European Journal of Neurology 2014, 21: e73–e74
doi:10.1111/ene.12473
LETTER TO THE EDITOR
Successful treatment of hypokalemic periodic paralysis with topiramate T. Garcıa-Sobrino and J. Pardo Department of Neurology, Hospital Clınico, Santiago de Compostela, Spain Correspondence: T. Garcıa-Sobrino, Department of Neurology, Hospital Clınico, Travesıa A Choupana, s/n. 15706, Santiago de Compostela (A Coru~ na), Spain (tel.: +34981950332; fax: +981 951098; e-mail: [email protected]).
Keywords: carbonic anhydrase inhibitor, hypokalemic, hypokalemic periodic paralysis, ion channel disorders, periodic paralysis, topiramate Received: 3 March 2014 Accepted: 22 April 2014 Hypokalemic periodic paralysis (hypoPP) is the most common form of periodic paralysis. It is an autosomal dominant neuromuscular disorder caused in 70% of cases by mutations in the CACNA1S gene. Current pharmacological treatment includes potassium supplements, potassium-sparing diuretics and carbonic anhydrase inhibitors. Topiramate is an antiepileptic drug known to have carbonic anhydrase inhibitory properties. We describe a patient diagnosed with hypoPP successfully treated with topiramate. A healthy 37-year-old man suffered from several recurrent attacks of weakness in the four limbs without respiratory difficulty, dysphagia or other neurological symptoms since the age of 14. These attacks were more frequent in the morning and lasted as long as 8–15 h. Neurological examination during the episodes showed proximal and distal weakness in all four limbs, the arms were weaker than the legs, deep tendon reflexes were absent and no sensory impairment was detected. Laboratory tests revealed low potassium levels during the attacks, as low as 2 mEq/l, and occasionally prominent T waves in electrocardiography were seen. Standard nerve conduction studies were normal and no myotonic discharges were seen on electromyography examination. Molecular genetic analysis revealed the R1239H mutation in the CACNA1S Patient consent: The patient gave his consent for the publication of the data.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
Figure 1 Clinical evolution from the diagnosis of hypokalemic periodic paralysis.
gene. Neurological examination and a genetic test carried out for his parents and his sister were normal. Treatment with oral potassium supplements was started until the age of 20, when the patient had a high frequency and severity of spells (he suffered 100– 150 attacks per year, requiring emergency assistance in 4% of them). Consequently, acetazolamide was started in association with potassium supplements. Five years later, dichlorphenamide was prescribed instead of acetazolamide due to a lack of improvement and the attacks decreased (1 year later he suffered 10 attacks and none required emergency assistance). At the age of 27, the episodes increased once again so dichlorphenamide was stopped and acetazolamide was started again. Between 27 and 34 years of age, a high recurrence of attacks was evident and he required higher doses of potassium supplements until the age of 34 when we decided to switch acetazolamide to topiramate 50 mg twice daily in June 2011. Two years later he had a remarkable clinical improvement without new attacks (Fig. 1). Discussion The mainstay of treatment for hypoPP is to council the patient to avoid known triggers (certain foods, cold exposure, strenuous exercise), prophylactic treatment with potassium supplements, potassium-sparing diuretic drugs and carbonic anhydrase inhibitors [1–3] and, finally, acute treatment of attacks. Despite undergoing all these types of treatments, our patient showed no lasting improvement. Considering the report of two siblings successfully treated with topiramate [4] we decided to try this treatment on our patient. Since then, only two mild spells were observed at the beginning of
the treatment and the patient has remained asymptomatic for the last 2 years. Topiramate is a sulphamate-substituted monosaccharide which has several mechanisms of action [5,6] used as an antiepileptic drug and for migraine prophylaxis. It seems to be an effective treatment in hypoPP with an unknown mechanism of action, but inhibition of carbonic anhydrase isozymes II and IV leading to metabolic acidosis which increases potassium plasma levels could explain its effect on hypoPP [5,6]. Nevertheless, other mechanisms of action of this drug cannot be ruled out. Conclusion Topiramate seems to be an effective treatment in hypoPP. To our knowledge, this is the second report of the therapeutic benefit of topiramate in cases of refractory hypoPP. A clinical trial with this drug is warranted as an additional treatment option for hypoPP. Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest. References 1. Matthews E, Portaro S, Ke Q, et al. Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology 2011; 29: 1960–1964. 2. Matthews E, Hanna MG. Muscle channelopathies: does the predicted channel gating pore offer new treatment insights for hypokalaemic periodic paralysis? J Physiol 2010; 588: 1879–1886. 3. Tricarico D, Camerino DC. Recent advances in the pathogenesis and drug action in periodic paralyses and related channelopathies. Front Pharmacol 2011; 2: 8.
e74
Letters to the Editor
4. Fiore DM, Strober JB. Treatment of hypokalemic periodic paralysis with topiramate. Muscle Nerve 2011; 43: 127–129.
5. Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 2000; 41(Suppl. I): S35–S39.
6. Mirza N, Marson AG, Pirmohamed M. Effect of topiramate on acid base balance: extent, mechanism and effects. Br J Clin Pharmacol 2009; 68: 655–661.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
doi:10.1111/ene.12473
LETTER TO THE EDITOR
Successful treatment of hypokalemic periodic paralysis with topiramate T. Garcıa-Sobrino and J. Pardo Department of Neurology, Hospital Clınico, Santiago de Compostela, Spain Correspondence: T. Garcıa-Sobrino, Department of Neurology, Hospital Clınico, Travesıa A Choupana, s/n. 15706, Santiago de Compostela (A Coru~ na), Spain (tel.: +34981950332; fax: +981 951098; e-mail: [email protected]).
Keywords: carbonic anhydrase inhibitor, hypokalemic, hypokalemic periodic paralysis, ion channel disorders, periodic paralysis, topiramate Received: 3 March 2014 Accepted: 22 April 2014 Hypokalemic periodic paralysis (hypoPP) is the most common form of periodic paralysis. It is an autosomal dominant neuromuscular disorder caused in 70% of cases by mutations in the CACNA1S gene. Current pharmacological treatment includes potassium supplements, potassium-sparing diuretics and carbonic anhydrase inhibitors. Topiramate is an antiepileptic drug known to have carbonic anhydrase inhibitory properties. We describe a patient diagnosed with hypoPP successfully treated with topiramate. A healthy 37-year-old man suffered from several recurrent attacks of weakness in the four limbs without respiratory difficulty, dysphagia or other neurological symptoms since the age of 14. These attacks were more frequent in the morning and lasted as long as 8–15 h. Neurological examination during the episodes showed proximal and distal weakness in all four limbs, the arms were weaker than the legs, deep tendon reflexes were absent and no sensory impairment was detected. Laboratory tests revealed low potassium levels during the attacks, as low as 2 mEq/l, and occasionally prominent T waves in electrocardiography were seen. Standard nerve conduction studies were normal and no myotonic discharges were seen on electromyography examination. Molecular genetic analysis revealed the R1239H mutation in the CACNA1S Patient consent: The patient gave his consent for the publication of the data.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
Figure 1 Clinical evolution from the diagnosis of hypokalemic periodic paralysis.
gene. Neurological examination and a genetic test carried out for his parents and his sister were normal. Treatment with oral potassium supplements was started until the age of 20, when the patient had a high frequency and severity of spells (he suffered 100– 150 attacks per year, requiring emergency assistance in 4% of them). Consequently, acetazolamide was started in association with potassium supplements. Five years later, dichlorphenamide was prescribed instead of acetazolamide due to a lack of improvement and the attacks decreased (1 year later he suffered 10 attacks and none required emergency assistance). At the age of 27, the episodes increased once again so dichlorphenamide was stopped and acetazolamide was started again. Between 27 and 34 years of age, a high recurrence of attacks was evident and he required higher doses of potassium supplements until the age of 34 when we decided to switch acetazolamide to topiramate 50 mg twice daily in June 2011. Two years later he had a remarkable clinical improvement without new attacks (Fig. 1). Discussion The mainstay of treatment for hypoPP is to council the patient to avoid known triggers (certain foods, cold exposure, strenuous exercise), prophylactic treatment with potassium supplements, potassium-sparing diuretic drugs and carbonic anhydrase inhibitors [1–3] and, finally, acute treatment of attacks. Despite undergoing all these types of treatments, our patient showed no lasting improvement. Considering the report of two siblings successfully treated with topiramate [4] we decided to try this treatment on our patient. Since then, only two mild spells were observed at the beginning of
the treatment and the patient has remained asymptomatic for the last 2 years. Topiramate is a sulphamate-substituted monosaccharide which has several mechanisms of action [5,6] used as an antiepileptic drug and for migraine prophylaxis. It seems to be an effective treatment in hypoPP with an unknown mechanism of action, but inhibition of carbonic anhydrase isozymes II and IV leading to metabolic acidosis which increases potassium plasma levels could explain its effect on hypoPP [5,6]. Nevertheless, other mechanisms of action of this drug cannot be ruled out. Conclusion Topiramate seems to be an effective treatment in hypoPP. To our knowledge, this is the second report of the therapeutic benefit of topiramate in cases of refractory hypoPP. A clinical trial with this drug is warranted as an additional treatment option for hypoPP. Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest. References 1. Matthews E, Portaro S, Ke Q, et al. Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology 2011; 29: 1960–1964. 2. Matthews E, Hanna MG. Muscle channelopathies: does the predicted channel gating pore offer new treatment insights for hypokalaemic periodic paralysis? J Physiol 2010; 588: 1879–1886. 3. Tricarico D, Camerino DC. Recent advances in the pathogenesis and drug action in periodic paralyses and related channelopathies. Front Pharmacol 2011; 2: 8.
e74
Letters to the Editor
4. Fiore DM, Strober JB. Treatment of hypokalemic periodic paralysis with topiramate. Muscle Nerve 2011; 43: 127–129.
5. Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 2000; 41(Suppl. I): S35–S39.
6. Mirza N, Marson AG, Pirmohamed M. Effect of topiramate on acid base balance: extent, mechanism and effects. Br J Clin Pharmacol 2009; 68: 655–661.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
