Background:Despite availability and administration of numerous antiepileptic drugs (AEDs) nearly 15% of childhood epilepsy cases are resistant to treatment; in traditional medicine however Nigella sativa L. (Black seed) has been known for its anticonvulsant effects.Materials and Methods:In this double-blind clinical trial conducted on children with refractory epilepsy we administered the aqueous extract of black seed as an adjunct therapy and compared the effects with those of a placebo. The study was performed between Sep 2003 and Nov 2004. The subjects received either extract or placebo for a period of four weeks and between these two periods for two weeks they received only their pre-existing anti-epileptic drugs (AEDs).Results:The mean frequency of seizures decreased significantly during treatment with extract, (p-value =0/007).Conclusion:It can be concluded that the water extract of Nigella sativa L. has antiepileptic effects in children with refractory seizures that do not respond to known AEDS.keywords:Nigella sativa, Intractable seizures, Childre

AKHONDIAN MD, J.

PARSA MD, A.

RAKHSHANDE MD, H.

English

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11Iran J Child Neurology  June 2006THE EFFECT OF NIGELLA SATIVA L. ONINTRACTABLE PEDIATRIC SEIZURESJ. AKHONDIAN MD 1,A. PARSA  MD 2,H. RAKHSHANDE MD 3RESEARCHAbstract:Background:Despite availability and administration of numerous antiepilepticdrugs (AEDs) nearly 15% of childhood epilepsy cases are resistant totreatment; in traditional medicine however Nigella sativa L. (Blackseed) has been known for its anticonvulsant effects.Materials and Methods:In this double–blind clinical trial conducted on children with refractoryepilepsy we administered the aqueous extract of black seed as anadjunct therapy and compared the effects with those of a placebo.The study was performed between Sep 2003 and Nov 2004. Thesubjects received either extract or placebo for a period of four weeksand between these two periods for two weeks they received onlytheir pre-existing anti-epileptic drugs (AEDs).Results:The mean frequency of seizures decreased significantly duringtreatment with extract, (p-value =0/007).Conclusion:It can be concluded that the water extract of Nigella sativa L. hasantiepileptic effects in children with refractory seizures that do notrespond to known AEDS.keywords: Nigella sativa, Intractable seizures, Children1.Pediatrics neurologist, Associateprofessor of , Mashhad Universityof Medical Sciences, Ghaemmedical center, Mashhad,Iran.2.Pediatrician, Mashhad Universityof Medical Sciences, Ghaemmedical center ,3.Pharm.D ., Mashhad Universityof Medical Sciences, Ghaemmedical centerCorresponding Author:J. Akhondian MDTel: +985117615101Fax: +985118417451E-mail: J-akhondian@mums.ac.irIntroductionDespite administration of numerous antiepileptic drugs (AEDs) nearly 15% ofchildhood epilepsy cases are resistant to treatment; these drugs fail to provideadequate control of epileptic seizures and do not prevent progressive epileptogenicchanges (1,2). Recurrent seizures are still common clinical problems of hospitalizedpediatric patients (3).Black cumin seed (botanical name is Nigella sativa L, Ranulacea family) or “Blackseed” for short; although believed to be indigenous the Mediterranean region, hasbeen cultivated in other parts of the world; through the years it has played animportant role in ancient Islamic medical practice. Much research is available onits various therapeutic effects such as anti cancer (4), diuretic and hypotensiveeffects (5), antihistaminic (6,7), antihypertensive (8), hypoglycemic (9) anti-inflammatory, analgesic (10), antifungal and antibacterial (11,12). The oil is usefulin diseases12 Iran J Child Neurology  June 2006THE EFFECT OF NIGELLA SATIVA L. ON INTRACTABLE PEDIATRIC SEIZURESin which free radicals are involved, e.g. anoxia andischemia of brain and heart as well as arteriosclerosis,rheumatism and cancer (8,11,13,14,15).In ancient Islamic medicine, Nigella sativa (Black cumin)was known for its anticonvulsant effects. (16) Blackseed, in particular its major constituent thmoquinine,have recently shown antiepileptic effects in mice. (17,18).Furthermore several studies based on the toxicity ofblack seed have been reported. It has been shown thatthere were no toxic effects when Nigella sativa seed oilwas given to the mouse via the stomach; it has been alsoreported that the nigella seed powder does not produceany toxic effect when given to rabbit again by gastricintubation (19). Also acute and chronic toxicity of Nigellasativa fixed oil was investigated in rats and mice andthere were no evidence of toxicity (20) In this study wehave assessed oral administration of black seed aqueous(soxhlet) extract as an adjunct to AEDs in a double-blindclinical trial and compared the results with those of aplacebo.Materials &Methods:This pilot study was performed between Sep 2003 andNov 2004, in a tertiary referral center (Ghaem medicalcenter, Mashhad, Iran) Black cumin seeds were collectedfrom the southern part of the Khorasan province in Iran.Patients and their relatives were advised that black seedextract was registered for sale in USA as an immunemodulator (21), but without proven efficacy in epilepsyand asked to give informed consent.To be included in this pilot study, patients had to haveintractable epilepsy according to definition. (22),occurrence of at least one seizure during the four-weekbaseline period, relative absence of confounding illnesses,constant antiepileptic treatment at least one month beforethe study.Exclusion criteria were history of status epilepticus withinthe three months prior to the first visit, history of pseudoseizures, seizures that due to their fast and repetitivenature could not reliably be counted, current renal andcardiac or hepatic dysfunction and lack of co-operation.Patients who, qualified for the inclusion criteria, wereselected in sequential order of presentation from theroutine clinical caseload. Based on their type of seizuresand poor control with established AEDs, they wereselected over a consecutive period of 11 months; in thisperiod of time 23 patients were enrolled, but only 20completed the study. The number of patients was deemedto be a sufficient sample size of a pilot study.Initially, prior to enrollment, each child underwent clinicalexaminations, both general and systemic. Patients werevisited once a week throughout the study and allinformation related to the number of seizures, history ofduration of, or possible changes in, seizures was obtainedfrom the parents. The clinicians were made familiar withthe nature and treatment history of patient's epilepsy.Diagnosis of intractable seizures was made prior to thestudy and type of seizures were categorized accordingto ILAE classification (23,24).Patients were provided with the syrup free of charge;they received either extract or placebo at the dose of 0/4ml/kg/8h for four-weeks and after a period of wash –out(2 weeks) they received the other (extract or placebo forthe same period). The dosage of concomitant AEDs wasmaintained throughout the treatment period. Throughoutthese periods, the number, type and duration of seizureswere registered; in addition any adverse effects thatoccurred were reported to the clinician and his assistant.This protocol provided a uniform measure of seizurefrequency for comparison and contrast. At the end ofeach period (placebo or extract) the degree of parentalsatisfaction was assessed.The study was reviewed and approved by the Researchand Ethics Committee of Mashhad University of MedicalSciences of Iran.All analysis was made using the SPSS statistical softwarepackage and probability value of less than 0.05 wasconsidered statistically significant.Results:20 patients were eventually enrolled for the pilot study(10 girls and 10 boys), ranging in age from 13months to13 years (mean 66.95   45.39 months).Seizure types were: 4 patients- generalized tonic-clonic,8 myoclonic, 2 complex partial seizures, 1 polymorphicseizure, 3 absence, 1 myoclonic with generalized tonic-clonic,1 tonic-clonic with infantile spasm attack. 25%were mentally retarded or had abnormal findings in theirneurological examinations.Electroencephalograms (EEGs) and Computed tomogram(CT-Scans) were abnormal in 90% and 20% respectively.Mean age of seizure onset was 19.15   23.06 months.13Iran J Child Neurology  June 2006Patients used between 2 and 5 AEDs at time of entry in to the study. Compliance with extract was found to be verygood, as verified by remaining syrup at the end of each week.The mean frequency of seizures in children at the end of extract period decreased from 5.78   7.2 seizures / day beforeinitiation of the study, to 4.21  5.77 seizures/day. At the end of the placebo period, mean frequency of seizures reachedto 6.14  6.75 seizures / day. The results of Friedman statistical test on these data showed a significant difference inseizure frequency between extract period and other periods (Pvalue <0/001). Since the number of seizures in childrenvaried widely, there was a need for testing of data using a non- parametric statistical test, independent of the mean,and hence the “Wilcoxon test” was used, the results demonstrating a significant difference between the extract periodand the period before initiation of the study, with p value of 0.007. Data from these two periods were comparedweekly with the Wilcoxon test; it seems that a statisticallysignificant difference between extract and placebo period.(Table 1)THE EFFECT OF NIGELLA SATIVA L. ON INTRACTABLE PEDIATRIC SEIZURESThe degree of parental satisfaction at the end of extract period and placebo period also showed a significant difference.(Table-2).Table-1: Results of the Wilcoxon test for frequency of seizures/dayTable-2: Parental satisfaction at the end of each periodDuring this study 3 patients reported adverse effects. One patient was constipated in the 2nd and 3rd weeks of theextract period; in another, the parents reported increased laughing at the time of seizure, during the placebo period;in the third, maculopapular rash appeared on the trunk on day 28.14 Iran J Child Neurology  June 2006THE EFFECT OF NIGELLA SATIVA L. ON INTRACTABLE PEDIATRIC SEIZURESDiscussionRecurrent seizures and intractable epilepsies are commonclinical problems of hospitalized pediatric patients,constituting a considerable number of outpatients referringto pediatric neurology clinics. In spite of advances in thetreatment of epilepsy, a significant number of childrenwith epilepsy do not respond appropriately to antiepilepticdrugs (AEDs) (1,3).Although an intensive search of literature failed to revealany clinical trial on the anticonvulsant effects of Nigellasativa L on humans, the same effect in thymoquinine,the major constituent of Nigella sativa l. have beeninvestigated in mice using pentylenetetrazole (PTZ)- andmaximal electroshock (MES)- induced seizure models.In this study thymoquinone did exhibit anticonvulsantactivity in the PTZ – induced seizure model, but nosimilar activity was seen in the MES model (17).Generally, compounds with the anticonvulsant activityin petit mal epilepsy, are effective in PTZ – inducedseizure models and drugs that possess anticonvulsantactivity in MES, may be considered as an effective againstgrand mal epilepsy (25). It can hence be concluded thatthymoquinone may be useful in petit mal epilepsy, throughan opioid–mediated increase in the GABAergic tonemechanism (17).Recently anticonvulsant and antioxidanteffects of Nigella sativa oil against PTZ-induced kindlingin mice were investigated, this study clearly demonstrateda potent anticonvulsant property for Nigella sativa oilagainst the development of kindling consequences inPTZ-kindled mice, and was more potent as ananticonvulsant agent than Valporate when they werecompared experimentally. The mechanism for theanticonvulsant effect seems to be correlated with theantioxidative effect. (18).In our study, during the extract period, the mean ofseizures decreased gradually, whereas this was not so inthe placebo period.At the end of the fourth week of the Nigella sativa period,3 children had become seizure free; two of them hadmyoclonic seizures. In one patient with Lennox-Gastautthe number of seizures in the extract period was morethan in the placebo period. Results of our study showedthat aqueous extract of Nigella sativa has andanticonvulsant effect, which may be explained bythymoquinone the major constituent of Nigella sativaseeds. Furthermore oil and fatty acids of Nigella sativaseeds seem to play a role in this effect.ConclusionOn the basis of the above observations, it may beconcluded that the aqueous extract of Nigella sativa L.has anticonvulsant effects and can improve seizure controlin children suffering from refractory epilepsy. There ishowever the need for more extensive trials to be conductedin such patients to confirm these preliminary findings.Acknowledgment:We wish to express our appreciation to he vice-chancellorfor research of Mashhad University of Medical Sciencesfor supporting this study. We especially wish to thankDr.Habib Esmaili for the statistical review of this study.References:1. Verhelst H , Boon P ,et al: Steroids in intractable childhood   epilepsy. Clinical experience and review of the literature    Seizure 14: 412-421, 2005.2. Cockerell, O.C: The prognosis of epilepsy. In: Shorvon  S,   Dreifuss  F , Fish  D , Thomas  D. (Eds.), the treatment of  epilepsy. Oxford: Blackwell Science, pp. 97-113,1996.3. Jiao FY, Gao DY, Takuma Y:  Randomized, controlled trial of    high-dose intravenous pyridoxine in the treatment of recurrent  seizures in children. Pediatr Neurol  17: 54-57, 1997.4. Swamy MK:Cytotoxic and immunopotentiating effects of     ethanolic extract of nigella sativa L. seeds. J Ethnopharmacol     70(4): 1-7, 2000. 5. Zaoui A : Diuretic and hypotensive effects of nigella sativa in    the spontaneously hypertensive rat. Therapie 55(3):379-82,     May-Jun 2000.6. Chakravarty N: Inhibition of histamine release from mast cells    by Nigellone. Ann Allergy  70: 237-242, 1993.7. Mahfouz  M, Abdel-Maguid R, El-Dakhakhny M: The effect   of "nigellone therapy" on the histaminopexic power of the    blood sera in asthmatic patients. Arzneim.-Forsch 15:1230- 1234, 1965.8. El-Tahir KE, Ashour MM, Al-Harbi MM: The cardiovascular    actions of the volatile oil of the black seeds (Nigella sativa) in    rats: elucidation of the mechanism of action. Gen Pharmacol    24: 1123-1131, 1993.9. Al-Hader AA, Aqel MB, Hasan ZA: Hypoglycemic effects of   the volatile oil of Nigella saliva seeds. Int J Pharmacogn    31:96-100, 1993.10. Abdel-Fatlah AFM, Matsumoto K, Watanabe H:     Antinociceptive effects of Nigella sativa oil and its major      component, thymoquinone, in mice. Eur J Pharmacol 400:       89-97, 2000.11. Al-Ghamdi MS: The anti-inflammatory, analgesic and      antipyretic activity of Nigella saliva. J Ethnopharmacol 76:       45-48, 2001.12. Topozada HH, Mazolum HA, El-Dakhakhny M: The       antibacterial properties of Nigella sativa seeds, active principle      with some clinical applications. J Egypt Med Assoc  48: 187-      202, 1965.13. Salomi NJ, Nair SC, Jayawardhanane KK, et al:  Antitumour      principles from Nigella sativa seeds. Cancer Lett   63: 41-46,      1992.14. Worten DR, Ghosheh OA, Crooks PA: The in vitro anti-tumor      activity of some crude and purified components of blackseed,    Nigella sativa L. Anticancer Res18: 1527-1532, 1998.15. Medenica R , Janssens J , Tarasenko, A: Anti-angiogenic     activity of Nigella sativa plant extract in cancer therapy.       Proceeding Annual Meeting of the American Association for      Cancer Research    38, A 1377, 1997.16. AL-Akhaveini , al-bokhary:Hedayaton lel-moteallemin fe-     teb. Mashhad: Ferdowsi University. p 259,2nd ed., 1992.17. Hosseinzadeh  H, Parvardeh  S: Anticonvulsant effects of      thymoquinone, the major constituent of Nigella sativa seeds,   in mice.Phytomedicine11(1): 56-59, Jan 2004.18. Ilhan A, Gurel A, Armutcu F, et al: Antiepileptogenic and        antioxidant effect of Nigella sativa oil against pentylentetrazole-      induced kindling in mice. Neuropharmacology   49(4): 456-       464 ,Sep 2005 .19. Tissera MHA: Toxicology study of oil of nigella sativa.      Pharmacological & Toxicological studies  48(1):39-42,2002.20. Zaoui A: Acute and chronic toxicity of nigella sativa fixed      oil. Phytomedicine 28(1):   69-74, Jan 2002.21. Islamic bulletin: FDA approved Black seed oil, [1]. Available   at http://www.islamic bulletine.com/issues/issues 922. Chapell R, Reston J, Snyder D:Management of treatment -     resistant epilepsy. Washington: AHRQ publication,  pp. 11-     25 , 2003.23. Commission on classification and terminology of the ILAE    proposal for revised clinical and electro-encephalographic   classification of seizures. Epilepsia 22: 489-501, 1981.24. J Parra, P.B. Augustijn, Y. Geerts ,et al : Classification of     epileptic seizures: a comparison of two systems. Epilepsia      42(4):476-482,2001.25. Vida JA: Anticonvulsants. In: Foye WO, Lemke TL, Williams       DA, eds. Principles of Medicinal Chemistry, London: Williams      and Wilkins ,pp. 182-198, 4th ed., 1995.15Iran J Child Neurology  June 2006THE EFFECT OF NIGELLA SATIVA L. ON INTRACTABLE PEDIATRIC SEIZURES

THE EFFECT OF NIGELLA SATIVA L. ON INTRACTABLE PEDIATRIC SEIZURES

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THE EFFECT OF NIGELLA SATIVA L. ON INTRACTABLE PEDIATRIC SEIZURES

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