Hypokalemic periodic paralysis

A 21-year old man was brought to the emergency department (ED) with complaints of acute, progressive generalized weakness and deteriorating mental status. The patient was well until 4 h prior to hospital admission, when he noted difficulty in climbing stairs due to weakness in his thighs. The weakness then progressed to involve the upper extremities and finally his face, affecting his speech. Approximately 4 to 6 h before the onset of his symptoms, he had played soccer and then had a large meal that included canned food imported from Mexico. His companions spoke only Spanish and were not aware of any medical history. They knew of no similar events or any other associated symptoms.

Physical Examination

Physical examination revealed a muscular man who was stuporous. He was afebrile and had a BP of 140/80 mm Hg. His pulse rate was 64 beats/min and irregular. He was tachypneic (22 breaths/min), and his respirations were shallow. Pulse oximetry revealed an oxygen saturation of 82% while breathing room air. His pupils were 4 mm and reactive to light bilaterally. Lungs were clear, with diminished chest wall excursions bilaterally and thoracoabdominal paradox with inspiration. Auscultation of the heart revealed irregular heartbeats. The abdominal examination was unremarkable. The neurologic examination was significant for flaccid paralysis in all extremities, a poor gag reflex, and absence of deep tendon reflexes.

Laboratory Findings

Arterial blood gas analysis on room air showed the following: pH, 7.23; PaC[O.sub.2], 64 mm Hg; and Pa[O.sub.2], 54 mm Hg. The patient was intubated for airway protection and treatment of acute hypercapnic respiratory failure. While in the ED, before he was transferred to the medical ICU, frequent bouts of nonsustained ventricular tachycardia developed. His ECG is shown in Figure 1. A diagnostic test was performed.

[FIGURE 1 OMITTED]

What is the diagnosis?

Diagnosis: Hypercapnic respiratory failure due to hypokalemic periodic paralysis

Hypokalemic periodic paralysis (hypoKPP) causes episodic weakness that usually involves proximal, more than distal, limb muscles. Rarely, it affects bulbar functions and respiratory muscles. Meals high in carbohydrates or sodium, rest after exercise, or emotional stress can provoke attacks. Deep tendon reflexes become hypoactive or even absent, and cardiac arrhythmias may occur during attacks.

hypoKPP occurs in both autosomal dominant (two thirds of the cases) and sporadic forms. It has been estimated to have a prevalence of 1 in 100,000. Mutations in the dihydropyridine receptor of the [[alpha].sub.1] subunit of skeletal muscle [Ca.sup.2+] channel account for the majority of cases. This channel acts as a pore for conducting [Ca.sup.2+] ions in the T tubule; its dysfunction produces a reduction in [Ca.sup.2+] current in the T tubule and results in an inability of myocytes to maintain a normal transmembrane potential. The precise mechanism by which mutations of the dihydropyridine receptor lead to [K.sup.+] shifts is unknown. In hypoKPP, total body [K.sup.+] is normal and acute hypokalemia occurs as a result of [K.sup.+] shifts from the extracellular fluid into muscle cells.

hypoKPP is the most frequent form of periodic paralysis. It is more common in male subjects, with a reduced penetrance in female subjects. Typically, the duration of the attacks is usually between 2 h and 12 h but occasionally may last up to 72 h. The frequency of attacks is variable, ranging from daily to only once or twice in a lifetime. Onset is invariably before the age of 30 years; most patients experience their first attack in adolescence. Muscle biopsy often shows the presence of single or multiple centrally placed vacuoles. In younger subjects, the only detectable interictal abnormality is eyelid myotonia, which may be seen in up to half of patients. In older subjects, the frequency of attacks often decreases, but they may have persistent weakness.

The diagnosis is established by demonstrating a low serum [K.sup.+] level during a paralytic attack and by excluding secondary causes of hypokalemia. In patients who have mild and infrequent attacks, provocative testing using glucose and insulin administration can be done but this is potentially hazardous and requires careful monitoring. In the primary forms of hypoKPP, the serum [K.sup.+] level decreases during attacks and is normal between attacks of weakness. By contrast, in secondary periodic paralysis caused by [K.sup.+] depletion due to renal, endocrine, GI, or drug-induced mechanisms (Table 1), the serum [K.sup.+] level is markedly reduced during and between attacks.

Differential diagnoses of periodic paralysis include potassium-sensitive periodic paralysis (KPP) and paramyotonia congenita. Both of these are autosomal dominant diseases characterized by episodic weakness of skeletal muscles, usually sparing cranial and respiratory muscles. Additionally, paramyotonia congenita is associated with paradoxical myotonia and cold sensitivity. Serum [K.sup.+] levels in KPP are usually normal or high normal during attacks, but may even be low. Sensitivity to [K.sup.+] is the fundamental finding in KPP, as [K.sup.+] administration precipitates attacks. Both KPP and paramyotonia congenita are channelopathies involving a mutation in skeletal muscle voltage-gated [Na.sup.+] channel.

The goal of therapy in hypoKPP is to prevent attacks. Prophylactic [K.sup.+] supplementation is ineffective. Preventive measures include a low-carbohydrate, low-sodium diet, and drugs such as carbonic anhydrase inhibitors (eg, acetazolamide, dichlorphenamide), spironolactone, and triamterene. Carbonic anhydrase inhibitors prevent paralytic attacks and improve residual weakness between attacks. While the mechanism of action is not clear, these medications may work by inducing metabolic acidosis and preventing intracellular [K.sup.+] shifts. In those who are unresponsive to or even worsen with these medications, triamterene or spironolactone may be used. Acute attacks are treated with oral [K.sup.+] until muscle strength improves. In severe episodes, parenteral [K.sup.+] may be necessary but should be administered in mannitol, not in dextrose or NaCl, which may lower [K.sup.+] levels.

The arterial blood gas findings and clinical presentation in the ED were consistent with acute hypercapnic respiratory failure due to acute hypoventilation. Frequent premature ventricular beats and nonsustained ventricular tachycardia and the presence of U waves on ECG prompted immediate analysis of electrolytes. His [K.sup.+] level was found to be 1.5 mEq/L. The rest of the electrolytes were normal. The diagnosis of hypoKPP was made. The patient's mother, who arrived at the hospital 2 h later, indicated that the patient had similar episodes in the past that were treated with [K.sup.+] and confirmed the diagnosis of hypoKPP. In this case, [K.sup.+] replacement led to resolution of ventricular tachyarrhythmias and prompt return of muscle strength. Ventilatory support was discontinued within 10 h of hospital admission (following restoration of near-normal [K.sup.+] levels).

CLINICAL PEARLS

1. Episodic weakness usually involving proximal more than distal limb muscles is the main feature of hypoKPP; bulbar functions and respiratory muscles are rarely involved.

2. High carbohydrate or sodium meals and prolonged immobility can provoke attacks.

3. There is a defect in the voltage-gated skeletal muscle calcium channel preventing maintenance of a normal transmembrane potential in the myocyte.

4. Diagnosis is established by demonstrating a low serum potassium level during a paralytic attack and excluding secondary causes of hypokalemia.

5. Preventive measures are the mainstay of therapy and include a low-carbohydrate and low-sodium diet and drugs such as as carbonic anhydrase inhibitors (eg, acetazolamide, dichlorphenamide), spironolactone, and triamterene.

(6.) Prophylactic [K.sup.+] supplementation is ineffective as a preventive therapy.

SUGGESTED READINGS

Bella I, Chad DA. Neuromuscular disorders and acute respiratory failure. Neurol Clin 1998; 16:391-417

Felix R. Channelopathies: ion channel defects linked to heritable clinical disorders. J Med Genet 2000; 37:729-740

Fontaine B, Vale Santos JM, Jurkat-Rott K, et al. Mapping of hypokalemic periodic paralysis (HypoPP) to chromosome 1q31-q32 by a genome-wide search in three European families. Nat Genet 1994; 6:267-272

Greenberg DA. Calcium channels in neurological disease. Ann Neurol 1997; 42:275-282

Gutmann L. Periodic paralyses. Neurol Clin 2000; 18:195-202

Lehmann-Horn F, Rudel R. Channelopathies: the nondystrophic myotonias and periodic paralyses. Semin Pediatr Neurol 1996; 3:122-139

LoVecchio F, Jacobson S. Approach to generalized weakness and peripheral neuromuscular disease. Emerg Med Clin North Am 1997; 15:605-623

Ptacek LJ, Tawil R, Griggs RC, et al. Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 1994; 77:863-868

Riggs JR. The periodic paralyses. Neurol Clin 1988; 6:485-498

Surtees R. Inherited ion channel disorders. Eur J Pediatr 2000; 159(Suppl 3):S199-S203

Tawil R, McDermott MP, Brown R Jr, et al. Randomized trials of dichlorphenamide in the periodic paralyses: Working Group on Periodic Paralysis. Ann Neurol 2000; 47:46-53

* From the Division of Pulmonary and Critical Care Medicine, Evanston Northwestern Healthcare, Evanston, Northwestern University Medical School, Chicago, IL.

Manuscript received August 20, 2001; revision accepted November 26, 2001.

Correspondence to: Gokhan M Mutlu, MD, Division of Pulmonary and Critical Care Medicine, Evanston-Northwestern Healthcare, 2650 Ridge Ave, Evanston, IL 60201; e-mail: g-mutlu@northwestern.edu

COPYRIGHT 2002 American College of Chest Physicians
COPYRIGHT 2002 Gale Group