Mashhad University of Medical Sciences Clinical Research Development Center (MUMS) Reviews in Clinical Medicine Ghaem Hospital

Refractory seizures in children

Seyed Ebrahim Mansoorinejad (MD)*, Farah Ashrafzadeh (MD), Javad Akhondian (MD), Mehran Beiraghi Toosi (MD)

Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

ARTICLE INFO ABSTRACT Article type Epilepsy is described as a heterogeneous clinical syndrome results from Review article various cerebral destructions. It is categorized to partial and generalized forms. Degree of neural system impairment and affected area determine Article history the severity and pattern of symptoms. Patients might experience sensory, Received: 25 Dec 2013 Revised: 7 Jan 2014 motor, or both signs and symptoms. About 60% of epileptic patients suffer Accepted: 9 Jan 2014 from partial type. It is estimated that up to 30% of epilepsy cases would not be controlled adequately despite sufficient and proper management. Keywords Anacyclus pyrethrum, Citrus aurantium var. amara, Paeonia officinalis, Children Rosa Damascena and Nigella Sativa are some of herbal drugs which have Epilepsy antiepileptic effect. Natural agents are valuable sources to treat chronic Seizure diseases and a huge number of world`s population believe herbs are ef- fective and safe for daily primary health care needs. There is not enough evidence about their efficacy and safety obtained from randomized con- trol trials.

Please cite this paper as: Mansoorinejad SE, Ashrafzadeh F, Akhondian J, Beiraghi Toosi M. Refractory seizures in children. Rev Clin Med. 2014;1(1):29-32.

Introduction Convulsion is the most common form such as metabolic diseases, electrolyte of neurologic disease in childhood. Single imbalances and trauma, etc. When seizure seizure episode might happen in 4 to 10 attacks become recurrent, they are called percents of children younger than 16 epilepsy. Fifty million of world population years (1). Childhood seizures might be a are affected by this disease (2). Epilepsy transient feature. Convulsions should be is described as a heterogeneous clinical differentiated from epilepsy, because they syndrome, results from various cerebral happen due to a wide spectrum of disorders destructions. It is categorized to partial and

*Corresponding author: Seyed Ebrahim This is an Open Access article distributed under the Mansoorinejad . terms of the Creative Commons Attribution License Department of Pediatrics, School of Medicine, (http://creativecommons.org/licenses/by/3.0), Mashhad University of Medical Sciences, Mashhad, which permits unrestricted use, distribution, and Iran reproduction in any medium, provided the original E-mail: [email protected] work is properly cited. Tel:0511-8012469 29 Rev Clin Med 2014; Vol 1 (No 1) Published by: Mashhad University of Medical Sciences (http://rcm.mums.ac.ir) Mansoorinejad SE et al. generalized forms. Degree of neural system so they have been considered as safe agents impairment and affected area determines especially in childhood (7). the severity and pattern of symptoms. Epilepsy is a historical issue in Iran, and Patients might experience sensory, motor different traditional methods were described or both signs and symptoms. About 60% of for its treatment. In recent years traditional epileptic patients suffer from partial type. medicine has been revised so again herbs It is estimated that up to 30% of epilepsy have been proposed for epilepsy treatment, cases would not be controlled adequately particularly for DRE (4). Anacyclus despite sufficient and proper management pyrethrum, Citrus aurantium var. amara, (3). Resistance epileptic cases, who do Paeonia officinalis, Rosa Damascena and not respond properly to antiepileptic drug Nigella Sativa are some of the herbal drugs (AED), are considered as DRE (drug which have antiepileptic effects (8). resistant epilepsy). Between 6 to 35% of Valeriana officinalis has been used in seizures would be refractory. It is estimated convulsion management which might have that about 70000 children suffer from DRE an impact in adenosine system activation in Iran and there are some diagnostic and (9). therapeutic challenges about it (4). With recent technical revolutions, Discussion different medications and therapeutic In recent years the role of herbal medicine methods are introduced to control DRE, has been established in some chronic such as Levetiracetam, Topiramate and diseases like epilepsy and some botanical different surgical methods. Promotion drugs have been approved by FDA. Herbal of herbal and Chinese medicine leads to drugs are more acceptable in our country extensive application of traditional drugs because of Iranian culture (9). On the for untreated controversy issues (5). other hand Iran is a developing country On the other hand some fruit and food that economic factor might influence the could influence the bioavailability of treatment method and herbs are available antiepileptic drugs, for example there are and cheaper. Other complications such several researches about ketotonic diet as sleep disorders and gastrointestinal and its effect on epilepsy. Grapefruit juice malfunctions are also common in patients inhibits CYP3A4 enzymes and increases with epilepsy, particularly in children the bioavailability of carbamazepine (6). and herbal drugs might reduce all of their Although there are different and effective problems (8). In Table 1 the effect of herbal drugs for epilepsy, a number of patients still medicine is shown in childhood refractory have seizures with proper treatment and also seizure in different parts of world. a proportion of patients have to discontinue Some different herbal medicines that have medication because of severe side effects. been described as antiepileptic agents are Modern therapeutic agents are expensive mentioned as below: Debnath showed that so they might not be prescribed for all the Terminalia chebula ethanolic extract patients. It has been shown that synthetic colud reduce seizures duration in mice (10). antiepileptic drugs cause some various The anticonvulsive and neuroprotective ef- side effects and complications such as fects of Pimpinella anisum were revealed liver toxicity, teratogenicity, psychological in another study (11). disorders and GI problems. Plant derived Agher Gherha or Anacyclus pyrehrun medications might have less side effects, could increase seizure threshold. Laurus

Rev Clin Med 2014; Vol 1 (No 1) 30 Published by: Mashhad University of Medical Sciences (http://rcm.mums.ac.ir) Mansoorinejad SE et al.

Table 1. The effect of herbal medicine in childhood refractory seizure

Author Publication Title Type of Treatment Outcome year seizure method Ashrafzadeh 2007 Effect of Rosa Damascena Refractory Rosa Damascena Antiepilep- (7) oil as adjunctive treatment seizures tic effect for refractory seizures in children Carvalho- 2002 Anxiolytic and sedative ef- Epilepsy Citrus aurantium L Increased Freitas fects of extracts and essential the latency oil from Citrus aurantium L period )12( of tonic seizures Hung-Ming 2002 Antioxidant and anticon- Refractory Chaihu-longu- Reduce (13) vulsant effect of a modified seizures muli-tang the seizure formula of chaihu-longu-mu- frequency li-tang Ma 2003 Clinical observation on Epilepsy Anti- Reduce the 930 child epilepsy cases epilepsy capsules frequency )14( treated with anti-epilep- and sy capsules duration of seizures Akhondian 2011 The effect of thymoquinone Refractory Thymoquinone Anti-epilep- (15) on intractable pediatric sei- seizures tic effects )zures (pilot study Wang 1996 Effects of Chinese medi- grand Zhenxianling Effective cine zhenxianling in 239 mal epi- rate of )16( cases of epilepsy lepsy 97.2% Akhondian 2007 The effect of Nigella sativa Intractable Black cumin seed Antiepilep- (17) L. (black cumin seed) on pediatric tic effects intractable pediatric seizures seizures nobilis oil might have an anticonvulsant applicable. Extracting and drying are the first effect in tonic seizures (18,19). Piper stages of processing the herbal medicine. longum is an antioxidant which could be Although ancient science described many used as an anticonvulsant medication by antiepileptic agents, it is found that none influencing the GABA system (20). of them are useful. One of the herbal drugs Ostokhoddos could act as diazepam and limitations is that their dosage might not be is sedative (21,22). Efficacy of some herbal cautiously adjusted. All of their side effects drugs such as Nigella sativa and Piper and interactions are not well known too longum have been proved in childhood (22). refractory epilepsy by randomized control It is crucial to know that some herbs could trials and there are several reports about induce seizure such as gingko, ginseng, anticonvulsant effect of plant derived agents and evening primrose. Some traditional in animal models (23). medicine might interact with antiepileptic Herbal drugs were important in Asian and drugs and increase or decrease their serum African folk medicine. Traditional drugs level and efficacy. are derived from the flowers, leaves, roots, or other parts of plants. Some herbs could Conclusion be used directly as medication, but most Natural agents are valuable sources to of them need to be processed to become treat chronic diseases and a huge number

31 Rev Clin Med 2014; Vol 1 (No 1) Published by: Mashhad University of Medical Sciences (http://rcm.mums.ac.ir) Mansoorinejad SE et al. of world`s population believe herbs are rats: possible involvement of adenosine. J effective and safe for daily primary health Ethnopharmacol. 2010;127:313-318. 10. Debnath J, Sharma U, Kumar B et al. care needs. But there is not enough evidence Anticonvulsant activity of ethanolic extract of about their efficacy and safety obtained fruits of Terminalia chebula on experimental from randomized control trials. animals,” Int JDrug Dev Res. 2010;2:764–768. 11. Shojaii A, Abdollahi Fard M.Review of pharmacological properties and chemical Acknowledgement constituents of Pimpinella anisum. ISRN We would like to thank Clinical Research Pharmaceutics. 2012;20:586-589. Development Center of Ghaem Hospital for 12. Carvalho-Freitas MI, Costa M. Anxiolytic their assistant in this manuscript. This study and sedative effects of extracts and essential oil from Citrus aurantium L.Biol Pharm Bull. was supported by a grant from the Vice 2002;25:1629-1633. Chancellor for Research of the Mashhad 13. Hung-Ming W, Liu CS, Tsai JJ, et al. Antioxidant University of Medical Sciences for the and anticonvulsant effect of a modified formula research project as a medical student thesis. of chaihu-longu-muli-tang.Am J Chin Med. 2002;30:339-346. 14. Ma R, Li S, Li X,et al. Clinical observation Conflict of Interest on 930 child epilepsy cases treated with The authors declare no conflict of interest. anti-epilepsy capsules.J Tradit Chin Med. 2003;23:109-112. 15. Akhondian J, Kianifar H, Raoofziaee M, et References al. The effect of thymoquinone on intractable pediatric seizures (pilot study). Epilepsy Res. 1. Swaiman K, Ashwal S, Ferriero D, et al. 2011;93:39-43. Swaiman’s Pediatric Neurology, 5th ed. 16. Wang T. Effects of Chinese medicine Elsevier; 2011. zhenxianling in 239 cases of epilepsy. J Tradit 2. Chapell R, Retson J, Synder D. Management Chin Med. 1996;16:94-97. of treatment-resistant epilepsy: summary. In: 17. Akhondian J, Parsa A, Rakhshande H. The AHRQ evidence report summaries; 2003. effect of Nigella sativa L. (black cumin seed) on 3. Engel J. What is epilepsy? In: Engel J, Pedly TA, intractable pediatric seizures. Med Sci Monit. editors. Epilepsy: a comprehensive- textbook. 2007;13:555-559. Philadelphia: Lippincott- raven; 2007 p. 76-80. 18. Zaidi SM, Pathan SA, Jain GA.Anticonvulsant 4. Hosseini M, Ghasemzadeh Rahbardar M, and neuropharmacological studies of Anacyclus Sadeghnia HR, et al. Effects of different extracts pyrethrum root extract. Neurosci Res. of Rosa damascena on pentylenetetrazol- 2009;65:250. induced seizures in mice.Zhong Xi Yi Jie He 19. Sayyah M, Valizadeh J, Kamalinejad M. Xue Bao. 2011;9:1118-1124. Anticonvulsan activity of the leaf essential oil 5. Suo C, Liao J, Lu X, et al. Efficacy and safety of Laurus nobilis against pentylenetetrazole- of the ketogenic diet in Chinese children. and maximal electroshock-induced seizures. Seizure.2013;22:174-178 Phytomedicine. 2002;9:212-216. 6. Garg SK, Kumar N, Bhargava VK, et al. 20. Cruz G, Felipe C, Scorza F. Piperine decreases Effect of grapefruit juice on carbamazepine pilocarpine-induced convulsions by GABAergic bioavailability in patients with epilepsy. Clin mechanisms. Pharmacol Biochem Behav. Pharmacol Ther. 1998;64:286-288. 2013;104:144-153. 7. Ashrafzadeh F, Rakhshandeh H, Mahmodi 21. Gilani AH, Aziz N, Khan MA. E. Rosa damascena oil: an adjuvant therapy Ethnopharmacological evaluation of the for pediatric refractory seizures. Iran J child anticonvulsant, sedative and antispasmodic neurology.2007;1:13-17. activities of Lavandula stoechas L. J 8. Giorelli AS, Passos P, Carnaval T, et al. Ethnopharmacol. 2000;7:161-167. Excessive daytime sleepiness and epilepsy: A 22. Abdollahi Fard M, Shojaii A. Efficacy of Systematic Review.Epilepsy Res Treat. 2013. Iranian traditional medicine in the treatment of 9. Rezvani ME, Roohbakhsh A, Allahtavakoli M, epilepsy. Biomed Res Int. 2013. et al. Anticonvulsant effect of aqueous extract of Valeriana officinalis in amygdale kindled

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