Epilepsy of Infancy with Migrating Focal Seizures: Six Patients Treated with Bromide

Home , Potassium bromide

Seizure 23 (2014) 899–902

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Short communication

Epilepsy of infancy with migrating focal seizures: Six patients treated

with bromide

a, a a

Roberto Caraballo *, Marı´a Constanza Pasteris , Pablo Sebastian Fortini , b

Ernesto Portuondo

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: Purpose: We present six patients with epilepsy of infancy with migrating focal seizures (EIMFS) and

Received 7 May 2014

provide a comprehensive evaluation of potassium bromide therapy.

Received in revised form 25 June 2014

Method: Between February 1, 2007 and July 31, 2012, six patients who met the diagnostic criteria of

Accepted 27 June 2014

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

Keywords:

therapeutic bromide concentration between 75 and 125 mg/dL was considered to be ideal.

Potassium bromide

Results: Four of six children responded well to bromide. One of these patients became seizure free, but

Epileptic encephalopathy

remained severely mentally impaired. Two boys, currently 4 and 6 years of age, respectively, have

Focal seizures

Infants monthly seizures as well as axial hypotonia and severe language impairment. The fourth child responded

Multifocal seizures well to bromide, having only weekly seizures and moderate psychomotor retardation. The patient who

Refractory epilepsy 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.

1. Introduction ruﬁnamide, and potassium bromide alone or in combinations with

3–5

variable results. Triple bromides have also been used in the

Epilepsy of infancy with migrating focal seizures (EIMFS) is a treatment of refractory epilepsy, but in the literature we did not

well-deﬁned and rare epileptic syndrome characterized by an ﬁnd any important differences between these two forms of

onset of multifocal seizures before 6 months of age and a typical bromides in terms of efﬁcacy and tolerability.

ictal electroencephalography (EEG) pattern consisting of seizures Recently, EIMFS has been described related to different genes in

1 6

that arise independently and sequentially from both hemispheres. sporadic and familial cases. These ﬁndings suggest a genetic

The seizures are refractory to antiepileptic drugs (AEDs) and cause heterogeneity.

1,2

subsequent severe mental retardation. Here, we present six patients with EIMFS and provide a

Several reports have focused on seizure control or reduction comprehensive evaluation of potassium bromide therapy.

with the use of different AEDs, such as levetiracetam, adreno-

corticotropic hormone (ACTH), benzodiazepines, stiripentol, and

2. Methods

Between February 1, 2007, and July 31, 2012, six patients who

* Corresponding author at: Neurology Department, Hospital de Pediatrı´a ‘‘Prof.

met the diagnostic criteria of EIMFS were treated with potassium

Dr. Juan P. Garrahan’’, Combate de los Pozos 1881, CP 1245, Buenos Aires, Argentina.

bromide. We used potassium bromide as this was the formula we

Tel.: +54 11 49436116; fax: +54 11 49436116.

E-mail address: [email protected] (R. Caraballo). found in Argentina. The charts of all patients were analyzed

http://dx.doi.org/10.1016/j.seizure.2014.06.016

900 R. Caraballo et al. / Seizure 23 (2014) 899–902

considering response to therapy – especially to potassium bromide 3. Results

– and ﬁnal outcome.

All patients underwent brain computed tomography (CT) scan 3.1. General characteristics

and magnetic resonance imaging (MRI) as well as EEG recordings,

neurometabolic tests, and karyotyping. No genetic markers A total of six patients (four boys and two girls) were identiﬁed

associated with EIMFS were investigated in any of the patients. between 2005 and 2012 at the Garrahan Hospital of Buenos Aires.

All patients had received more than one of the conventional and In all patients, the neurological examination showed hypotonia

new AEDs, before bromide was introduced: Carbamazepine was after the seizures became refractory, but there were no other

used in six patients, valproic acid in ﬁve, phenobarbital in four, neurological abnormalities. The initial head circumferences of the

diphenylhydantoin in four, clobazam in four, clonazepam in three, children were normal for age.

levetiracetam in four, topiramate in four, zonisamide in three, At onset, brain CT scans and MRIs were normal in all patients.

lamotrigine in three, ACTH in three, the ketogenic diet in one, and Subsequent repetitive MRIs showed mild ventricular enlargement

rufinamide in one. Bromide was added to levetiracetam and in one, and a moderate degree of the same finding in five. In one,

topiramate in two patients, to zonisamide and clonazepam in one, the MRIs showed unilateral mesial temporal sclerosis. Electroreti-

to valproic acid and clobazam in one, to levetiracetam and nogram and visual and auditory evoked potentials were normal in

ruﬁnamide in one, and to lamotrigine and clobazam in the all cases, but somatosensory evoked potentials, performed before

remaining one. No AEDs were withdrawn after the introduction of bromide initiation, showed increased amplitude and prolonged

bromide. The average dose of bromide was 65 mg/kg/day (range, latency in the cortical component in two patients. No etiologies

30–80 mg/kg/day). The starting dose was 10 mg/kg/day divided were found.

into two or three doses. No protocol was used to adjust the doses.

Due to its exceptionally long half-life, plasma bromide concentra- 3.2. Electroclinical ﬁndings

tion was monitored to prevent toxicity. The dose was titrated over

one to two months and bromide levels were monitored every 3–4 The mean and median ages at the time of the ﬁrst seizure were

months. A therapeutic bromide concentration of between 75 and 45 days and 30 days, respectively (range, 15–60 days). Three

125 mg/dL was considered to be ideal. The effectiveness of the electroclinical patterns were recognized according to seizure

maintenance dose was evaluated based on the quality of life of the frequency, recurrence, and topography: (1) Alternating simple

patients and their families. The parents of one patient did not focal motor seizures at onset with an ictal EEG pattern that was

accept to increase the dose of bromides. 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) 899–902 901

sharp activity in the theta to alpha frequency range involving the occasions. All patients had progressive neurological deterioration

rolandic region of the contralateral hemisphere in three cases; (2) with generalized hypotonia, loss of visual contact and grasping,

focal complex seizures and progressive appearance of polymorphic and loss of other motor and social skills. All developed

delta–theta activity of variable amplitude in one temporo-occipital microcephaly. One patient died at 18 months of age due to status

region recurring independently in one case. These seizures, which epilepticus. Mean age at bromide introduction was 7 months

lasted from one to several minutes, tended to recur independently (range, 6–12 months) and mean interval between seizure onset

in both hemispheres from onset, frequently evolving into long- and bromide introduction was 7.5 months (range, 5–11 months).

lasting clusters. In the absence of an EEG recording, it was On bromide therapy, four of six children evolved well in terms

impossible to recognize the hemisphere involved, as the clinical of seizure outcome. One of these patients, a girl, became seizure

symptoms were not lateralizing; and (3) focal complex seizures free at 1 year of age, but remained severely mentally impaired. Two

with motor manifestations with an ictal EEG showing ﬂattening or boys, currently 4 and 6 years of age, respectively, have monthly

a small discharge of fast or theta activity in one fronto-temporal fronto-temporal seizures while awake and during sleep with axial

region followed by unilateral fast polyspikes in alternating clusters hypotonia as well as severe language impairment. The fourth

in both hemispheres in two cases (Figs. 1A–D and 2A–D). The patient, a 2.5-year-old boy, responded relatively well to bromide

seizures were followed by prolonged post-ictal hemispheric slow- having weekly complex focal seizures without generalized motor

wave activity interposed by ample isolated spikes that became seizures and moderate psycho-motor retardation.

bilateral when the alternating seizures in clusters involved both Reduced seizure frequency was ﬁrst observed between 1 and

hemispheres. 2.5 months after starting bromide therapy. The patient who

became seizure free patient improved visual contact and head

3.3. Treatment and follow-up control. In the other three patients with good control, the seizures

became focal without secondary generalization and status

The seizures became very frequent within a month after onset, epilepticus. Hospital admission was not required. The remaining

occurring several times a day in long-lasting clusters or as a simple two patients did not respond well to bromide.

partial motor status. Concomitantly, the children became ﬂoppy No correlation between response and the clinical-EEG pattern

and somnolent with feeding difﬁculties. All patients were was found, however, the series was too small to draw any

refractory to AEDs, which was why bromide was added. Three deﬁnitive conclusions. Additionally, in this retrospective study the

patients needed general anesthetic treatment on one or more 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.

902 R. Caraballo et al. / Seizure 23 (2014) 899–902

Table 1

The efﬁcacy and tolerability of bromide treatment in six patients with EIMFS.

Patients Seizure frequency Dose Range Efﬁcacy Adverse Period of bromide Time of At the last control

before bromide (mg/kg/day) (mg/dL) effects treatment years follow-up

treatment years

1 Daily 30 71 Seizure free – 4 5.5 Severe mental retardation

2 Daily 80 123 No response Drowsiness 0.5 1 Severe mental retardation

3 Daily 65 114 Monthly Vomiting 5 6 Hypotonia and severe

seizures language impairment

4 Daily 70 115 No response Skin rash 0.5 1 Severe mental retardation

5 Daily 60 95 Weekly seizures – 1 1.5 Moderate mental retardation

6 Daily 55 89 Monthly seizures – 2.5 3.5 Hypotonia and severe

language impairment

12,13

stormy phase, and more detailed electroclinical information is syndrome with good results. Considering that different types

lacking. In the patient who became seizure free, the interictal sleep of seizures in Dravet syndrome responded well to bromide, the

EEG recording showed bilateral independent spikes. drug may be tried in the treatment of refractory epilepsy, mainly

Adverse effects were seen in three cases; vomiting in one, epileptic encephalopathy.

drowsiness in another, and acneiform eruption in the face in the

remaining patient. They were resolved with dose reduction.

5. Conclusions

Table 1 shows the efﬁcacy and tolerability of bromide treatment

in our series of patients with EIMFS.

Potassium bromide is a good option in patients with refractory

After a mean follow-up of 3.5 years (range, 1–6 years), all four

seizures. Monitoring of plasma concentration is important to avoid

children with a good response regarding neurological examination toxicity.

and seizure frequency remained unchanged.

A better recognition of EIMFS will allow starting adequate and

aggressive treatment to improve prognosis.

4. Discussion

Conﬂict of interest statement

We describe six patients who presented with EIMFS refractory

to AEDs before 5 months of age and who were treated with

We disclose we have no ﬁnancial and personal relationships

potassium bromide. Four of six patients responded well to the

with other people or organizations that could inappropriately

drug.

inﬂuence this work.

Most patients with EIMFS are refractory to antiepileptic drugs,

but some have shown a good evolution or a near satisfactory

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