ARTICLE
Auteur(s) : Mar
Carreño1, Dionisio Garcia-Alvarez2,
Iratxe Maestro1, Santiago Fernández1, Antonio
Donaire1, Teresa Boget1, Jordi
Rumià1, Luis Pintor1, Xavier
Setoain1
1Epilepsy Unit, Department of Neurology,
Hospital Clínic, Barcelona
2Department of Neurology, Hospital Universitario de
Canarias, Tenerife, Spain
Article reçu le 14 Octobre 2009, accepté le 22 F�vrier 2010
Nocturnal frontal lobe epilepsy (NFLE) is characterized by
seizures occurring predominantly during sleep and a seizure
semiology which is suggestive of a frontal lobe origin (Ryvlin
et al., 2006). NFLE includes both sporadic and familial forms.
Inheritance may be autosomal dominant and such cases are referred
to as ADNFLE (8% to 43% of cases). Three ADNFLE loci, including two
mutant genes encoding for the α4 and β2 subunits of the nicotinic
acetylcholine receptor have been identified (De Fusco et al.,
2000; Phillips et al., 1995; Phillips et al., 1998).
These mutations are identified only in a minority of patients with
ADNFLE.
In both sporadic and familial forms, seizures are usually
responsive to antiepileptic drugs. However, in one third of cases,
seizures are refractory to medical treatment (Ryvlin et al.,
2006), and may evolve into status epilepticus (Derry et al.,
2008). These patients may display, in addition, cognitive and
behavioural disturbances, which seem to occur with worsening of
seizures or episodes of status (Derry et al., 2008). The
relevance of vagal nerve stimulation (VNS) to treat seizures in
this particular syndrome has not been reported so far.
In this case study, we report a 29-year-old patient with
refractory ADNFLE and repeated episodes of convulsive status
epilepticus who underwent VNS therapy.
Case study
Our patient has a strong family history of epilepsy. His mother had
nocturnal motor seizures which were easily controlled with
carbamazepine. His maternal grandmother had sporadic generalized
motor seizures starting at the age of 21 years. One of his
mother's cousins had nocturnal motor seizures which started
during her pregnancy and were refractory to medical treatment.
A maternal uncle had nocturnal seizures since the age of
15 years, and his son (the patient's cousin) had nocturnal
hemimotor simple partial seizures. None of the family members,
except our patient, underwent prolonged video-EEG monitoring or
genetic testing.
Pregnancy and delivery were uneventful. At the age of three
months the patient had generalised convulsive SE, without fever.
Lumbar puncture was unrevealing. After the status he started to
have clusters of infantile spasms (10-15 a day) and later, afebrile
generalized tonic clonic seizures. From the age of six years he
only had nocturnal seizures. The family reported motor seizures
with sudden extension of both arms, occurring in clusters during
the first half of the night (two or three clusters every night, up
to a total of 30-40 seizures) and also seizures with generalized
shaking, sometimes preceded by stiffening of the trunk (1-2 every
night). Approximately once every six months he had prolonged
convulsive seizures lasting more than 30 minutes which
required hospital admission and treatment with intravenous
benzodiazepines and even pentobarbital coma. Neurological
examination was normal except for marked psychomotor slowing.
Genetic testing for known mutations of ADNFLE was negative,
however, a clinical diagnosis of ADNFLE was made based on nocturnal
seizures, a seizure semiology suggestive of frontal lobe origin and
family history.
The patient was treated with multiple antiepileptic
drugs, both as mono and polytherapy, including phenobarbital,
carbamazepine, phenytoin, valproic acid, clobazam, lamotrigine,
vigabatrin, gabapentin, ethosuximide, clonazepam, topiramate and
levetiracetam, without effectiveness. Nicotine patches were used,
which seemed to temporarily decrease seizure frequency. When
admitted to our Unit he was being treated with phenytoin,
topiramate and clonazepam. Blood level of phenytoin was around 35
μg/mL. Lower levels systematically resulted in increased seizure
frequency and convulsive status epilepticus. Higher levels produced
somnolence and severe ataxia.
Prolonged video-EEG monitoring showed bilateral asymmetric tonic
seizures with sudden extension of both arms (right more than left),
axial tonic seizures with generalized stiffening and hypermotor
seizures that sometimes evolved into clonic jerking of the right
limbs. All seizures arose from sleep. Interictal EEG showed
polyspikes, spikes and sharp waves over the vertex and
fronto-central regions, bilaterally. Ictal EEG showed repetitive
spiking over the midline and both frontal regions, maximum over the
left (figure 1) or a
diffuse electrodecremental pattern followed by a rhythmic theta
pattern over the left frontocentral region (Fz > Cz > F3 >
C3). Neuropsychological assessment showed intelligence in the lower
end of normal range, with impaired attention, operative memory and
verbal fluency. Subtle asymmetry in hippocampal size was identified
by 3T brain MRI, with no evident lesions in the frontal region.
The patient was not considered a surgical candidate. Given the
refractoriness to medical therapy and the repeated episodes of
convulsive status epilepticus, a vagal nerve stimulator (VNS) was
implanted.
Following implantation, the intensity of stimulation was
increased, in steps of 0.25 mA every two weeks. After three
months at an intensity of 1.5 mA, a significant reduction
(50%) in seizure frequency was noticed by the family. After one
year at an intensity of 2 mA, seizure frequency decreased by
80%, as confirmed by repeated video-EEG monitoring; response to
stimulation was maintained after 3.5 years of follow-up.
Generalized tonic clonic seizures became rare (once every 2-3
months, approximately) and he did not have any more episodes of
status epilepticus since implantation. The patient continues to
have brief nocturnal bilateral tonic seizures which do not
interfere significantly with sleep. An attempt to decrease the dose
of phenytoin resulted in increased seizure frequency, thus
medication remained unchanged.
The patient now works in a restaurant and shares a supervised
apartment. The family reports increased alertness, improved
psychomotor speed and mood, without adverse effects from
stimulation. Follow-up neuropsychological assessment has shown
improved visual memory relative to previous tests.
Discussion
Vagal nerve stimulation is considered an effective and generally
safe therapy for patients with intractable epilepsy who are not
candidates for epilepsy surgery. Controlled and long-term studies
(Montavont et al., 2007; Fisher and Handforth, 1999) have
shown that more than 50% seizure reduction occurs in about half of
patients. VNS has also been successfully used to abort refractory
status epilepticus (De Herdt et al., 2009). A clear
response to stimulation was observed early after implantation and
at medium intensities which was increased and maintained with time
(Montavont et al., 2007), as well as increased alertness and
improved psychomotor speed (Hallbook et al., 2005). In our
casestudy, the complete control of repeated episodes of
life-threatening convulsive status epilepticus is particularly
impressive and resulted in a radical change in quality of life for
the patient and his family.
To our knowledge, this is the first report in the literature
concerning the effectiveness of VNS in patients with ADNFLE and
drug refractory seizures. Animal models have shown that mutated
nicotine receptors of acetylcholine (nAChRs) display increased
sensitivity to Ach (Klaassen et al., 2006). PET studies in
humans have shown significant changes in brain nAChR density, with
a high concentration of receptors in the thalamus, pointing towards
an over-activated cholinergic pathway ascending from the brainstem
(Picard et al., 2006). Other neurotransmitter systems, such as
the GABAergic system, may also be enhanced in ADNFLE (Klaassen
et al., 2006). Although the exact mechanism of action of VNS
remains to be elucidated, it has been postulated that afferent
vagal synapses attenuate seizure activity through neurotransmitter
modulation (Zagon and Kemeny, 2000). Crucial brainstem and
intracranial structures which may be influenced by chronic
stimulation include the locus coeruleus, nucleus of the solitary
tract, thalamus and limbic structures (Cunningham et al.,
2008). This is accompanied by changes in cerebral blood flow and
cerebral metabolism. Positive clinical efficacy has been correlated
with chronic thalamic hypoperfusion in SPECT studies (Vonck
et al., 2008). This downregulation of enhanced cholinergic
thalamocortical pathways may be related to the anti-seizure effect
in patients with ADNFLE.
In summary, vagal nerve stimulation may be an effective therapy
for malignant cases of epilepsy of presumed genetic origin as well
as repeated status epilepticus.
Disclosure
None of the authors has any conflict of interest to disclose.
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