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Epilepsy of infancy with migrating focal seizures: Six patients treated with bromide
Seizure 23 (2014) 899–902
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Short communication
Epilepsy of infancy with migrating focal seizures: Six patients treated with bromide Roberto Caraballo a,*, Marı´a Constanza Pasteris a, Pablo Sebastian Fortini a, Ernesto Portuondo b a b
Neurology Department, Pediatric Hospital ‘‘Prof. Dr. Juan P. Garrahan’’, Buenos Aires, Argentina Hospital Pedia´trico Universitario de Centro Habana, La Habana, Cuba
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 May 2014 Received in revised form 25 June 2014 Accepted 27 June 2014
Purpose: We present six patients with epilepsy of infancy with migrating focal seizures (EIMFS) and provide a comprehensive evaluation of potassium bromide therapy. Method: Between February 1, 2007 and July 31, 2012, six patients who met the diagnostic criteria of EIMFS were treated with potassium bromide. Potassium bromide was added to other antiepileptic drugs (AEDs) in doses ranging from 30 to 80 mg/kg/day. Plasma bromide concentration was monitored. A therapeutic bromide concentration between 75 and 125 mg/dL was considered to be ideal. Results: Four of six children responded well to bromide. One of these patients became seizure free, but remained severely mentally impaired. Two boys, currently 4 and 6 years of age, respectively, have monthly seizures as well as axial hypotonia and severe language impairment. The fourth child responded well to bromide, having only weekly seizures and moderate psychomotor retardation. The patient who became seizure free improved visual contact and head control. In the other three patients with good control, the seizures became focal without secondary generalization and status epilepticus and hospital admission was not required. The remaining two patients did not respond well to bromide. Adverse effects were seen in three cases: vomiting in one, drowsiness in another, and acneiform eruption in the face in the remaining patient. Adverse effects resolved with dose reduction. Conclusion: Early treatment with bromides should be considered in EIMFS to control the seizures and status epilepticus and to avoid progressive cognitive impairment. Potassium bromide is an old AED. Plasma concentration monitoring should be considered. ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Potassium bromide Epileptic encephalopathy Focal seizures Infants Multifocal seizures Refractory epilepsy
1. Introduction Epilepsy of infancy with migrating focal seizures (EIMFS) is a well-defined and rare epileptic syndrome characterized by an onset of multifocal seizures before 6 months of age and a typical ictal electroencephalography (EEG) pattern consisting of seizures that arise independently and sequentially from both hemispheres.1 The seizures are refractory to antiepileptic drugs (AEDs) and cause subsequent severe mental retardation.1,2 Several reports have focused on seizure control or reduction with the use of different AEDs, such as levetiracetam, adrenocorticotropic hormone (ACTH), benzodiazepines, stiripentol, and
rufinamide, and potassium bromide alone or in combinations with variable results.3–5 Triple bromides have also been used in the treatment of refractory epilepsy, but in the literature we did not find any important differences between these two forms of bromides in terms of efficacy and tolerability. Recently, EIMFS has been described related to different genes in sporadic and familial cases.6 These findings suggest a genetic heterogeneity. Here, we present six patients with EIMFS and provide a comprehensive evaluation of potassium bromide therapy.
2. Methods * Corresponding author at: Neurology Department, Hospital de Pediatrı´a ‘‘Prof. Dr. Juan P. Garrahan’’, Combate de los Pozos 1881, CP 1245, Buenos Aires, Argentina. Tel.: +54 11 49436116; fax: +54 11 49436116. E-mail address: [email protected] (R. Caraballo).
Between February 1, 2007, and July 31, 2012, six patients who met the diagnostic criteria of EIMFS were treated with potassium bromide. We used potassium bromide as this was the formula we found in Argentina. The charts of all patients were analyzed
http://dx.doi.org/10.1016/j.seizure.2014.06.016 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
900
R. Caraballo et al. / Seizure 23 (2014) 899–902
considering response to therapy – especially to potassium bromide – and final outcome. All patients underwent brain computed tomography (CT) scan and magnetic resonance imaging (MRI) as well as EEG recordings, neurometabolic tests, and karyotyping. No genetic markers associated with EIMFS were investigated in any of the patients. All patients had received more than one of the conventional and new AEDs, before bromide was introduced: Carbamazepine was used in six patients, valproic acid in five, phenobarbital in four, diphenylhydantoin in four, clobazam in four, clonazepam in three, levetiracetam in four, topiramate in four, zonisamide in three, lamotrigine in three, ACTH in three, the ketogenic diet in one, and rufinamide in one. Bromide was added to levetiracetam and topiramate in two patients, to zonisamide and clonazepam in one, to valproic acid and clobazam in one, to levetiracetam and rufinamide in one, and to lamotrigine and clobazam in the remaining one. No AEDs were withdrawn after the introduction of bromide. The average dose of bromide was 65 mg/kg/day (range, 30–80 mg/kg/day). The starting dose was 10 mg/kg/day divided into two or three doses. No protocol was used to adjust the doses. Due to its exceptionally long half-life, plasma bromide concentration was monitored to prevent toxicity. The dose was titrated over one to two months and bromide levels were monitored every 3–4 months. A therapeutic bromide concentration of between 75 and 125 mg/dL was considered to be ideal. The effectiveness of the maintenance dose was evaluated based on the quality of life of the patients and their families. The parents of one patient did not accept to increase the dose of bromides.
3. Results 3.1. General characteristics A total of six patients (four boys and two girls) were identified between 2005 and 2012 at the Garrahan Hospital of Buenos Aires. In all patients, the neurological examination showed hypotonia after the seizures became refractory, but there were no other neurological abnormalities. The initial head circumferences of the children were normal for age. At onset, brain CT scans and MRIs were normal in all patients. Subsequent repetitive MRIs showed mild ventricular enlargement in one, and a moderate degree of the same finding in five. In one, the MRIs showed unilateral mesial temporal sclerosis. Electroretinogram and visual and auditory evoked potentials were normal in all cases, but somatosensory evoked potentials, performed before bromide initiation, showed increased amplitude and prolonged latency in the cortical component in two patients. No etiologies were found. 3.2. Electroclinical findings The mean and median ages at the time of the first seizure were 45 days and 30 days, respectively (range, 15–60 days). Three electroclinical patterns were recognized according to seizure frequency, recurrence, and topography: (1) Alternating simple focal motor seizures at onset with an ictal EEG pattern that was characterized by recurrence of rhythmic focal spikes or rhythmic
Fig. 1. A 2-month-20-day-old girl with seizure onset with right posterior temporal theta rhythms. B and C: 68 and 94 s after onset, respectively, the ictal EEG recording shows theta rhythms propagating to the anterior regions of the same hemisphere. D: Two minutes and 16 s after onset, rhythmic theta activity appears in the left hemisphere.
R. Caraballo et al. / Seizure 23 (2014) 899–902
sharp activity in the theta to alpha frequency range involving the rolandic region of the contralateral hemisphere in three cases; (2) focal complex seizures and progressive appearance of polymorphic delta–theta activity of variable amplitude in one temporo-occipital region recurring independently in one case. These seizures, which lasted from one to several minutes, tended to recur independently in both hemispheres from onset, frequently evolving into longlasting clusters. In the absence of an EEG recording, it was impossible to recognize the hemisphere involved, as the clinical symptoms were not lateralizing; and (3) focal complex seizures with motor manifestations with an ictal EEG showing flattening or a small discharge of fast or theta activity in one fronto-temporal region followed by unilateral fast polyspikes in alternating clusters in both hemispheres in two cases (Figs. 1A–D and 2A–D). The seizures were followed by prolonged post-ictal hemispheric slowwave activity interposed by ample isolated spikes that became bilateral when the alternating seizures in clusters involved both hemispheres. 3.3. Treatment and follow-up The seizures became very frequent within a month after onset, occurring several times a day in long-lasting clusters or as a simple partial motor status. Concomitantly, the children became floppy and somnolent with feeding difficulties. All patients were refractory to AEDs, which was why bromide was added. Three patients needed general anesthetic treatment on one or more
901
occasions. All patients had progressive neurological deterioration with generalized hypotonia, loss of visual contact and grasping, and loss of other motor and social skills. All developed microcephaly. One patient died at 18 months of age due to status epilepticus. Mean age at bromide introduction was 7 months (range, 6–12 months) and mean interval between seizure onset and bromide introduction was 7.5 months (range, 5–11 months). On bromide therapy, four of six children evolved well in terms of seizure outcome. One of these patients, a girl, became seizure free at 1 year of age, but remained severely mentally impaired. Two boys, currently 4 and 6 years of age, respectively, have monthly fronto-temporal seizures while awake and during sleep with axial hypotonia as well as severe language impairment. The fourth patient, a 2.5-year-old boy, responded relatively well to bromide having weekly complex focal seizures without generalized motor seizures and moderate psycho-motor retardation. Reduced seizure frequency was first observed between 1 and 2.5 months after starting bromide therapy. The patient who became seizure free patient improved visual contact and head control. In the other three patients with good control, the seizures became focal without secondary generalization and status epilepticus. Hospital admission was not required. The remaining two patients did not respond well to bromide. No correlation between response and the clinical-EEG pattern was found, however, the series was too small to draw any definitive conclusions. Additionally, in this retrospective study the three electroclinical patterns described corresponded to the
Fig. 2. The same patient and the same ictal event as in Fig. 1A, 2 min and 35 s after onset shows rhythmic theta activity in the left hemisphere and brief rhythmic delta activity with interposed spikes in right frontotemporal region. B and C: Three minutes and 35 s and 5 min and 55 s after onset, respectively, the ictal EEG recording shows irregular, rhythmic theta activity in the left hemisphere. D: Seven minutes and 3 s after seizure onset, rhythmic theta activity appears in the right hemisphere.
R. Caraballo et al. / Seizure 23 (2014) 899–902
902
Table 1 The efficacy and tolerability of bromide treatment in six patients with EIMFS. Patients
Seizure frequency before bromide treatment
Dose (mg/kg/day)
Range (mg/dL)
Efficacy
Adverse effects
Period of bromide treatment years
Time of follow-up years
At the last control
1 2 3
Daily Daily Daily
30 80 65
71 123 114
– Drowsiness Vomiting
4 0.5 5
5.5 1 6
4 5 6
Daily Daily Daily
70 60 55
115 95 89
Seizure free No response Monthly seizures No response Weekly seizures Monthly seizures
Skin rash – –
0.5 1 2.5
1 1.5 3.5
Severe mental retardation Severe mental retardation Hypotonia and severe language impairment Severe mental retardation Moderate mental retardation Hypotonia and severe language impairment
stormy phase, and more detailed electroclinical information is lacking. In the patient who became seizure free, the interictal sleep EEG recording showed bilateral independent spikes. Adverse effects were seen in three cases; vomiting in one, drowsiness in another, and acneiform eruption in the face in the remaining patient. They were resolved with dose reduction. Table 1 shows the efficacy and tolerability of bromide treatment in our series of patients with EIMFS. After a mean follow-up of 3.5 years (range, 1–6 years), all four children with a good response regarding neurological examination and seizure frequency remained unchanged. 4. Discussion We describe six patients who presented with EIMFS refractory to AEDs before 5 months of age and who were treated with potassium bromide. Four of six patients responded well to the drug. Most patients with EIMFS are refractory to antiepileptic drugs, but some have shown a good evolution or a near satisfactory response to treatment.1,2 The AEDs used alone or in combination that may achieve seizure control or reduction are potassium bromide, levetiracetam, ACTH, stiripentol, clonazepam, and rufinamide.1–5 Potassium bromide is a typical ionic salt which is fully dissociated and near pH 7 in aqueous solution. The bromide ion has a relatively long half-life of 12 days in the blood,7,8 making bromide salts difficult to adjust and dose. Bromide has strong interactions with chloride in the body, the normal body uptake and excretion of which strongly influences bromide excretion.8 Therefore, excretion of bromide may be accelerated by administration of chloride in case of acute intoxication. As chloride levels increase linearly to bromide serum concentration, an indirect determination of bromide levels may be obtained by measuring chloride.8 The therapeutic index (ratio of effectiveness to toxicity) of bromide is low and thus even therapeutic doses (3–5 g per day, taking 6–8 weeks to reach stable levels) may lead to intoxication, often indistinguishable from ‘expected’ adverse effects.7,8 Nevertheless, bromide is still used in refractory patients in tertiary institutions specialized in epilepsy.8 Adverse effects involve the central nervous system, skin, and gastrointestinal system7,8 and most commonly are drowsiness and acneiform eruption.8 The drug might potentiate the effect of g-aminobutyric acid by hyperpolarizing the postsynaptic membrane.8 There is little experience with potassium bromide in the treatment of patients with EIMFS.1,9–11 Reported patients showed sustained seizure control and neurological improvement,9,11 however, in one patient with a gradual decrease in seizure frequency bromide was discontinued due to adverse effects.10 Potassium bromide has been used in patients with severe epilepsy and generalized tonic–clonic seizures and Dravet
syndrome with good results.12,13 Considering that different types of seizures in Dravet syndrome responded well to bromide,12 the drug may be tried in the treatment of refractory epilepsy, mainly epileptic encephalopathy. 5. Conclusions Potassium bromide is a good option in patients with refractory seizures. Monitoring of plasma concentration is important to avoid toxicity. A better recognition of EIMFS will allow starting adequate and aggressive treatment to improve prognosis. Conflict of interest statement We disclose we have no financial and personal relationships with other people or organizations that could inappropriately influence this work. References 1. Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia 1995;36: 1017–24. 2. Caraballo R, Fontana E, Darra F, Cassar L, Negrini F, Fiorini E, et al. Bernardina migrating focal seizures in infancy: analysis of the electroclinical pattern in 17 patients. J Child Neurol 2008;23(5):497–506. 3. Djuric M, Kravljanac R, Kovacevik G, Martic J. The efficacy of bromides, stiripentol and levetiracetam in two patients with malignant migrating partial seizures in infancy. Epileptic Disord 2011;13:22–6. 4. Vendrame M, Podori A, Loddenkemper T, Kluger G, Coppola G, Kothare V. Treatment of malignant migrating partial epilepsy of infancy with rufinamide: report of five cases. Epileptic Disord 2011;13:18–21. 5. Merdariu D, Delanoe C, Mahfoufi N, Bellavoine V, Auvin S. Malignant migrating partial seizures of infancy controlled by stiripentol and clonazepam. Brain Dev 2013;35:177–80. 6. Striano P, Coppola G, Zara F, Nabbout R. Genetic heterogeneity in malignant partial seizures of infancy. Ann Neurol 2014. http://dx.doi.org/10.1002/ ana.24055. 7. Woody RC. Bromide therapy for pediatric seizure disorder intractable to other antiepileptic drugs. J Child Neurol 1990;5(1):65–7. 8. Browne T, Leduc B, Kosta Rokosz M, Bromfield E, Ramsay RE, Toledo J. Trimethadione, paraldehyde, phenacemide, bromides, sulthiame, acetazolamide, and methsuximide. In: Engel J, Pedley T, editors. Epilepsy: a comprehensive textbook. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2008 . p. 1703–19. 9. Okuda K, Yasuhara A, Kamei A, Araki A, Kitamura N, Kobayashi Y. Successful control with bromide of two patients with malignant migrating partial seizures in infancy. Brain Dev 2000;22:56–9. 10. Nabatame S, Saito Y, Sakuma H, Komaki H, Nakagawa E, Sugai K, et al. Bromoderma in a patient with migrating partial seizures in infancy. Epilepsy Res 2010;91:283–8. 11. Unver O, Incecik F, Dundar H, Komur M, Unver A, Okuyaz C. Potassium bromide for treatment of malignant migrating partial seizures in infancy. Pediatr Neurol 2013;49:355–7. 12. Oguni H, Hayashi K, Oguni M, Mukahira A, Uehara T, Fukuyama Y, et al. Treatment of severe myoclonic epilepsy in infancy and it’s borderline variant with bromide. Epilepsia 1994;35:1140–5. 13. Korinthenberg R, Burkart P, Woelfle C, Moenting JS, Ernst JP. Pharmacology, efficacy, and tolerability of potassium bromide in childhood epilepsy. J Child Neurol 2007;22:414–8.
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Short communication
Epilepsy of infancy with migrating focal seizures: Six patients treated with bromide Roberto Caraballo a,*, Marı´a Constanza Pasteris a, Pablo Sebastian Fortini a, Ernesto Portuondo b a b
Neurology Department, Pediatric Hospital ‘‘Prof. Dr. Juan P. Garrahan’’, Buenos Aires, Argentina Hospital Pedia´trico Universitario de Centro Habana, La Habana, Cuba
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 May 2014 Received in revised form 25 June 2014 Accepted 27 June 2014
Purpose: We present six patients with epilepsy of infancy with migrating focal seizures (EIMFS) and provide a comprehensive evaluation of potassium bromide therapy. Method: Between February 1, 2007 and July 31, 2012, six patients who met the diagnostic criteria of EIMFS were treated with potassium bromide. Potassium bromide was added to other antiepileptic drugs (AEDs) in doses ranging from 30 to 80 mg/kg/day. Plasma bromide concentration was monitored. A therapeutic bromide concentration between 75 and 125 mg/dL was considered to be ideal. Results: Four of six children responded well to bromide. One of these patients became seizure free, but remained severely mentally impaired. Two boys, currently 4 and 6 years of age, respectively, have monthly seizures as well as axial hypotonia and severe language impairment. The fourth child responded well to bromide, having only weekly seizures and moderate psychomotor retardation. The patient who became seizure free improved visual contact and head control. In the other three patients with good control, the seizures became focal without secondary generalization and status epilepticus and hospital admission was not required. The remaining two patients did not respond well to bromide. Adverse effects were seen in three cases: vomiting in one, drowsiness in another, and acneiform eruption in the face in the remaining patient. Adverse effects resolved with dose reduction. Conclusion: Early treatment with bromides should be considered in EIMFS to control the seizures and status epilepticus and to avoid progressive cognitive impairment. Potassium bromide is an old AED. Plasma concentration monitoring should be considered. ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Potassium bromide Epileptic encephalopathy Focal seizures Infants Multifocal seizures Refractory epilepsy
1. Introduction Epilepsy of infancy with migrating focal seizures (EIMFS) is a well-defined and rare epileptic syndrome characterized by an onset of multifocal seizures before 6 months of age and a typical ictal electroencephalography (EEG) pattern consisting of seizures that arise independently and sequentially from both hemispheres.1 The seizures are refractory to antiepileptic drugs (AEDs) and cause subsequent severe mental retardation.1,2 Several reports have focused on seizure control or reduction with the use of different AEDs, such as levetiracetam, adrenocorticotropic hormone (ACTH), benzodiazepines, stiripentol, and
rufinamide, and potassium bromide alone or in combinations with variable results.3–5 Triple bromides have also been used in the treatment of refractory epilepsy, but in the literature we did not find any important differences between these two forms of bromides in terms of efficacy and tolerability. Recently, EIMFS has been described related to different genes in sporadic and familial cases.6 These findings suggest a genetic heterogeneity. Here, we present six patients with EIMFS and provide a comprehensive evaluation of potassium bromide therapy.
2. Methods * Corresponding author at: Neurology Department, Hospital de Pediatrı´a ‘‘Prof. Dr. Juan P. Garrahan’’, Combate de los Pozos 1881, CP 1245, Buenos Aires, Argentina. Tel.: +54 11 49436116; fax: +54 11 49436116. E-mail address: [email protected] (R. Caraballo).
Between February 1, 2007, and July 31, 2012, six patients who met the diagnostic criteria of EIMFS were treated with potassium bromide. We used potassium bromide as this was the formula we found in Argentina. The charts of all patients were analyzed
http://dx.doi.org/10.1016/j.seizure.2014.06.016 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
900
R. Caraballo et al. / Seizure 23 (2014) 899–902
considering response to therapy – especially to potassium bromide – and final outcome. All patients underwent brain computed tomography (CT) scan and magnetic resonance imaging (MRI) as well as EEG recordings, neurometabolic tests, and karyotyping. No genetic markers associated with EIMFS were investigated in any of the patients. All patients had received more than one of the conventional and new AEDs, before bromide was introduced: Carbamazepine was used in six patients, valproic acid in five, phenobarbital in four, diphenylhydantoin in four, clobazam in four, clonazepam in three, levetiracetam in four, topiramate in four, zonisamide in three, lamotrigine in three, ACTH in three, the ketogenic diet in one, and rufinamide in one. Bromide was added to levetiracetam and topiramate in two patients, to zonisamide and clonazepam in one, to valproic acid and clobazam in one, to levetiracetam and rufinamide in one, and to lamotrigine and clobazam in the remaining one. No AEDs were withdrawn after the introduction of bromide. The average dose of bromide was 65 mg/kg/day (range, 30–80 mg/kg/day). The starting dose was 10 mg/kg/day divided into two or three doses. No protocol was used to adjust the doses. Due to its exceptionally long half-life, plasma bromide concentration was monitored to prevent toxicity. The dose was titrated over one to two months and bromide levels were monitored every 3–4 months. A therapeutic bromide concentration of between 75 and 125 mg/dL was considered to be ideal. The effectiveness of the maintenance dose was evaluated based on the quality of life of the patients and their families. The parents of one patient did not accept to increase the dose of bromides.
3. Results 3.1. General characteristics A total of six patients (four boys and two girls) were identified between 2005 and 2012 at the Garrahan Hospital of Buenos Aires. In all patients, the neurological examination showed hypotonia after the seizures became refractory, but there were no other neurological abnormalities. The initial head circumferences of the children were normal for age. At onset, brain CT scans and MRIs were normal in all patients. Subsequent repetitive MRIs showed mild ventricular enlargement in one, and a moderate degree of the same finding in five. In one, the MRIs showed unilateral mesial temporal sclerosis. Electroretinogram and visual and auditory evoked potentials were normal in all cases, but somatosensory evoked potentials, performed before bromide initiation, showed increased amplitude and prolonged latency in the cortical component in two patients. No etiologies were found. 3.2. Electroclinical findings The mean and median ages at the time of the first seizure were 45 days and 30 days, respectively (range, 15–60 days). Three electroclinical patterns were recognized according to seizure frequency, recurrence, and topography: (1) Alternating simple focal motor seizures at onset with an ictal EEG pattern that was characterized by recurrence of rhythmic focal spikes or rhythmic
Fig. 1. A 2-month-20-day-old girl with seizure onset with right posterior temporal theta rhythms. B and C: 68 and 94 s after onset, respectively, the ictal EEG recording shows theta rhythms propagating to the anterior regions of the same hemisphere. D: Two minutes and 16 s after onset, rhythmic theta activity appears in the left hemisphere.
R. Caraballo et al. / Seizure 23 (2014) 899–902
sharp activity in the theta to alpha frequency range involving the rolandic region of the contralateral hemisphere in three cases; (2) focal complex seizures and progressive appearance of polymorphic delta–theta activity of variable amplitude in one temporo-occipital region recurring independently in one case. These seizures, which lasted from one to several minutes, tended to recur independently in both hemispheres from onset, frequently evolving into longlasting clusters. In the absence of an EEG recording, it was impossible to recognize the hemisphere involved, as the clinical symptoms were not lateralizing; and (3) focal complex seizures with motor manifestations with an ictal EEG showing flattening or a small discharge of fast or theta activity in one fronto-temporal region followed by unilateral fast polyspikes in alternating clusters in both hemispheres in two cases (Figs. 1A–D and 2A–D). The seizures were followed by prolonged post-ictal hemispheric slowwave activity interposed by ample isolated spikes that became bilateral when the alternating seizures in clusters involved both hemispheres. 3.3. Treatment and follow-up The seizures became very frequent within a month after onset, occurring several times a day in long-lasting clusters or as a simple partial motor status. Concomitantly, the children became floppy and somnolent with feeding difficulties. All patients were refractory to AEDs, which was why bromide was added. Three patients needed general anesthetic treatment on one or more
901
occasions. All patients had progressive neurological deterioration with generalized hypotonia, loss of visual contact and grasping, and loss of other motor and social skills. All developed microcephaly. One patient died at 18 months of age due to status epilepticus. Mean age at bromide introduction was 7 months (range, 6–12 months) and mean interval between seizure onset and bromide introduction was 7.5 months (range, 5–11 months). On bromide therapy, four of six children evolved well in terms of seizure outcome. One of these patients, a girl, became seizure free at 1 year of age, but remained severely mentally impaired. Two boys, currently 4 and 6 years of age, respectively, have monthly fronto-temporal seizures while awake and during sleep with axial hypotonia as well as severe language impairment. The fourth patient, a 2.5-year-old boy, responded relatively well to bromide having weekly complex focal seizures without generalized motor seizures and moderate psycho-motor retardation. Reduced seizure frequency was first observed between 1 and 2.5 months after starting bromide therapy. The patient who became seizure free patient improved visual contact and head control. In the other three patients with good control, the seizures became focal without secondary generalization and status epilepticus. Hospital admission was not required. The remaining two patients did not respond well to bromide. No correlation between response and the clinical-EEG pattern was found, however, the series was too small to draw any definitive conclusions. Additionally, in this retrospective study the three electroclinical patterns described corresponded to the
Fig. 2. The same patient and the same ictal event as in Fig. 1A, 2 min and 35 s after onset shows rhythmic theta activity in the left hemisphere and brief rhythmic delta activity with interposed spikes in right frontotemporal region. B and C: Three minutes and 35 s and 5 min and 55 s after onset, respectively, the ictal EEG recording shows irregular, rhythmic theta activity in the left hemisphere. D: Seven minutes and 3 s after seizure onset, rhythmic theta activity appears in the right hemisphere.
R. Caraballo et al. / Seizure 23 (2014) 899–902
902
Table 1 The efficacy and tolerability of bromide treatment in six patients with EIMFS. Patients
Seizure frequency before bromide treatment
Dose (mg/kg/day)
Range (mg/dL)
Efficacy
Adverse effects
Period of bromide treatment years
Time of follow-up years
At the last control
1 2 3
Daily Daily Daily
30 80 65
71 123 114
– Drowsiness Vomiting
4 0.5 5
5.5 1 6
4 5 6
Daily Daily Daily
70 60 55
115 95 89
Seizure free No response Monthly seizures No response Weekly seizures Monthly seizures
Skin rash – –
0.5 1 2.5
1 1.5 3.5
Severe mental retardation Severe mental retardation Hypotonia and severe language impairment Severe mental retardation Moderate mental retardation Hypotonia and severe language impairment
stormy phase, and more detailed electroclinical information is lacking. In the patient who became seizure free, the interictal sleep EEG recording showed bilateral independent spikes. Adverse effects were seen in three cases; vomiting in one, drowsiness in another, and acneiform eruption in the face in the remaining patient. They were resolved with dose reduction. Table 1 shows the efficacy and tolerability of bromide treatment in our series of patients with EIMFS. After a mean follow-up of 3.5 years (range, 1–6 years), all four children with a good response regarding neurological examination and seizure frequency remained unchanged. 4. Discussion We describe six patients who presented with EIMFS refractory to AEDs before 5 months of age and who were treated with potassium bromide. Four of six patients responded well to the drug. Most patients with EIMFS are refractory to antiepileptic drugs, but some have shown a good evolution or a near satisfactory response to treatment.1,2 The AEDs used alone or in combination that may achieve seizure control or reduction are potassium bromide, levetiracetam, ACTH, stiripentol, clonazepam, and rufinamide.1–5 Potassium bromide is a typical ionic salt which is fully dissociated and near pH 7 in aqueous solution. The bromide ion has a relatively long half-life of 12 days in the blood,7,8 making bromide salts difficult to adjust and dose. Bromide has strong interactions with chloride in the body, the normal body uptake and excretion of which strongly influences bromide excretion.8 Therefore, excretion of bromide may be accelerated by administration of chloride in case of acute intoxication. As chloride levels increase linearly to bromide serum concentration, an indirect determination of bromide levels may be obtained by measuring chloride.8 The therapeutic index (ratio of effectiveness to toxicity) of bromide is low and thus even therapeutic doses (3–5 g per day, taking 6–8 weeks to reach stable levels) may lead to intoxication, often indistinguishable from ‘expected’ adverse effects.7,8 Nevertheless, bromide is still used in refractory patients in tertiary institutions specialized in epilepsy.8 Adverse effects involve the central nervous system, skin, and gastrointestinal system7,8 and most commonly are drowsiness and acneiform eruption.8 The drug might potentiate the effect of g-aminobutyric acid by hyperpolarizing the postsynaptic membrane.8 There is little experience with potassium bromide in the treatment of patients with EIMFS.1,9–11 Reported patients showed sustained seizure control and neurological improvement,9,11 however, in one patient with a gradual decrease in seizure frequency bromide was discontinued due to adverse effects.10 Potassium bromide has been used in patients with severe epilepsy and generalized tonic–clonic seizures and Dravet
syndrome with good results.12,13 Considering that different types of seizures in Dravet syndrome responded well to bromide,12 the drug may be tried in the treatment of refractory epilepsy, mainly epileptic encephalopathy. 5. Conclusions Potassium bromide is a good option in patients with refractory seizures. Monitoring of plasma concentration is important to avoid toxicity. A better recognition of EIMFS will allow starting adequate and aggressive treatment to improve prognosis. Conflict of interest statement We disclose we have no financial and personal relationships with other people or organizations that could inappropriately influence this work. References 1. Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia 1995;36: 1017–24. 2. Caraballo R, Fontana E, Darra F, Cassar L, Negrini F, Fiorini E, et al. Bernardina migrating focal seizures in infancy: analysis of the electroclinical pattern in 17 patients. J Child Neurol 2008;23(5):497–506. 3. Djuric M, Kravljanac R, Kovacevik G, Martic J. The efficacy of bromides, stiripentol and levetiracetam in two patients with malignant migrating partial seizures in infancy. Epileptic Disord 2011;13:22–6. 4. Vendrame M, Podori A, Loddenkemper T, Kluger G, Coppola G, Kothare V. Treatment of malignant migrating partial epilepsy of infancy with rufinamide: report of five cases. Epileptic Disord 2011;13:18–21. 5. Merdariu D, Delanoe C, Mahfoufi N, Bellavoine V, Auvin S. Malignant migrating partial seizures of infancy controlled by stiripentol and clonazepam. Brain Dev 2013;35:177–80. 6. Striano P, Coppola G, Zara F, Nabbout R. Genetic heterogeneity in malignant partial seizures of infancy. Ann Neurol 2014. http://dx.doi.org/10.1002/ ana.24055. 7. Woody RC. Bromide therapy for pediatric seizure disorder intractable to other antiepileptic drugs. J Child Neurol 1990;5(1):65–7. 8. Browne T, Leduc B, Kosta Rokosz M, Bromfield E, Ramsay RE, Toledo J. Trimethadione, paraldehyde, phenacemide, bromides, sulthiame, acetazolamide, and methsuximide. In: Engel J, Pedley T, editors. Epilepsy: a comprehensive textbook. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2008 . p. 1703–19. 9. Okuda K, Yasuhara A, Kamei A, Araki A, Kitamura N, Kobayashi Y. Successful control with bromide of two patients with malignant migrating partial seizures in infancy. Brain Dev 2000;22:56–9. 10. Nabatame S, Saito Y, Sakuma H, Komaki H, Nakagawa E, Sugai K, et al. Bromoderma in a patient with migrating partial seizures in infancy. Epilepsy Res 2010;91:283–8. 11. Unver O, Incecik F, Dundar H, Komur M, Unver A, Okuyaz C. Potassium bromide for treatment of malignant migrating partial seizures in infancy. Pediatr Neurol 2013;49:355–7. 12. Oguni H, Hayashi K, Oguni M, Mukahira A, Uehara T, Fukuyama Y, et al. Treatment of severe myoclonic epilepsy in infancy and it’s borderline variant with bromide. Epilepsia 1994;35:1140–5. 13. Korinthenberg R, Burkart P, Woelfle C, Moenting JS, Ernst JP. Pharmacology, efficacy, and tolerability of potassium bromide in childhood epilepsy. J Child Neurol 2007;22:414–8.