Hypokalemic Periodic Paralysis

A 38-year-old man presents to the emergency room for acute onset weakness for the past day.

History. The patient reported acute onset lower extremity weakness that started the same morning of presentation. He felt his proximal muscle weakness was worse in both of his thighs. He attempted to walk but the weakness was so profound that he fell down a flight of stairs in his home. Upon trying to get up, he was unable to move or feel his legs. He also reported that he tried to push himself up and was completely unable to, which prompted him to notice his arms felt profoundly weak.

The patient went on a recent trip to Cuba and upon return 1 month ago noted 1-2 days of watery, non-bloody diarrhea that has since resolved. The patient had a personal history of bipolar II disorder, panic disorder, and hypertension. His list of daily medications included lamotrigine 100 mg, duloxetine 40 mg, and propranolol 80 mg. The patient denies taking any additional over-the-counter medications. He has no known family history of periodic paralysis. However, he does note estrangement with members of his family.

On physical examination, vital signs were unremarkable. The results of the Medical Research Council Manual Muscle Testing scale was 2/5 hip flexion, dorsiflexion, plantar flexion, and knee flexion/extension bilaterally; 2/5 shoulder abduction, elbow flexion, and extension bilaterally; and diffusely decreased reflexes (0/4). General examination, cardiac examination, and pulmonary examination were unremarkable.

Diagnostic testing. Initial laboratory testing showed marked hypokalemia of 1.1 mmol/L pH. Random blood glucose, serum bicarbonate, other electrolytes, and renal and liver function tests were all within normal limits. Thyroid function including thyroid stimulating hormone, free thyroxine (T4), and free triiodothyronine (T3) were also within normal limits. A polymerase-chain reaction test was positive for rhinovirus and enterovirus. An electrocardiogram (EKG) revealed sinus rhythm within normal limits but was significant for U wave (Figure 1). These findings are consistent with hypokalemia.

Figure 1. The patient’s EKG on admission showing first degree atrioventricular block and U waves, consistent with EKG findings in the setting of hypokalemia.

Differential diagnoses. The differential diagnosis in this case included normokalemic and hyperkalemic periodic paralysis, myasthenia gravis, Guillain-Barré syndrome, thyrotoxic periodic paralysis, and secondary causes of hypokalemia.

Normokalemic and hyperkalemic periodic paralysis differ from hypokalemic periodic paralysis in that serum potassium is often within normal limits or elevated during paralysis attacks. Supplementation of potassium in these cases can improve or worsen symptoms.¹ In this case, the patient presented with attacks only when serum potassium was significantly decreased, making this diagnosis less likely.

Myasthenia gravis is often characterized by predictable and progressive weakness that is precipitated by exertion.² This patient did not have any symptoms often associated with myasthenia including diplopia, ptosis, dysphagia, or dysarthria, so it was felt this diagnosis did not match with his clinical picture.

The initial attacks of weakness in hypokalemic periodic paralysis can often be confused with the paralytic attacks seen in Guillain-Barré syndrome. The patient did have a history of recent travel and a self-limited diarrheal illness upon return; however, on physical examination there was no evidence of any other specific findings of sensory abnormalities consistent with polyneuropathy that is typically observed in cases of Guillain-Barré syndrome.² Additionally, the laboratory findings of significant hypokalemia in the setting of acute weakness did not support this diagnosis.

The presentation of thyrotoxic periodic paralysis is often like that of the clinical presentation of hypokalemic periodic paralysis, with the key difference being the presence of clinical findings consistent with hyperthyroidism, such as palpitations, tachycardia, heat intolerance, a goiter on physical examination, and exophthalmos.^3,4 In this case, the patient’s thyroid function was within normal limits and clinically there was no evidence of hyperthyroidism features on physical examination.

It is important to rule out additional secondary causes of hypokalemia including potassium wasting in the form of a renal tubular acidosis, diuretic use, hyperaldosteronism, and others. One finding that would indicate secondary causes of hypokalemia may be present is the finding of hypokalemia between paralysis attacks.³ Clinical and laboratory findings should be analyzed carefully including patient’s blood pressure, urine potassium, and serum bicarbonate levels, all of which could indicate secondary causes of hypokalemia.³

Treatment and management. He was treated with intravenous (IV) potassium replacement 80 mEq. His symptoms resolved with appropriate potassium repletion and repeat neurological examination following completion of potassium supplementation showed marked improvement in weakness and resolution of hyporeflexia. The repeat Manual Muscle Testing scale showed improvement in strength to 4/5 hip flexion, dorsiflexion, plantar flexion, and knee flexion/extension bilaterally, as well as 2/5 shoulder abduction, elbow flexion, and extension bilaterally. He was monitored closely by internal medicine specialists for 4 days while inpatient and started indefinitely on oral potassium supplementation 20 mEq three times daily.

Outcome and follow-up. He did have two subsequent hospitalizations in the months following this initial occurrence with similar presentations. The recurring periodic weakness seemed to resolve after appropriate potassium supplementation at the same dosage as initial treatment. He was not found to have significant hypokalemia between attacks.

He was evaluated by nephrology and neurology specialists on multiple occasions. He was evaluated by neurology specialists during the hospitalizations; they performed extensive physical examination during the acute attack and after resolution of hypokalemia, noting similar findings of marked improvement in weakness. They did not feel there was any value in more invasive testing in this case such as a lumbar puncture, as there seemed to be a plausible reason for his acute weakness but recommended continued follow-up outpatient. He was also evaluated by nephrology specialists to ascertain if there were any other secondary causes of hypokalemia; all additional urine studies were unremarkable but most notably his 24-hour urine potassium was within normal limits and not indicative of renal wasting.

Although this patient did not have a known family history of hypokalemic periodic paralysis, his low serum potassium level during what was felt were typical attacks of weakness established the diagnosis. He was formally diagnosed with hypokalemic periodic paralysis and was started on acetazolamide 250 mg twice daily for empiric therapy.

Discussion. Periodic paralysis is a rare disorder characterized by flaccid paralysis secondary to hypokalemia.⁵ There are different triggers that may precipitate the periodic paralysis including strenuous exercise, meals high in sodium, and a high carbohydrate diet. Weakness is often transient but can range from mild paralysis involving specific muscle groups to full body paralysis. There appears to be a genetic component to the condition and familial hypokalemic periodic paralysis is inherited in an autosomal dominant pattern.⁵ Familial periodic paralyses are channelopathies, often involving skeletal muscle calcium and sodium channels leading to episodic severe muscle weakness. There have also been cases of acquired periodic paralysis in the setting of underlying hyperthyroidism and in cases where there are significant renal or gastrointestinal losses of potassium. The electrolyte derangements can lead to cardiac arrhythmias. In rare cases, patients with severe hypokalemia may even experience respiratory failure due to paralysis.³ The differential diagnoses for acute onset weakness are broad and determining the appropriate diagnosis is crucial for appropriately treating these patients and avoiding unnecessary and costly interventions.

It is important to review the differential diagnosis of hypokalemia to rule out secondary causes. Clinicians should also evaluate for type I or type II renal tubular acidosis that could lead to renal wasting of potassium. Additionally, it is important to consider other neurologic and infectious disorders characterized by muscle weakness including myasthenia gravis and Guillain-Barré syndrome. These can be differentiated from hypokalemic periodic paralysis largely through obtaining an appropriate history from the patient and ruling out known insect bite or travel.² In this case, the patient had an episode of transient diarrhea, but this self-resolved over 1 month prior to presentation, which would not explain his marked hypokalemia at time of presentation. Urine studies were also performed and did not indicate any sort of renal loss of potassium. He was found to be positive for enterovirus and rhinovirus, which may be stressors that predisposed him to this periodic paralysis.

Treatment involves oral potassium replacement, often 1 mEq/kg of body weight per day.⁶ Additional treatment options include IV potassium replacement with frequent monitoring for EKG changes. Acetazolamide can be used as prophylactic treatment; the mechanism is unclear but creating a systemic acidosis by excreting bicarbonate will reduce recurrent episodes of paralysis.

Hypokalemic periodic paralysis is a rare disorder, with a prevalence of approximately 1 in 100,000 individuals. As this condition often has a strong genetic component, it is important to relay this information to the patient as their children are at a 50% risk of inheriting the condition. Research has shown a lower clinical expression in women than in men, thought to be due to incomplete penetrance of the trait.³

Patient education is one of the key steps in the management of this disorder. Indeed, patients should be advised to avoid triggers such as strenuous exercise, increased salt intake, stress, and prolonged immobilization.  It is recommended that patients make necessary lifestyle modifications to prevent recurrent hospitalizations.