doi:10.1684/epd.2011.0423 , 1 1 , Yuka Misawa 1 Epileptic Disord, Vol. 13, No. 2, June 2011 and defecation arevery rare recognized triggers of as reflex . We describe a casepatient with of reflex an seizuresby caused micturitionbased on andgraphic ictal findings. defecation, The electroencephalo- reflex literature on seizuresturition induced and/or byreviewed. defecation is mic- also , Kenichi Koike 1 , Tetsuhiro Fukuyama 1,2 , Motoki Ichikawa 1 reflex , micturition, defecation, supplementary motor – We report a six-year-old girl with seizures induced by both Epileptic Disord 2011; 13 (2): 166-71 Original article Department of Pediatrics, Shinshu UniversityDepartment School of of Pediatrics, Medicine, Nagano Matsumoto Prefectural Suzaka Hospital, Suzaka City, Japan Reflex seizuresspecific are stimulus evokedindividual by which to a is1994). each often Although case visualthe (Ritaccio, most stimuli frequent triggers are ofseizures, reflex reading,startled, auditory stimuli, writing, immersion in being hot water, eating, and somatosen- sory stimulationseizures can (Ritaccio, 1994). Micturition also induce Yuji Inaba Received February 23, 2010; Accepted February 28, 2011 Reflex seizures induced by micturition and defecation, successfully treated with clobazam and phenytoin Tsukasa Higuchi 1 2 ABSTRACT micturition and defecation.tonic-clonic Several seizures, she days developedextension after reflex of both seizures unprovoked arms characterised and generalised mal rhythmic by jerking findings the of were her noted upperelectroencephalography body. on No (EEG) abnor- brain showed magnetic spike-and-wave resonanceelectrode activity recording, imaging. and on rhythmic Interictal central fast activity was recordedtrodes by during central the elec- ictal EEG uponand micturition. The combination phenytoin of clobazam wasAlthough effective some previous for reportsby both have described either unprovoked reflex micturition and seizuresseizures or triggered reflex induced defecation, by seizures. this bothBased is micturition on a and the comparison with defecation previous first cases in ofby case reflex the seizures micturition induced report same either or patient. of defecation,musculature reflex the to the neuronal supplementary pathway motorcondition from area in the our may patient. be pelvic responsible base for the Key words: area, pelvic base musculature, excretion-induced seizures 166 Correspondence: T. Higuchi Department of Pediatrics, Nagano Prefectural Suzaka Hospital, 1332 Suzaka, Suzaka City, 382-0091, Japan Excretion-induced reflex seizures

Case report increased blood flow in her left angular gyrus and left temporal lobe, and decreased flow in her left hip- A five-year-old girl had a mild delay in language deve- pocampus. An interictal electroencephalogram (EEG) lopment and received speech therapy. She had no showed continuous 20-Hz beta activity in the frontal history of febrile convulsions or head injury. Her uncle region, intermittent high-voltage theta waves in the had epilepsy, but detailed information could not be frontal and central regions, and some spike-and-waves obtained. in Cz (figure 1). An ictal EEG recorded on micturition At the age of six years, she was admitted to a nearby revealed the initiation of rhythmic theta waves through hospital because of recurrent generalised tonic-clonic the central electrodes (figure 2). seizures (GTCS) without fever. Several days later, she She was diagnosed with focal epilepsy with reflex developed another type of seizure immediately fol- seizures on the basis of her seizure manifestations lowing micturition, characterised by brief growling, and ictal EEG findings. Her clinical course is shown in eye-opening, the symmetrical extension of both arms figure 3 . The administration of (CBZ) as if to hug or hold someone, and rhythmic jerking resulted in significant decreases in the frequency of of her upper body. These seizures lasted for 10 to 20 both GTCS and reflex seizures, but was discontinued seconds. She remained conscious and reported expe- because of an allergic rash. Zonisamide was not bene- riencing fear at the time of these seizures, and thus ficial and did not reduce the frequency of seizures. The became hesitant to urinate. Since both types of seizure patient then developed brief tonic partial seizures of occurred one to two times daily even after the admi- her left shoulder which occurred in clusters, 39 days nistration of sodium (up to 30 mg/kg/day), after the onset of her seizures. Her reflex seizures she was transferred to our hospital, 14 days after the began to occur not only upon every micturition but onset of her seizures. also on defecation. Clobazam (CLB) was started on On admission, she was alert and physical, neurological, day 41 after seizure onset, at gradually increasing blood, and cerebrospinal fluid examinations revealed doses. Frequent seizures prompted us to begin con- no abnormalities. The KIDS questionnaire-based tinuous intravenous infusion of midazolam (MDZ) on developmental scale evaluated her developmental day 43. However, the medication made her somewhat quotient (DQ) as 65. No abnormalities were detected drowsy and her seizure frequency increased to more on brain magnetic resonance imaging (MRI). Interic- than 60 per day. Treatment with phenytoin (PHT) was th tal 99mTc-ethyl-cysteinate dimer (ECD) single photon attempted on the 46 day in progressively increasing emission computed tomography (SPECT) indicated doses. Despite PHT levels higher than 40 ␮g/mL, the

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Figure 1. Interictal recorded during sleep.

Epileptic Disord, Vol. 13, No. 2, June 2011 167 T. Higuchi, et al.

Micturition started Seizure started Seizure ended

x1 1 Fp1-A1 2 Fp2-A2 3 F3-A1 4 F4-A2 5 C3-A1 6 C4-A2 7 P3-A1 8 P4-A2 9 O1-A1 10 O2-A2 11 F7-A1 12 F8-A2 13 T3-A1 14 T4-A2 15 T5-A1 16 T6-A2 17 Fz-A1 18 Cz-A2 19 Cz-A1 20 E-X9 21 PG1-PG2 M

Figure 2. Ictal electroencephalography recorded on micturition.

VPA MDZ CBZ ZNS PHT CLB CLB DMCLB (µg/mL) (µg/mL) (ng/mL) PHT 50 500 5,000

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Figure 3. Clinical and laboratory course. CBZ: carbamazepine; CLB: clobazam; DMCLB: desmethylclobazam; MDZ: midazolam; PHT: phenytoin; VPA: sodium valproate; ZNS: zonisamide. Serum concentrations of PHT, CLB, and DMCLB are shown.

168 Epileptic Disord, Vol. 13, No. 2, June 2011 Excretion-induced reflex seizures

seizures did not decrease in frequency and so the dose only at Cz on interictal EEG records and seizure acti- was lowered. The seizures disappeared on the 54th vity started at Cz. The electrical activity in the SMA is day after seizure onset, as the serum concentration recorded at or near the Cz electrode on EEG. In six of of desmethylclobazam (DMCLB), the major metabo- seven cases with evident EEG foci, the seizure focus lite of CLB which also exhibits antiepileptic properties, was observed at Cz, C3, or F4 (table 1). This supports increased. She subsequently had no seizures for two the possibility that the SMA is a seizure focus in many years with the combination of 11 mg/day of CLB and cases of reflex seizures induced by micturition and/or 120 mg/day of PHT. The serum concentrations of CLB, defecation. DMCLB, and PHT were 110-180 (reference range: 50- The reflex seizures induced by micturition or defe- 300) ␮g/mL, 1,400-2,200 (reference range: 1,000-4,000) cation in this case were characterised by tonic ng/mL and 9.7-12.1 (reference range: 10-20) ␮g/mL, posturing of the upper limbs, preserved conscious- respectively. When the PHT dose was decreased in ness, and growling, and suggested involvement of a stepwise fashion to 50 mg/day, micturition-induced a common neuronal pathway. These characteristics seizures occurred three times in one week. At that closely resembled those of reflex seizures in cases time, serum concentrations of CLB, DMCLB, and reported previously (Ikeno et al., 1998; Glass et al., PHT were 132 ␮g/mL, 1,442 ng/mL, and 3.1 ␮g/mL, 2006; Okumura et al., 2007). Bass et al. clarified, using respectively. Accordingly, the PHT dose was raised to video-EEG and subdural electrodes, that such seizure 110 mg/day, which resulted in complete control of the attacks, characterised by sudden tonic posturing of the seizures. limbs and often accompanied by unintelligible fearful vocalization, were derived from the SMA (Bass et al., 1995). These findings also provide supporting evidence Discussion that seizure activity induced by micturition/defecation originates in the SMA in some cases. Reflex seizures often occur together with unprovoked Reflex seizures generally respond to conventional seizures and are rarely triggered by micturition and antiepileptic drugs (Ferlazzo et al., 2005). However, defecation. In the literature, we were able to find only there is no standard antiepileptic drug regime effec- nine reports of reflex seizures induced by micturition tive against all reflex seizures, as illustrated in nine or defecation, but not by both, (Zivin and Rowley, 1964; reported cases of patients who achieved remission Yamatani et al., 1987; Pradhan and Kalita, 1993; Ikeno et with different drugs (table 1). In our case, her seizures al., 1998; Bourgeois, 1999; Harbord and Mitchell, 2002; responded well to CBZ at the beginning of the clinical Glass et al., 2006; Okumura et al., 2007) (table 1). Six course. After the discontinuation of CBZ, because of cases were also reported with unprovoked seizures, a skin rash, her seizures became uncontrolled. Finally, consistent with the high prevalence of spontaneous an increase in the serum concentration of DMCLB seizures in patients with reflex seizures (Ritaccio, 1994). (>3,000 ng/mL), in combination with PHT, resulted While reflex seizures occur at any age, those induced in seizure disappearance. Interestingly, her seizures by either micturition or defecation are observed only responded to CLB, but not to MDZ, despite both drugs in childhood (6 to 14 years). Additionally, develop- being which enhance the inhibitory mental delay is documented in four cases, including action of ␥-aminobutyric acid receptors in the ner- the present patient. Taken together, pre-existing brain vous system. The reason for the difference in action impairment as well as brain immaturity may be impor- between the two benzodiazepines may be attributed tant in the pathogenesis of this type of reflex seizure. to the drowsiness that accompanied the continuous In reflex seizures, readily excitable cortical regions are infusion of MDZ, but not CLB administration. It is well considered to be present at or near areas physiologi- known that drowsiness or oversedation can activate cally activated by specific stimuli (Ferlazzo et al., 2005). seizures (Gayatri and Livingston, 2006), which may Using SPECT and functional MRI, Fukuyama et al. and have been the case here. Another possibility is the Bittorf et al. showed, respectively, that the activity of structural difference between the two drugs; MDZ has sphincters involved in micturition/defecation is neu- a 1, 4- structure, whereas CLB has a 1, ronally transmitted to the supplementary motor area 5-benzodiazepine structure. Meldrum et al. reported (SMA) (Fukuyama et al., 1996; Bittorf et al., 2006). Using that different benzodiazepines bind to each of the positron emission computed tomography (PET), Blok three benzodiazepine-receptor subtypes with varying et al. revealed that the SMA is one of the regions affinities, which contributes to the different action physiologically activated by contraction of the pelvic and efficacy of each drug (Meldrum and Chapman, floor muscles (external urethral sphincter, external 1986). Accordingly, the discrepancy observed between anal sphincter, levator ani muscle, and puborectal mus- the clinical effects of the two benzodiazepines may cle) involved in micturition/defecation (Blok et al., have been due, in part, to their different chemical 1997). In our case, spike-and-wave activity was detected structures.

Epileptic Disord, Vol. 13, No. 2, June 2011 169 T. Higuchi, et al. Year 2002 2006 2007 1987 1998 et al. et al. et al. et al. Mitchell Remission Yamatani Refractory Glass Remission The present case 2009 Remission Zivin and Rowley 1964 Remission Ikeno CBZ+VPA Treatment Outcome Author CZP → TPM, LTG, CLB, KD → PHT+CLB MDZ EEG focus NEC3 PRM CBZ → + F4Cz CBZ → VPA CBZ RemissionF7 Pradhan and Kalita CBZ → LTG 1993 Cz PB, VPA, CZP, NE Remission Harbord CBZ, and CZP → PHT Remission Okumura Cz CBZ → CBZ+VPA Remission Bourgeois 1999 Cz VPA, CBZ, ZNS, seizure - - + + - + + + hot water - Reported cases of micturition- and/or defecation-induced seizures. Stimuli Other stimuli Spontaneous MicturitionMicturition - - MicturitionMicturition - Micturition - Immersion in Defecation - Micturition EmotionMicturitionMicturition - and + defecation Table 1. delay Age Sex Developmental Case No. 12 14 M 83 - 4 F 105 - M 9 - 86 F M - 97 + M 128 + F9 8 + 6 F F - + PRM: primidone; TPM: ; VPA: valproate; ZNS: zonisamide. CBZ: carbamazepine; CLB: clobazam; CZP: ; KD: ketogenic diet; LTG: ; MDZ: midazolam; NE: not evident; PB: phenobarbital; PHT: phenytoin;

170 Epileptic Disord, Vol. 13, No. 2, June 2011 Excretion-induced reflex seizures

In conclusion, reflex seizures triggered by micturition Fukuyama H, Matsuzaki S, Ouchi Y, et al. Neural control of or defecation appear to be rare and only reported in micturition in man examined with single photon emission children. This is the first case report where seizures computed tomography using 99mTc-HMPAO. Neuroreport triggered by both occurred in the same patient. These 1996; 7: 3009-12. seizures often respond to antiepileptic medication, Gayatri NA, Livingston JH. Aggravation of epilepsy by anti- although no standard effective regimes have been epileptic drugs. Dev Med Child Neurol 2006; 48: 394-8.  established. Glass HC, Prieur B, Molnar C, Hamiwka L, Wirrell E. Micturi- tion and emotion-induced reflex epilepsy: case report and Disclosure. review of the literature. Epilepsia 2006; 47: 2180-2. None of the authors has any conflict of interest or financial support to disclose. Harbord MG, Mitchell C. Reflex seizures induced by defeca- tion, with an ictal EEG focus in the left frontotemporal region. Epilepsia 2002; 43: 946-7. Ikeno T, Morikawa A, Kimura I. A case of epileptic References seizure evoked by micturition (in Japanese). Rinsho Nouha 1998; 40: 205-8. Bass N, Wyllie E, Comair Y, Kotagal P, Ruggieri P, Holthausen Meldrum B, Chapman A. Benzodiazepine receptors and H. Supplementary sensorimotor area seizures in children and their relationship to the treatment of epilepsy. Epilepsia adolescents. J Pediatr 1995; 126: 537-44. 1986; 27: S3-S13. Bittorf B, Ringler R, Forster C, Hohenberger W, Matzel KE. Okumura A, Kondo Y, Tsuji T, et al. Micturition induced Cerebral representation of the anorectum using functional seizures: ictal EEG and subtraction ictal SPECT findings. magnetic resonance imaging. Br J Surg 2006; 93: 1251-7. Epilepsy Res 2007; 73: 119-21. Blok BF, Sturms LM, Holstege G. A PET study on cortical and Pradhan S, Kalita J. Micturition induced reflex epilepsy. Neu- subcortical control of pelvic floor musculature in women.J rol India 1993; 41: 221-3. Comp Neurol 1997; 389: 535-44. Ritaccio AL. Reflex seizures. Neurol Clin 1994; 12: 57-83. Bourgeois BF. A retarded boy with seizures precipitated by stepping into the bath water. Semin Pediatr Neurol Yamatani M, Murakami M, Konda M, et al. An 8-year-old 1999; 6: 151-6. girl with micturition-induced epilepsy. No To Hattatsu (in Japanese) 1987; 19: 58-62. Ferlazzo E, Zifkin BG, Andermann E, Andermann F. Cortical triggers in generalized reflex seizures and . Brain Zivin I, Rowley W. Psychomotor Epilepsy With Micturition. 2005; 128: 700-10. Arch Intern Med 1964; 113: 8-13.

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