserum potassium from 2 to 3 m-equiv/l. duringthe first 10 days of treatment in association withretention of 350 m-equiv potassium. It is prob-able that this figure would be much greater bythe time his serum value had reached the finalstable level of 4.5 m-equiv/l. Of this total potas-sium only 10% could be accounted for in theextracellular fluid, suggesting that the rest hadentered the intracellular compartment. Thesefigures are consistent with those of Scribner andBurnell (1956) who showed that a serum potas-sium of 2 m-equiv/l. usually indicated a totalbody loss of approximately 500 to 600 m-equiv.In addition to changes in his body potassium,treatment produced a simultaneous correctionof his sodium and acid-base disturbances.The role of potassium in the regulation of

muscular function is well established. The intra-to extracellular concentration has been shown tobe vital for the control of the resting membranepotential of muscle fibres. This potential iselevated in hypokalaemia, resulting in a decreas-ed muscle excitability and contractility which isone of the major factors responsible for theweakness observed in potassium depletion. Evi-dence has also accumulated that potassium isnecessary for intracellular metabolism. It isrequired for the phosphorylation of high energycompounds such as creatinine phosphate andadenosine triphosphate (Boyer, Lardy, andPhillips, 1943) and it has been shown experi-mentally that when rats are depleted ofpotassium,

growth and protein synthesis cannot proceednormally (Cannon, Frazier, and Hughes, 1952).Structural disintegration of muscle may developand Smith, Black-Schaffer, and Lasater (1950)were able to demonstrate the development ofsevere muscular weakness followed by respira-tory paralysis in dogs depleted of potassium.Examination of the skeletal muscle fibres showedZenker's hyaline degeneration with infiltrationby mononuclear cells. In man necrosis of cardiacmuscle fibre has been reported in conditions ofacute and chronic hypokalaemia (Rodriquez,Wolfe, and Bergstrom, 1950). During the pastfive years several case reports have appearedof acute myopathies associated with hypoka-laemia after abuse of laxatives, carbenoxolone,and diuretics (Gross, Dexter, and Roth, 1966;Mohamed, Chapman, and Crooks, 1966; For-shaw, 1969; Van Horn, Drori, and Schwartz,1970). In all these cases there was histologicalevidence of muscle fibre necrosis and elevatedserum muscle enzymes. Potassium repletion re-sulted in recovery of muscular power and thedisappearance of the histological abnormalities.These observations, taken in conjunction withthe findings in our patient, are strongly suggestivethat potassium depletion may well have beenthe major factor responsible for the developmentof his myopathy but it is important to realize thatduring the corrective period there was a markedloss of sodium and striking changes in hydrogenion concentration, and at present neither ofthese can be disregarded when considering theaetiology of the myopathy.More extensive investigation of patients with

Conn's syndrome may reveal further cases ofassociated myopathy and it is interesting tospeculate on the possible influence of electrolytedisturbances in the causation of myopathies seenin association with Cushing's syndrome and withcorticosteroid therapy.

We wish to thank Dr. J. Morgan Hughes for pre-paring the muscle histology; Mr. J. G. Gray fordetails of the surgical procedure, and Dr. J. J. S.Robertson of the M. R. C. Blood Pressure Unit,Western Infirmary, Glasgow, for the plasma reninand aldosterone estimations.

REFERENCES

Astrom, K.-E., Kugelberg, E., and Muller, R. (1961). Hypo-thyroid myopathy. Archives of Neurology, 5, 472-482.

Bathurst, L. W. (1895). A case of Graves' disease associatedwith idiopathic muscular atrophy. Remarks. Lancet, ii,529-530.

206P

rotected by copyright. on M

arch 17, 2020 by guest.http://jnnp.bm

j.com/

J Neurol N

eurosurg Psychiatry: first published as 10.1136/jnnp.35.2.202 on 1 A

pril 1972. Dow

nloaded from

Myopathy in association with primary hyperaldosteronism

Boyer, P. D., Lardy, H. A., and Phillips, P. H. (1943). Furtherstudies on the r6le of potassium and other ions in thephosphorylation of the adenylic system. Journal of Bio-logical Chemistry, 149, 529-541,

Cannon, P. R., Frazier, L. E., and Hughes, R. H. (1952).Influence of potassium on tissue protein synthesis. Meta-bolisti, 1, 49-57.

Conn, J. W., Knopf, R. F., and Nesbit, R. M. (1964). Clinicalcharacteristics of primary aldosteronism from an analysisof 145 cases. Amnerican Journal of Suirgery, 107, 159-172.

Forshaw, J. (1969). Muscle paresis and hypokalaemia aftertreatment with duogastrone. British MedicalJouirnal, 2, 674.

Gross, E. G., Dexter, J. D., and Roth, R. G. (1966). Hypo-kalemic myopathy with myoglobinuria associated withlicorice ingestion. New-? England Jouirnal of Medicine, 274,602-606.

Mohamed, S. D., Chapman, R. S., and Crooks, J. (1966).Hypokalaemia, flaccid quadraparesis, and myoglobinuriawith carbenoxolone (Biogastrone). British Medical Joturnal,1, 1581-1582.

Muller, R., and Kugelberg, E. (1959). Myopathy in Cushing'ssyndrome. Jouirnal of Neuirology, Neutrosurgery, and Psy-chiatry, 22, 314-319.

Ramsay, 1. D. (1965). Electromyography in thyrotoxicosis.Quiarterly Jourznal of Medicine, 34, 255-267.

Rodriguez, C. E., Wolfe, A. L., and Bergstrom, V. W. (1950).Hypokalemic myocarditis: report of two cases. AmiericanJournal of Clinical Pathology, 20, 1050-1055.

Scribner, B. H., and Burnell, J. M. (1956). Interpretation ofthe serum potassium concentration. Metabolistu, 5, 468-479.

Shy, G. M. (1960). Some metabolic and endocrinologicalaspects of disorders of striated muscle. Research Publica-tions, Association for Resear-c h in Nerv olus and MentalDisease, 38, 274-317.

Smith, S. G., Black-Schaffer, B., and Lasater, T. E. (1950).Potassium deficiency syndrome in the rat and the dog.Archices of Pathology, 49, 185-199.

Van Horn, G., Drori, J. B., and Schwartz, F. D. (1970).Hypokalemic myopathy and elevation of serum enzymes.Archives of Neurology, 22, 335-341.

Vicale, C. T. (1949). The diagnostic features of a muscularsyndrome resulting from hyperparathyroidism, osteo-malacia due to renal tubular acidosis, and perhaps torelated disorders of calcium metabolism. Transactions ofthe American Neuirological Association, 74, 143-147.

Walton, J. N. (1960). Muscular dystrophy and its relation tothe other myopathies. Research Publications, Associationfor Research in Nervous and Mental Disease, 38, 378-421,

207P

rotected by copyright. on M

arch 17, 2020 by guest.http://jnnp.bm

j.com/

J Neurol N

eurosurg Psychiatry: first published as 10.1136/jnnp.35.2.202 on 1 A

pril 1972. Dow

nloaded from