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The primary periodic paralyses: diagnosis, pathogenesis and treatment
S. L. Venance, S. C. Cannon, D. Fialho, B. Fontaine, M. G. Hanna, L. J. Ptacek, M. Tristani-Firouzi, R. Tawil, R. C. Griggs and the CINCH investigators
(Brain, Volume 129, pp. 87-17, Jan. 2006)
The management of PP has been symptomatic and behavioural; affected individuals learn to avoid precipitating triggers through lifestyle and dietary modification. Patients with hypokalaemic attacks eat frequent small meals to avoid large carbohydrate loads. In contrast, those with The primary periodic paralyses hyperkalaemic attacks stay away from K rich foods, medications that increase serum K (e.g. spironolactone) and fasting.
There are no randomized clinical trials in the acute management of paralytic attacks, which targets normalization of serum K levels. For HypoPP, the administration of oral K (20–30 mEq/l orally every 15–30 min until serum K is normalized) is usually sufficient for resolution of weakness.
Patients may take oral potassium (15–30 mEq) at the beginning of an attack to alleviate or shorten the episode.
Conversely, patients with HyperPP will continue with mild activity or ingest sweets to prevent or shorten attacks. Beta agonist inhalers (1–2 puffs of 0.1 mg salbutamol or albuterol) attenuate hyperkalaemic attacks (Ricker et al., 1989).
Anecdotal evidence showed benefit with sodium restriction and potassium supplementation (Conn et al., 1957) in HypoPP as well as with acetazolamide (125–1000 mg/day) treatment in HyperPP (McArdle, 1956) and HypoPP (Resnick et al., 1968). Dichlorphenamide (50–200 mg/day) is another carbonic anhydrase inhibitor that reduces attack frequency (Dalakas and Engel, 1983). These observations led to the only randomized, double blind clinical trial in PP.
Dichlorphenamide, when compared with placebo, significantly reduced attack frequency in patients with HyperPP and HypoPP (Tawil et al., 2000). HypoPP2 patients, i.e. those with SCN4A mutations, may have been excluded from the trial because of reports of worsening of attacks with acetazolamide treatment (Torres et al., 1981; Sternberg et al., 2001) although there are other reports of patients with SCN4A mutations deriving benefit with acetazolamide (Davies et al., 2001; Venance et al., 2004; Vicart et al., 2004). A clinical trial is currently underway comparing treatment with dichlorphenamide and acetazolamide on the primary outcome, attack frequency. Despite this, <50% of affected individuals are prescribed prophylactic medication (Tawil et al., 2000). The observation that prophylactic treatment improves fixed weakness (Griggs et al., 1970; Dalakas and Engel, 1983) is also under investigation in the randomized controlled trial.
The mechanism of action of carbonic anhydrase inhibitors is unclear and is independent of carbonic anhydrase inhibition. In vitro studies show that carbonic anhydrase inhibitors relieve weakness in K+ -deficient rats through activation of calcium-activated K channels (Tricarico et al., 2000, 2004) rather than direct inhibition of carbonic anhydrase.
No prospective, randomized therapeutic trials have been completed in ATS. Anecdotal evidence suggests that like HyperPP and HypoPP, carbonic anhydrase inhibitors may be effective in the prevention of attacks of PP. K-wasting diuretics and other drugs that prolong the QT interval may be hazardous. There is very limited data demonstrating clear efficacy of any antiarrhythmic agent, alone or in combination, to control the frequent ventricular ectopy manifested by ATS patients. While many ATS subjects are treated empirically with beta-blockers, there is little evidence that betablockers alter the frequency of ventricular tachycardia. The primary question as to whether asymptomatic patients with frequent runs of non-sustained ventricular tachycardia are better off without therapy remains to be determined from natural history cohort studies. For patients with tachycardia-induced syncope or aborted sudden cardiac death, an implantable cardioverter-defibrillator is a prudent option (Chun et al., 2004). Kir2.1 channels are paradoxically sensitive to external K+ concentration, increasing their conductance with increasing external K+. Likewise, the hERG K channel is also paradoxically sensitive to external potassium and this effect was recently exploited to shorten the QT interval in LQT2 subjects with hERG mutations by combining spironolactone and oral K supplementation (Etheridge et al., 2003). Prospective studies are needed to determine
whether a similar approach may benefit ATS patients.Click for speech