+Model
ARTICLE IN PRESS
EPIRES-5158; No. of Pages 5 Epilepsy Research (2014) xxx, xxx—xxx
journal homepage: www.elsevier.com/locate/epilepsyres
Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: A prospective study P. Satishchandra a, S. Dilipkumar a, D.K. Subbakrishna b, S. Sinha a,∗ a
Department of Neurology, National Institute of Mental Health and NeuroSciences [NIMHANS], Bangalore, India b Department of Biostatistics, National Institute of Mental Health and NeuroSciences [NIMHANS], Bangalore, India Received 23 December 2013; received in revised form 19 March 2014; accepted 27 April 2014
KEYWORDS AEDs; Clobazam prophylaxis; Hot water epilepsy; Non-reflex seizure
Summary Purpose: To evaluate the role of intermittent prophylaxis with clobazam in the management of HWE in a long-term prospective study. Material and methods: Two hundred and sixty patients [M:F — 194:66] with HWE were recruited. Patients were divided into: (a) ‘HWE alone’ (n = 198) — received intermittent clobazam prophylaxis, 1—1½ h prior to hot water head bath (group A); (b) 62 patients (20.4%) with ‘HWE with spontaneous seizures were treated with continuous AEDs along with intermittent clobazam therapy (group B). Results: Patients (n = 198) in group A was followed for mean of 17.6 ± 10.6 months (range: 3—57). One hundred and forty seven patients (74.2%) had excellent response with complete seizure freedom with clobazam therapy while 12 (6.1%) had >75% reduction in seizure frequency. Remaining 39 (19.7%) required additional standard AED along with clobazam and 18 patients among them developed spontaneous/unprovoked seizure at follow up of 6.7 ± 4.1 months. Forty five patients in group B were seizure free while on continuous AEDs. Conclusions: Intermittent clobazam prophylaxis prior to head water bath might be a preferred mode of treatment of pure HWE. Additional AEDs are required if they have associated non-reflex unprovoked seizure. © 2014 Elsevier B.V. All rights reserved.
∗
Corresponding author. Tel.: +91 80 26995150; fax: +91 80 26564830. E-mail addresses: [email protected] (P. Satishchandra), [email protected] (S. Dilipkumar), [email protected] (D.K. Subbakrishna), sanjib [email protected] (S. Sinha). http://dx.doi.org/10.1016/j.eplepsyres.2014.04.016 0920-1211/© 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: Satishchandra, P., et al., Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: A prospective study. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.04.016
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P. Satishchandra et al.
Introduction
Material and methods
Hot water epilepsy (HWE) a type of reflex epilepsy that is precipitated by a bath or shower with hot water (Mani et al., 1968, 1974; Subrahmanyam, 1972; Satishchandra et al., 1988, 1998, 2003; Szymonowicz and Meloff, 1978). It is also variably known as water-immersion epilepsy or bathing epilepsy (Mofenson et al., 1965; Shaw et al., 1988; Lenoir et al., 1989). Though HWE was first described in 1945 from New Zealand (Allen, 1945), there have been case reports from all round the world: Australia (Keipert, 1969), the United States (Stensman and Ursing, 1971), Canada (Szymonowicz and Meloff, 1978), the United Kingdom (Parsonage et al., 1976), Japan (Kurata, 1979; Morimoto et al., 1985) and Turkey (Bebek et al., 2001). However, it is from southern India, that a large number of cases of HWE have been reported (Mani et al., 1968, 1974; Satishchandra et al., 1988; Satishchandra, 2003), possibly emphasizing the role of environmental and genetic influence. The concept of ‘hyperthermic kindling’ with aberrant thermoregulation in the genetically susceptible population with possible coexisting environmental influence could be the probable mechanism responsible for this epilepsy [Satishchandra et al., 1998; Satishchandra, 2003; Ullal et al., 1996, 2006]. It is reported that seizures can be controlled with optimum intervention, both lifestyle and pharmacological but if left untreated might progress to spontaneous seizure types with variable outcome (Satishchandra et al., 1998). About 17—25% of these HWE patients develop spontaneous, non-reflex seizures in their natural course (Satishchandra et al., 1998). These patients were managed with use of long term anti-epileptic medications similar to other epilepsies. Being a reflex epilepsy, avoidance of reflex factors such as head bath or use of luke warm water was practiced previously. However latter may not be suitable as number of these subjects has compulsive desire and develop self induced reflex seizures during the later part of their natural course. With the change in the understanding of its patho-mechanism as ‘hyperthermic seizure’ akin to febrile seizures, use of intermittent prophylaxis seems to be the most appropriate method of treatment. The exact etiopathogenesis of this type of epilepsy is not clear but several factors including genetic factors, environmental factors and habit of taking bath with high temperature water has been postulated as probable reasons (Satishchandra, 2003). Intermittent clobazam therapy has been used in the management of febrile seizures (Wolf, 2011). We have observed that it could be used as an effective prophylaxis in HWE cases if administered 1.5 h prior to hot water head bath (Satishchandra et al., 1998). This was further confirmed by Dhanaraj and Jayavelu (2003) from Chennai and by Meghana et al. (2012) from this center. However its role has not been evaluated in larger number of patients over a long term period to further ascertain its efficacy and tolerability. This study evaluated the role of intermittent prophylaxis with clobazam in the management of HWE through a long-term prospective basis to evaluate its efficacy and tolerability.
This prospective hospital based study was conducted at a university teaching hospital, a major tertiary care referral center for neuro-psychiatric disorders in south India. Two hundred and sixty patients (M:F = 194:66; age at evaluation: 18.6 ± 10.1 years; age at onset of HWE: 13.9 ± 8.1 years) with a diagnosis of HWE were recruited from the neurological services after obtaining written informed consent. The study was approved by the institute ethics committee (IEC). The diagnosis of HWE was based on proposed criteria by Commission of the International League Against Epilepsy (Commission on Classification and Terminology of the International League Against Epilepsy, 1989; Engel, 2001). There was no placebo controlled subgroup. This study group included those patients who had pure reflex epilepsy — ‘HWE alone’ and also those who had spontaneous non-reflex seizure along with HWE — ‘HWE with spontaneous seizure’. The recruited patients were evaluated in detail with regard to its demography, antecedent birth history, febrile seizures and data related to detailed history of epilepsy including bathing habits, precipitating factor—–hot water bath, triggering areas, seizure semiology from eye witness, age at onset of seizures, frequency of seizures, history of epilepsy/HWE in the family, previous history of febrile convulsions/birth related injuries, gross development; personal/family medical histories were recorded. The details of scalp EEG and neuroimaging observations carried out as per standard procedures were noted. Patients with ‘HWE alone’ were prescribed intermittent clobazam therapy to be used prophylactically 1—1½ h before hot water head bath and formed group A (n = 198; M:F — 2.8: 1; age at evaluation: 18.0 ± 10 years; age at onset: 13.6 ± 8.7 years). Patients of ‘HWE with spontaneous seizures’ constituted group B (n = 62; M:F — 3.4:1; age at evaluation: 19.0 ± 10.4 years; age at onset: 14 ± 8.8 years) and received standard AEDs in addition to intermittent clobazam (5 mg). All these patients were advised to avoid hot water head bath, maintain a seizure dairy and follow periodically once in 2—3 months. During follow up, according to a pre-designed protocol, patients were enquired about seizure control, drug compliance, onset of non-reflex epilepsy, adverse effects of clobazam and other AEDs used in the study. The dosages of the AEDs were adjusted based on standard clinical judgment.
Statistics Demographic characteristics between these groups were compared using standard ‘t’ tests and chisquare. Intentionto-treat analysis was done to note the efficacy of clobazam.
Results Demography and phenotype Hot water epilepsy (HWE) is commonly reported in men as compared to women and in this cohort the ratio of men:women was 2.94:1. The mean age of the patients was
Please cite this article in press as: Satishchandra, P., et al., Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: A prospective study. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.04.016
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Clobazam in hot water epilepsy Table 1
3
Demographic and clinical data of patient groups of HWE.
Parameters
Group An = 198
Group Bn = 62
Total n = 260
Male:Female Mean age at inclusion (years) Age at onset of HWE (years) Duration of HWE (months) Type of seizures HWE CPS CPS with generalization GTCS EEG (n = 240) Normal record Abnormal record Normal CT scan (brain)
2.8:1 18.0 ± 10 13.6 ± 8.7 52 ± 66
3.4:1 19 ± 10.4 14 ± 8.8 60 ± 60.7
2.94:1 18.6 ± 10.1 13.9 ± 8.1 56.3 ± 64.9
67 (33.8%) 114 (57.6%) 17 (8.6%)
26 (41.9%) 33 (53.2%) 03 (4.9%)
93 (35.7%) 147 (56.5%) 20 (07.7%)
148 (81.7%) 33/148 (18.3%) 171 (76.3%)
47 (79.7%) 12/47 (20.3%) 53 (23.7%)
195 (75%) 45/240 (23.07) 224 (all)
18.6 ± 10.1 years. The age at onset of HWE was 13.9 ± 8.1 years. The duration of HWE at recruitment ranged from 1 month to 284 months. Majority of the patients belonged to districts of Bangalore: 144; Mandya: 57; Tumkur: 24; Mysore: 21; Hassan: 4; other districts of Karnataka: 7; and other states of India: 3. Presence of family history was noted in 29 (10.9%) patients. All the patients had the habit of having hot water head bath with a frequency ranging from once in 2—7 days. All the attacks occurred while pouring the hot water on the head with a mug as is usually practiced in this part of the world except one patient wherein the seizure had occurred while taking shower bath with hot water. Family history of HWE was present in Table 1 depicts the phenotypic and demographic features of the two subgroups of patients with HWE. Among 198 cases of ‘HWE alone’, 50 had seizures while pouring even luke warm water and three patients had seizure while washing face with hot water. One hundred subjects had 1:1 episodes viz. seizures occur whenever they have hot water bath. In those with ‘HWE with spontaneous seizure’ subgroup (n = 62), 20 patients had 1:1 episode of seizures with hot water bath. Subjects had complex partial seizure (CPS) with or without secondary generalization. Voluntary act of taking bath stopped when seizure began, and similarly when the relatives were pouring hot water on head, they could recognize the onset and stopped further pouring of hot water. Majority of the patients got an attack wherein they would sit flexing their body and closing ears with both the hands with aura of fear, for few seconds followed by the seizure. They had varied manifestations which included loss of orientation and awareness, staring look, behavioral arrest, irrelevant speech, déjà vu, among feeling like fainting etc., lasting for few seconds to minutes. By and large, except for a tendency to look around aimlessly, rarely wandering, praying there was no other motor phenomena. Post ictal headache and sleep were present. The phenomenon of ‘‘self-induction of HWE’’ was seen about a third of patients. They had an aura of pleasure during hot water both and would continue to pour the hot water on head until they had seizure. About 8.6% of patients had history of febrile convulsion in their early childhood. Cranial CT scan, carried out in 224 patients, was normal in all.
Electroencephalogram (n = 240) Interictal scalp EEG was normal in 195 patients [81.25%]. The abnormalities were: (a) focal abnormality in the form of focal spikes or sharp waves with slow waves—–30 [12.5%]; predominantly from the fronto-temporal regions and (b) generalized seizure discharges—–15 [6.25%] patients. EEG records of 22 patients were unavailable for review.
Follow up analysis (Table 2) Patients under groups A and B were followed up for a mean period of 17.4 ± 10.6 months ranging from 3 to 57 months. Patients with ‘HWE only’ i.e. Group A (n = 198) were on intermittent prophylaxis with oral clobazam 10 mg, on the days of head bath, about 1—1½ h before the bath. Group B patients with ‘HWE and spontaneous seizures’ i.e. group B (n = 62) were on intermittent clobazam prophylaxis along with a regular AED viz. phenytoin or carbamazepine for non-reflex epilepsy as per standard practice. These patients were asked to maintain the diary regarding head bath, seizures and the treatment details and were followed once in 2—3 months with questionnaire-based protocol to assess the efficacy and tolerability. The time interval from the onset of reflex HWE to the onset of non-reflex epilepsy is quite significant in view of intermittent clobazam prophylaxis. In group A, the number of patients who showed poor therapeutic response to clobazam and developed non-reflex seizure were 18/198 (9.1%). The mean time interval for developing non-reflex (unprovoked) seizure from the onset of reflex epilepsy in these 18 patients of group A despite clobazam therapy was 6.7 ± 4.1 months with range from 3 to 19 months. In contrast, in group B patients who presented with reflex and non-reflex seizure, the mean time interval of the same was 36.6 ± 45.5 months. This finding provides strong evidence that patients who did not show good response to intermittent clobazam prophylaxis have high susceptibility for developing non-reflex seizure. The observations after a follow up of 17.6 ± 10.5 months were: (a) excellent response—–147 patients (74.2%), (b)
Please cite this article in press as: Satishchandra, P., et al., Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: A prospective study. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.04.016
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P. Satishchandra et al. Table 2
Details therapeutic response in groups A and B.
Group A (n = 198) Follow up (months) Excellent response (seizure free) Good response (>75% response) Poor response Adverse events Group B (n = 62) Follow up (months) Seizure free Adverse events
17.6 ± 10.6 (3—57) 147 (74.2%) 12 (6.1%) 39 (19.7%)a 21
17.4 ± 10.5 (3—57) 45 (72.6%) 10
a
18 patients with poor response also developed unprovoked spontaneous seizure
good response: improvement but not seizure free (moderate response) and did not require standard anti-epileptic drugs: 12 (6.1%), and (c) poor therapeutic response: 18 patients (9.1%) who also required the use of continuous AED for seizure control. Group B (62 patients) who had HWE plus seizures also had similar follow up. They received standard AED for unprovoked seizures in addition to the intermittent clobazam prophylaxis. Seizure freedom was achieved in about 72% of the patients in group B. Some of the adverse drug reactions in 21 patients with clobazam therapy included excessive drowsiness, weight gain, poor concentration and decreasing memory. Rest of the patients did not report any adverse effects and continued drug for more than 3 years. Ten patients on continuous AEDs did report minor side effects of the AEDs used.
Discussion Hot water epilepsy (HWE) a type of reflex seizure precipitated by hot water head bath, classified under somatosensory reflex seizure in the proposed ILAE classification. Animal experiments have proven this to be ‘hyperthermic’ seizure with possible kindling. Further, human studies have confirmed this to be ‘hyperthermic seizure’ possibly akin to febrile seizures (Satishchandra et al., 1998, 2003; Ullal et al., 1996, 2006). However, only 8.6% of this cohort had febrile seizures. Febrile seizures are often treated with intermittent clobazam prophylaxis (Wolf, 2011). Treatment for hot water epilepsy include avoidance of reflex precipitating factors. They have instead used luke warm water for head bath. Some of the patients had seizures even with luke warm water. Many patients in this cohort had ‘‘self-induction of hot water epilepsy’’ where in patients have a compulsive desire to pour hot water till they get the seizure. Hence, avoidance of reflex factor may not be the correct answer. About 20—25% of patients with HWE tend to develop non-reflex seizures (Satishchandra et al., 1998). This has led to the use of anti-epileptic drugs similar to other unprovoked epilepsies for along which cause untoward effects, stigma of epilepsy, and the cost of AEDs. Taking into consideration these facts and the knowledge regarding patho-mechanism of generation of these type of reflex
seizures, use of intermittent prophylaxis with clobazam has been proposed (Satishchandra et al., 1998; Dhanaraj and Jayavelu (2003); Meghana et al., 2012). This study tried to address the feasibility, efficacy and tolerability of the use of intermittent prophylaxis with oral clobazam using prospective cohort design in patients with HWE. This study included a large cohort with well-defined inclusion criteria, divided into two groups—–group A with pure hot water epilepsy (198 patients; 65.2%); and group B (62 patients; 20.4%) patients with HWE and non-reflex spontaneous seizures. But, one should be careful in interpreting the result of this study because of lack of placebo controlled group and absence of pre-intervention baseline data in both the subgroups. The demographic and clinical characteristics between these groups were identical. Being an open label long term follow up study, this is an important prerequisite. Nearly, 60% of the patients had more than 1-year follow-up ranging from 3 to 57 months, so as to give sufficient period to assess the role of intermittent clobazam. Untoward effects noticed with intermittent prophylaxis were very mild and reported only in 21 patients. There were in the form of excessive drowsiness, minimal weight gain, poor concentration etc. which is seen in less than 5% of patients and did not warrant discontinuity of drugs. In addition, it avoids the use of anticonvulsants and hence minimizes stigma attached to it. However, the latter point has not been evaluated in this cohort systematically. This prospective long-term study has confirmed the role of intermittent prophylaxis with oral clobazam for the management of HWE and establish this as the standard method of treatment. This needs to be administered only on the days of head bath and thus restricting the use of standard AEDS only for those with HWE plus non-reflex seizures group. Additional AEDs are required only if the patient develops non-reflex seizure or the patient shows poor response to clobazam prophylaxis. This will reduce both ‘pill and cost burden’ among the patients. The duration of treatment in pure HWE with clobazam prophylaxis and the steps of terminating the therapy requires further longitudinal study of this cohort.
References Allen, I.M., 1945. Observations on cases of reflex epilepsy. N Z. Med. 44, 135—142. Bebek, N., Gurses, C., Gokyigit, A., Baykan, B., Ozkara, C., Dervent, A., 2001. Hot water epilepsy: clinical and electrophysiologic findings based on 21 cases. Epilepsia 42, 1180—1184. Commission on Classification and Terminology of the International ¨artinez-lage, League Against EpilepsyRoger, J., Dreifuss, F.E., Y M., Munari, C., Porter, R.J., 1989. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30, 389—399. Dhanaraj, M., Jayavelu, A., 2003. Prophylactic use of clobazam in hot water epilepsy. J. Assoc. Physicians India 51, 43—44. Engel Jr., J., 2001. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 42, 706—803. Keipert, J.A., 1969. Epilepsy precipitated by bathing: waterimmersion epilepsy. Aust. Paediatr. J. 5, 244—247. Kurata, S., 1979. Epilepsy precipitated by bathing—–a follow up study. Brain Dev. 11, 400—405.
Please cite this article in press as: Satishchandra, P., et al., Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: A prospective study. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.04.016
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Clobazam in hot water epilepsy Lenoir, P., Ramet, J., De, M.L., D’Allest, A.M., Desprechins, B., Loeb, H., 1989. Bathing-induced seizures. Pediatr. Neurol. 5, 124—125. Mani, K.S., Gopalakrishnan, P.N., Vyas, J.N., Pillai, M.S., 1968. Hotwater epilepsy—–a peculiar type of reflex epilepsy. A preliminary report. Neurol. India 16, 107—110. Mani, K.S., Mani, A.J., Ramesh, C.K., 1974. Hot-water epilepsy—a peculiar type of reflex epilepsy: clinical and EEG features in 108 cases. Trans. Am. Neurol. Assoc. 99, 224—226. Meghana, A., Sinha, S., Sathyaprabha, T.N., Subbakrishna, D.K., Satishchandra, P., 2012. Hot water epilepsy clinical profile and treatment—a prospective study. Epilepsy Res. 102, 160—166. Mofenson, H.C., Weymuller, C.A., Greensher, J., 1965. Epilepsy due to water immersion: an unusual case of reflex sensory epilepsy. JAMA 191, 600—601. Morimoto, T., Hayakawa, T., Sugie, H., Awaya, Y., Fukuyama, Y., 1985. Epileptic seizures precipitated by constant light, movement in daily life, and hot water immersion. Epilepsia 26, 237—242. Parsonage, M.J., Moran, J.H., Exley, K.A., 1976. So Called Water Immersion Epilepsy. Thieme, Stuttgart, pp. 50—60. Satishchandra, P., 2003. Hot-water epilepsy. Epilepsia 44 (Suppl. 1), 29—32.
5 Satishchandra, P., Shivaramakrishana, A., Kaliaperumal, V.G., Schoenberg, B.S., 1988. Hot-water epilepsy: a variant of reflex epilepsy in southern India. Epilepsia 29, 52—56. Satishchandra, P., Ullal, G.R., Shankar, S.K., 1998. Hot water epilepsy. Adv. Neurol. 75, 283—293. Shaw, N.J., Livingston, J.H., Minns, R.A., Clarke, M., 1988. Epilepsy precipitated by bathing. Dev. Med. Child Neurol. 30, 108—111. Stensman, R., Ursing, B., 1971. Epilepsy precipitated by hot water immersion. Neurology 21, 559—562. Subrahmanyam, H.S., 1972. Hot water epilepsy. Neurol. India 329 (20), 241—243. Szymonowicz, W., Meloff, K.L., 1978. Hot water epilepsy. Can. J. Neurol. Sci. 5, 247—251. Ullal, G.R., Satishchandra, P., Kalladka, D., Rajashekar, K., Archana, K., Mahadevan, A., Shankar, S.K., 2006. Kindling & mossy fibre sprouting in the rat hippocampus following hot water induced hyperthermic seizures. Indian J. Med. Res. 124, 331—342. Ullal, G.R., Satishchandra, P., Shankar, S.K., 1996. Hyperthermic seizures: an animal model for hot-water epilepsy. Seizure 5, 221—228. Wolf, P., 2011. Acute drug administration in epilepsy. CNS Neurosci. Ther. 17, 442—448.
Please cite this article in press as: Satishchandra, P., et al., Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: A prospective study. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.04.016
ARTICLE IN PRESS
EPIRES-5158; No. of Pages 5 Epilepsy Research (2014) xxx, xxx—xxx
journal homepage: www.elsevier.com/locate/epilepsyres
Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: A prospective study P. Satishchandra a, S. Dilipkumar a, D.K. Subbakrishna b, S. Sinha a,∗ a
Department of Neurology, National Institute of Mental Health and NeuroSciences [NIMHANS], Bangalore, India b Department of Biostatistics, National Institute of Mental Health and NeuroSciences [NIMHANS], Bangalore, India Received 23 December 2013; received in revised form 19 March 2014; accepted 27 April 2014
KEYWORDS AEDs; Clobazam prophylaxis; Hot water epilepsy; Non-reflex seizure
Summary Purpose: To evaluate the role of intermittent prophylaxis with clobazam in the management of HWE in a long-term prospective study. Material and methods: Two hundred and sixty patients [M:F — 194:66] with HWE were recruited. Patients were divided into: (a) ‘HWE alone’ (n = 198) — received intermittent clobazam prophylaxis, 1—1½ h prior to hot water head bath (group A); (b) 62 patients (20.4%) with ‘HWE with spontaneous seizures were treated with continuous AEDs along with intermittent clobazam therapy (group B). Results: Patients (n = 198) in group A was followed for mean of 17.6 ± 10.6 months (range: 3—57). One hundred and forty seven patients (74.2%) had excellent response with complete seizure freedom with clobazam therapy while 12 (6.1%) had >75% reduction in seizure frequency. Remaining 39 (19.7%) required additional standard AED along with clobazam and 18 patients among them developed spontaneous/unprovoked seizure at follow up of 6.7 ± 4.1 months. Forty five patients in group B were seizure free while on continuous AEDs. Conclusions: Intermittent clobazam prophylaxis prior to head water bath might be a preferred mode of treatment of pure HWE. Additional AEDs are required if they have associated non-reflex unprovoked seizure. © 2014 Elsevier B.V. All rights reserved.
∗
Corresponding author. Tel.: +91 80 26995150; fax: +91 80 26564830. E-mail addresses: [email protected] (P. Satishchandra), [email protected] (S. Dilipkumar), [email protected] (D.K. Subbakrishna), sanjib [email protected] (S. Sinha). http://dx.doi.org/10.1016/j.eplepsyres.2014.04.016 0920-1211/© 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: Satishchandra, P., et al., Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: A prospective study. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.04.016
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2
P. Satishchandra et al.
Introduction
Material and methods
Hot water epilepsy (HWE) a type of reflex epilepsy that is precipitated by a bath or shower with hot water (Mani et al., 1968, 1974; Subrahmanyam, 1972; Satishchandra et al., 1988, 1998, 2003; Szymonowicz and Meloff, 1978). It is also variably known as water-immersion epilepsy or bathing epilepsy (Mofenson et al., 1965; Shaw et al., 1988; Lenoir et al., 1989). Though HWE was first described in 1945 from New Zealand (Allen, 1945), there have been case reports from all round the world: Australia (Keipert, 1969), the United States (Stensman and Ursing, 1971), Canada (Szymonowicz and Meloff, 1978), the United Kingdom (Parsonage et al., 1976), Japan (Kurata, 1979; Morimoto et al., 1985) and Turkey (Bebek et al., 2001). However, it is from southern India, that a large number of cases of HWE have been reported (Mani et al., 1968, 1974; Satishchandra et al., 1988; Satishchandra, 2003), possibly emphasizing the role of environmental and genetic influence. The concept of ‘hyperthermic kindling’ with aberrant thermoregulation in the genetically susceptible population with possible coexisting environmental influence could be the probable mechanism responsible for this epilepsy [Satishchandra et al., 1998; Satishchandra, 2003; Ullal et al., 1996, 2006]. It is reported that seizures can be controlled with optimum intervention, both lifestyle and pharmacological but if left untreated might progress to spontaneous seizure types with variable outcome (Satishchandra et al., 1998). About 17—25% of these HWE patients develop spontaneous, non-reflex seizures in their natural course (Satishchandra et al., 1998). These patients were managed with use of long term anti-epileptic medications similar to other epilepsies. Being a reflex epilepsy, avoidance of reflex factors such as head bath or use of luke warm water was practiced previously. However latter may not be suitable as number of these subjects has compulsive desire and develop self induced reflex seizures during the later part of their natural course. With the change in the understanding of its patho-mechanism as ‘hyperthermic seizure’ akin to febrile seizures, use of intermittent prophylaxis seems to be the most appropriate method of treatment. The exact etiopathogenesis of this type of epilepsy is not clear but several factors including genetic factors, environmental factors and habit of taking bath with high temperature water has been postulated as probable reasons (Satishchandra, 2003). Intermittent clobazam therapy has been used in the management of febrile seizures (Wolf, 2011). We have observed that it could be used as an effective prophylaxis in HWE cases if administered 1.5 h prior to hot water head bath (Satishchandra et al., 1998). This was further confirmed by Dhanaraj and Jayavelu (2003) from Chennai and by Meghana et al. (2012) from this center. However its role has not been evaluated in larger number of patients over a long term period to further ascertain its efficacy and tolerability. This study evaluated the role of intermittent prophylaxis with clobazam in the management of HWE through a long-term prospective basis to evaluate its efficacy and tolerability.
This prospective hospital based study was conducted at a university teaching hospital, a major tertiary care referral center for neuro-psychiatric disorders in south India. Two hundred and sixty patients (M:F = 194:66; age at evaluation: 18.6 ± 10.1 years; age at onset of HWE: 13.9 ± 8.1 years) with a diagnosis of HWE were recruited from the neurological services after obtaining written informed consent. The study was approved by the institute ethics committee (IEC). The diagnosis of HWE was based on proposed criteria by Commission of the International League Against Epilepsy (Commission on Classification and Terminology of the International League Against Epilepsy, 1989; Engel, 2001). There was no placebo controlled subgroup. This study group included those patients who had pure reflex epilepsy — ‘HWE alone’ and also those who had spontaneous non-reflex seizure along with HWE — ‘HWE with spontaneous seizure’. The recruited patients were evaluated in detail with regard to its demography, antecedent birth history, febrile seizures and data related to detailed history of epilepsy including bathing habits, precipitating factor—–hot water bath, triggering areas, seizure semiology from eye witness, age at onset of seizures, frequency of seizures, history of epilepsy/HWE in the family, previous history of febrile convulsions/birth related injuries, gross development; personal/family medical histories were recorded. The details of scalp EEG and neuroimaging observations carried out as per standard procedures were noted. Patients with ‘HWE alone’ were prescribed intermittent clobazam therapy to be used prophylactically 1—1½ h before hot water head bath and formed group A (n = 198; M:F — 2.8: 1; age at evaluation: 18.0 ± 10 years; age at onset: 13.6 ± 8.7 years). Patients of ‘HWE with spontaneous seizures’ constituted group B (n = 62; M:F — 3.4:1; age at evaluation: 19.0 ± 10.4 years; age at onset: 14 ± 8.8 years) and received standard AEDs in addition to intermittent clobazam (5 mg). All these patients were advised to avoid hot water head bath, maintain a seizure dairy and follow periodically once in 2—3 months. During follow up, according to a pre-designed protocol, patients were enquired about seizure control, drug compliance, onset of non-reflex epilepsy, adverse effects of clobazam and other AEDs used in the study. The dosages of the AEDs were adjusted based on standard clinical judgment.
Statistics Demographic characteristics between these groups were compared using standard ‘t’ tests and chisquare. Intentionto-treat analysis was done to note the efficacy of clobazam.
Results Demography and phenotype Hot water epilepsy (HWE) is commonly reported in men as compared to women and in this cohort the ratio of men:women was 2.94:1. The mean age of the patients was
Please cite this article in press as: Satishchandra, P., et al., Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: A prospective study. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.04.016
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Clobazam in hot water epilepsy Table 1
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Demographic and clinical data of patient groups of HWE.
Parameters
Group An = 198
Group Bn = 62
Total n = 260
Male:Female Mean age at inclusion (years) Age at onset of HWE (years) Duration of HWE (months) Type of seizures HWE CPS CPS with generalization GTCS EEG (n = 240) Normal record Abnormal record Normal CT scan (brain)
2.8:1 18.0 ± 10 13.6 ± 8.7 52 ± 66
3.4:1 19 ± 10.4 14 ± 8.8 60 ± 60.7
2.94:1 18.6 ± 10.1 13.9 ± 8.1 56.3 ± 64.9
67 (33.8%) 114 (57.6%) 17 (8.6%)
26 (41.9%) 33 (53.2%) 03 (4.9%)
93 (35.7%) 147 (56.5%) 20 (07.7%)
148 (81.7%) 33/148 (18.3%) 171 (76.3%)
47 (79.7%) 12/47 (20.3%) 53 (23.7%)
195 (75%) 45/240 (23.07) 224 (all)
18.6 ± 10.1 years. The age at onset of HWE was 13.9 ± 8.1 years. The duration of HWE at recruitment ranged from 1 month to 284 months. Majority of the patients belonged to districts of Bangalore: 144; Mandya: 57; Tumkur: 24; Mysore: 21; Hassan: 4; other districts of Karnataka: 7; and other states of India: 3. Presence of family history was noted in 29 (10.9%) patients. All the patients had the habit of having hot water head bath with a frequency ranging from once in 2—7 days. All the attacks occurred while pouring the hot water on the head with a mug as is usually practiced in this part of the world except one patient wherein the seizure had occurred while taking shower bath with hot water. Family history of HWE was present in Table 1 depicts the phenotypic and demographic features of the two subgroups of patients with HWE. Among 198 cases of ‘HWE alone’, 50 had seizures while pouring even luke warm water and three patients had seizure while washing face with hot water. One hundred subjects had 1:1 episodes viz. seizures occur whenever they have hot water bath. In those with ‘HWE with spontaneous seizure’ subgroup (n = 62), 20 patients had 1:1 episode of seizures with hot water bath. Subjects had complex partial seizure (CPS) with or without secondary generalization. Voluntary act of taking bath stopped when seizure began, and similarly when the relatives were pouring hot water on head, they could recognize the onset and stopped further pouring of hot water. Majority of the patients got an attack wherein they would sit flexing their body and closing ears with both the hands with aura of fear, for few seconds followed by the seizure. They had varied manifestations which included loss of orientation and awareness, staring look, behavioral arrest, irrelevant speech, déjà vu, among feeling like fainting etc., lasting for few seconds to minutes. By and large, except for a tendency to look around aimlessly, rarely wandering, praying there was no other motor phenomena. Post ictal headache and sleep were present. The phenomenon of ‘‘self-induction of HWE’’ was seen about a third of patients. They had an aura of pleasure during hot water both and would continue to pour the hot water on head until they had seizure. About 8.6% of patients had history of febrile convulsion in their early childhood. Cranial CT scan, carried out in 224 patients, was normal in all.
Electroencephalogram (n = 240) Interictal scalp EEG was normal in 195 patients [81.25%]. The abnormalities were: (a) focal abnormality in the form of focal spikes or sharp waves with slow waves—–30 [12.5%]; predominantly from the fronto-temporal regions and (b) generalized seizure discharges—–15 [6.25%] patients. EEG records of 22 patients were unavailable for review.
Follow up analysis (Table 2) Patients under groups A and B were followed up for a mean period of 17.4 ± 10.6 months ranging from 3 to 57 months. Patients with ‘HWE only’ i.e. Group A (n = 198) were on intermittent prophylaxis with oral clobazam 10 mg, on the days of head bath, about 1—1½ h before the bath. Group B patients with ‘HWE and spontaneous seizures’ i.e. group B (n = 62) were on intermittent clobazam prophylaxis along with a regular AED viz. phenytoin or carbamazepine for non-reflex epilepsy as per standard practice. These patients were asked to maintain the diary regarding head bath, seizures and the treatment details and were followed once in 2—3 months with questionnaire-based protocol to assess the efficacy and tolerability. The time interval from the onset of reflex HWE to the onset of non-reflex epilepsy is quite significant in view of intermittent clobazam prophylaxis. In group A, the number of patients who showed poor therapeutic response to clobazam and developed non-reflex seizure were 18/198 (9.1%). The mean time interval for developing non-reflex (unprovoked) seizure from the onset of reflex epilepsy in these 18 patients of group A despite clobazam therapy was 6.7 ± 4.1 months with range from 3 to 19 months. In contrast, in group B patients who presented with reflex and non-reflex seizure, the mean time interval of the same was 36.6 ± 45.5 months. This finding provides strong evidence that patients who did not show good response to intermittent clobazam prophylaxis have high susceptibility for developing non-reflex seizure. The observations after a follow up of 17.6 ± 10.5 months were: (a) excellent response—–147 patients (74.2%), (b)
Please cite this article in press as: Satishchandra, P., et al., Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: A prospective study. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.04.016
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P. Satishchandra et al. Table 2
Details therapeutic response in groups A and B.
Group A (n = 198) Follow up (months) Excellent response (seizure free) Good response (>75% response) Poor response Adverse events Group B (n = 62) Follow up (months) Seizure free Adverse events
17.6 ± 10.6 (3—57) 147 (74.2%) 12 (6.1%) 39 (19.7%)a 21
17.4 ± 10.5 (3—57) 45 (72.6%) 10
a
18 patients with poor response also developed unprovoked spontaneous seizure
good response: improvement but not seizure free (moderate response) and did not require standard anti-epileptic drugs: 12 (6.1%), and (c) poor therapeutic response: 18 patients (9.1%) who also required the use of continuous AED for seizure control. Group B (62 patients) who had HWE plus seizures also had similar follow up. They received standard AED for unprovoked seizures in addition to the intermittent clobazam prophylaxis. Seizure freedom was achieved in about 72% of the patients in group B. Some of the adverse drug reactions in 21 patients with clobazam therapy included excessive drowsiness, weight gain, poor concentration and decreasing memory. Rest of the patients did not report any adverse effects and continued drug for more than 3 years. Ten patients on continuous AEDs did report minor side effects of the AEDs used.
Discussion Hot water epilepsy (HWE) a type of reflex seizure precipitated by hot water head bath, classified under somatosensory reflex seizure in the proposed ILAE classification. Animal experiments have proven this to be ‘hyperthermic’ seizure with possible kindling. Further, human studies have confirmed this to be ‘hyperthermic seizure’ possibly akin to febrile seizures (Satishchandra et al., 1998, 2003; Ullal et al., 1996, 2006). However, only 8.6% of this cohort had febrile seizures. Febrile seizures are often treated with intermittent clobazam prophylaxis (Wolf, 2011). Treatment for hot water epilepsy include avoidance of reflex precipitating factors. They have instead used luke warm water for head bath. Some of the patients had seizures even with luke warm water. Many patients in this cohort had ‘‘self-induction of hot water epilepsy’’ where in patients have a compulsive desire to pour hot water till they get the seizure. Hence, avoidance of reflex factor may not be the correct answer. About 20—25% of patients with HWE tend to develop non-reflex seizures (Satishchandra et al., 1998). This has led to the use of anti-epileptic drugs similar to other unprovoked epilepsies for along which cause untoward effects, stigma of epilepsy, and the cost of AEDs. Taking into consideration these facts and the knowledge regarding patho-mechanism of generation of these type of reflex
seizures, use of intermittent prophylaxis with clobazam has been proposed (Satishchandra et al., 1998; Dhanaraj and Jayavelu (2003); Meghana et al., 2012). This study tried to address the feasibility, efficacy and tolerability of the use of intermittent prophylaxis with oral clobazam using prospective cohort design in patients with HWE. This study included a large cohort with well-defined inclusion criteria, divided into two groups—–group A with pure hot water epilepsy (198 patients; 65.2%); and group B (62 patients; 20.4%) patients with HWE and non-reflex spontaneous seizures. But, one should be careful in interpreting the result of this study because of lack of placebo controlled group and absence of pre-intervention baseline data in both the subgroups. The demographic and clinical characteristics between these groups were identical. Being an open label long term follow up study, this is an important prerequisite. Nearly, 60% of the patients had more than 1-year follow-up ranging from 3 to 57 months, so as to give sufficient period to assess the role of intermittent clobazam. Untoward effects noticed with intermittent prophylaxis were very mild and reported only in 21 patients. There were in the form of excessive drowsiness, minimal weight gain, poor concentration etc. which is seen in less than 5% of patients and did not warrant discontinuity of drugs. In addition, it avoids the use of anticonvulsants and hence minimizes stigma attached to it. However, the latter point has not been evaluated in this cohort systematically. This prospective long-term study has confirmed the role of intermittent prophylaxis with oral clobazam for the management of HWE and establish this as the standard method of treatment. This needs to be administered only on the days of head bath and thus restricting the use of standard AEDS only for those with HWE plus non-reflex seizures group. Additional AEDs are required only if the patient develops non-reflex seizure or the patient shows poor response to clobazam prophylaxis. This will reduce both ‘pill and cost burden’ among the patients. The duration of treatment in pure HWE with clobazam prophylaxis and the steps of terminating the therapy requires further longitudinal study of this cohort.
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