Hypokalaemia periodic paralysis

Background

Primary hypokalaemic periodic paralysis (HPP) is a rare skeletal muscle channelopathy, characterised by intermittent episodes of acute flaccid paralysis with associated hypokalaemia. Duration of symptoms can vary from minutes to days and resolve as serum potassium levels normalise. Episodes of paralysis commonly occur every few months without treatment; however, some patients report multiple attacks per week. ¹ Respiratory muscles and conscious level are usually unaffected. Although rarely life-threatening, HPP is associated with significant morbidity if episodes recur frequently. HPP is inherited in an autosomal dominant manner, although with reduced female penetrance, ² and has a prevalence of approximately 1 in 100,000. ³ Currently, only a handful of causative mutations have been identified. The disorder usually presents in adolescence with associated triggers including consumption of carbohydrate-rich meals and following strenuous exercise (due to release of endogenous insulin and relative influx of potassium into the intracellular space) as well as high sodium meals and emotional stress. ¹ Treatment centres around potassium replacement during the acute episodes. Longer term preventive management aims to reduce severity and frequency of attacks and thus improve quality of life. Focuses include avoidance of common triggers, long-term potassium supplementation and carbonic anhydrase inhibitors, such as acetazolamide and dichlorphenamide. Occasionally, potassium sparing diuretics have been tried in those who do not respond to carbonic anhydrase inhibitors. ⁴

Case presentation

A 33-year-old Caucasian man presented to the emergency department, in the evening, with generalised weakness and dysarthria which had been present upon waking that morning. The patient worked as a manual labourer in construction and reported consuming a carbohydrate-heavy meal (Pasta with a large quantity of sugary, carbonated drinks) the evening prior to presentation. He reported numerous previous similar episodes over the past 10 years ranging in severity from generalised fatigue to complete paralysis. This had been his most severe episode. These had not been investigated further following two previous emergency department presentations at the same hospital. The patient was initially referred as a ‘social admission’ due to reduced mobility.

The patient reported an episode of previous low potassium during a surgical admission which was associated with partial flaccid paralysis. This was not investigated further at the time. Hypokalaemia <3.0 mmol/l was confirmed upon review of previous blood tests. Medical background included gastro-oesophageal reflux, depression and chronic lower back pain for which he took regular omeprazole and fluoxetine, and PRN dihydrocodeine. There was no known family history of flaccid paralysis.

Initial neurological examination revealed normal tone throughout all four limbs with global reduction of power (MRC grade: 2/5). Sensation was normal throughout to light touch (pinprick and temperature sensation were not tested). Reflexes were recorded as reduced in the lower limbs and normal in the upper limbs with equivocal plantar responses. Examination of the cranial nerves revealed reduced power of trapezius and sternocleidomastoid muscles when examining cranial nerve XI. All other cranial nerves were intact, with no visual disturbance elicited and normal power within the facial muscles. The patient demonstrated no red flag signs or symptoms for Spinal Cord Compression. Systemic examination was unremarkable, and the patient was normotensive.

Admission blood tests showed an undetectable serum potassium concentration of <1.5 mmol/l; bicarbonate was low at 15 mmol/l with evidence of mild acute kidney injury; with creatinine of 113 µmol/l compared to a baseline of 61 µmol/l. Creatinine kinase was raised at 857. There were no other electrolyte disturbances at admission.

Admission ECG showed sinus bradycardia with prolonged QTc interval and visible U waves which resolved with potassium replacement.

The patient was transferred to an HDU setting where cardiac monitoring could be performed, while the patient underwent IV and oral potassium replacement. Serum potassium was measured at 6-h intervals until concentrations stabilised within normal limits.

The patient was investigated for other causes of hypokalaemia. Urinary electrolytes demonstrated no excessive excretion, while normal Renin and Aldosterone levels excluded a differential diagnosis of Conn’s Syndrome. Urinary cortisol and ACTH levels also demonstrated no evidence of Cushing’s Syndrome. Normal thyroid function tests made a possible diagnosis of thyrotoxic periodic paralysis unlikely, thus making a diagnosis of primary hypokalaemic Periodic paralysis likely (the patient meets all but one of the suggested criteria for diagnosis as per the European Neuromuscular Centre International Workshop in 2000 (see Box 1), lacking only a family history of weakness with confirmed hypokalaemia).

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Box 1.

Diagnostic Criteria for HPP.

Diagnostic criteria proposed by the European Neuromuscular Centre (ENMC) International Workshop in 2000 suggests a diagnosis of HPP in patients meeting all of the 4 criteria below. 5 (Note does not rule out diagnosis if patient does not meet all criteria)

(1) Two or more attacks of muscle weakness with documented  serum K <3.5 mEq/L.

(2) One attack of muscle weakness in the proband and one attack  of weakness in one relative with documented serum  K <3.5 mEq/L in at least one attack.

(3) Three of six clinical or laboratory features outlined below:

(a) Onset in the first or second decade.

(b) Attack duration (muscle weakness involving one or more   limbs) >2 h.

(c) Positive triggers (high CHO rich meal, rest after exercise,   stress).

(d) Improvement with potassium intake.

(e) Positive family history or genetically confirmed skeletal   calcium or sodium channel mutation.

(f) Positive McManis short exercise test.

(4) Exclusion of other causes of hypokalaemia (renal, adrenal,  thyroid dysfunction; renal tubular acidosis; diuretic and  laxative abuse).

Neuromuscular studies were inconclusive, and the patient underwent subsequent genetic testing at a tertiary centre which showed no match to known genetic mutations. However, following specialist neurology review, it was felt that this presentation may be secondary to a new mutation which may explain the absence of a family history of HPP.

The patient experienced no complications during inpatient treatment and was discharged with regular oral potassium replacement, plus regular monitoring of serum potassium levels with his GP. He was advised to avoid strenuous activity and to follow a low carbohydrate, low sodium diet.

Discussion

The diagnosis of HPP is made mainly on the basis of clinical history, low serum potassium and a positive family history (although up to a third of cases are secondary to new mutations ⁶ ). Hypokalaemia is caused by relative intracellular influx of potassium, ⁷ as opposed to total body depletion and care must be taken during treatment of acute attacks to avoid rebound hyperkalaemia. ⁸

Trigger avoidance is the mainstay of long-term management. ⁵ However, this is often not practical owing to the patient’s employment and personal life, as in this patient’s case. Recurrent episodes of paralysis may cause significant morbidity and can lead to difficulties maintaining employment and affect the patient’s social, physical and mental well-being.

Prophylactic potassium replacement is considered as first-line medical management for patients in whom trigger avoidance is either unfeasible or unsuccessful. ⁸ Further treatment with carbonic anhydrase inhibitors is used in patients with ongoing debilitating episodes of paralysis. Evidence for their use is limited. A Cochrane systematic review of trials between 1966 and 2007 showed only three publications meeting a selection criteria of being ‘Randomised.. in patients with a diagnosis of Primary Periodic Paralysis.. in which a form of treatment is compared with Placebo’. ⁸ One double-blind study of 42 patients with HPP, suggested a reduction in frequency of attacks with regular use of Dichlorphenamide; ⁹ another double-blind study of only eight patients demonstrated an improvement of muscle strength with regular use of acetazolamide as compared to placebo. ¹⁰ The third study, in 1996, did show benefit from the use of Pinacidl (a potassium channel activator); however, this is not generally considered in the management of HPP. ¹¹ A subsequent retrospective analysis of 74 patients, in 2010, showed that 46% of patients found benefit when treated with acetazolamide. ¹² Conversely, two publications (one case report of a family with HPP and one retrospective analysis) indicated an increase in frequency and severity of attacks in patient with a specific type of gene mutation (SCN4A) when treated with acetazolamide.^13,14

HPP is inherited in an autosomal dominant manner, with 100% penetrance in males; and therefore genetic counselling should be offered to all patients’ planning to have children. Although penetrance is reduced in females, 50% of female offspring will be carriers of the disease regardless of phenotype. ¹

HPP is an extremely rare presentation that can often be missed despite typical onset of symptoms in adolescence or early adulthood. As it tends to affect younger patients who are otherwise fit and well, partial paralysis could be dismissed as secondary to anxiety. Breakdown of trust between the patient and medical professionals, therefore, may occur when patients feel their symptoms are not being taken seriously. These points are illustrated within this case.

Conclusion

While HPP is a rare diagnosis which many physicians may not encounter during their career, it should be an important consideration in younger patients, with limited medical histories, presenting with episodes of sudden onset muscle weakness. HPP can easily be excluded by checking a patient’s serum potassium during an acute episode. Failure to recognise a presentation of HPP can result in significant morbidity and harm the doctor–patient relationship.

Learning points

HPP should be considered as a differential diagnosis in younger patients presenting with sudden onset weakness and can be excluded by checking a patient’s serum potassium at admission.