Seizure 23 (2014) 899–902
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Seizure
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Short communication
Epilepsy of infancy with migrating focal seizures: Six patients treated
with bromide
Roberto Caraballo a,*, Marı́a 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 Pediátrico 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 Pediatrı́a ‘‘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.
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