Vagus nerve stimulation in a case of epilepsy with CSWSS: respiratory side effects during sleep.

Full text

Page 1

Letters
Original Letters
**This letter was subject to peer-review.
Vagus Nerve Stimulation in a Case of Epilepsy with CSWSS:
Respiratory Side Effects during Sleep
*Claire Héberlé, †Patrick Berquin, ‡Nicole Larnicol, and *Fabrice Wallois
*Service d’Explorations Fonctionnelles du Système Nerveux and †Fe ´de ´ration de Pe ´diatrie, Unité Neuropédiatrique,
Amiens, France, and ‡Laboratoire de Neurophysiologie, Faculte ´ de Me ´decine, Amiens, France
We would like to alert the medical community to pos-
sible respiratory side effects of vagal nerve stimulation
(VNS) during the treatment of nonsurgical refractory
partial epilepsy. We observed hypopneic–polypneic epi-
sodes during sleep in a 9-year-old girl with epilepsy with
continuous spike–waves during slow sleep (CSWSS)
syndrome. These events were time-locked to each period
of VNS stimulation and occurred without any modifica-
tion of cardiac frequency. VNS may elicit a reduction of
25–50% in seizure frequency in both adults and children
with intractable epilepsy (1). Adverse side effects and
complications of VNS were few and mostly transient and
were reported in adult patients only. They include
hoarseness, neck pain, hypersalivation, cough, and short-
ness of breath (“air-missing”) sensations during physical
exercise. These sensations might be related to the in-
crease in end-expiratory volume observed in some pa-
tients receiving stimulation at high intensity. In contrast
to the common observation that VNS modifies the respi-
ratory pattern in animals, only one study has reported
alterations in the respiratory pattern in humans (2).
In the present case, the mother’s pregnancy was
marked by fetal death of a twin sister at 24 weeks of
postconceptional age. Birth was uneventful at 36 weeks
of gestational age. Systematic transfontanellar ultrasound
analysis revealed bilateral diffuse periventricular leuko-
malacia. At age 2 years, she had right tonic partial sei-
zures with loss of contact, and magnetic resonance
imaging (MRI) evidenced a left parietal extended isch-
emic lesion.
At age 5 years, her seizures changed and increased in
frequency: during daytime, they were characterized by
absence seizures associated with mild and inconstant ato-
nia (up to one seizure every 2–3 min). Sleep EEG
showed CSWSS. Over the course of the following year,
she was treated unsuccessfully with seven different an-
tiepileptic drugs (AEDs). A ketogenic diet also was in-
effective. She was considered an ineligible candidate for
surgery because of the extent of the left sylvian ischemic
lesion.
At age 6 years, a neurocybernetic prosthesis (Cyberon-
ics, Houston, Texas U.S.A.) was implanted. The stimu-
lation allowed a drug-free period of 2 months, during
which there was an initial seizure-free period of 6 weeks.
Then absences reappeared but were less numerous than
before implantation. Subsequently she was given la-
motrigine (LTG) with VNS. Despite the use of various
AED combinations and changes in stimulation param-
eters over the next year, the absences persisted.
At age 61⁄2 years, while she was being treated with
clonazepam (CZP) with VNS, a brief switching off of the
stimulator resulted in the frequency of absence returning
to preimplantation values (>100/day), indicating the rela-
tive efficacy of VNS in CSWSS.
At age 7 years, the introduction of felbamate (FBM)
and clobazam (CLB) with high-intensity VNS (intensity,
1.75 mA; frequency, 30 Hz; pulse width, 500 ?s; and
on-time/off-time 60 s/1.8 min) freed the child from sei-
zures for 2 years until the present day.
At age 8 years, an overnight polysomnographic re-
cording included 20 EEG derivations, an electrooculo-
gram, a submental electromyogram, a respiratory
Accepted May 26, 2002.
Address correspondence and reprint requests to Dr. F. Wallois at
Service d’Explorations Fonctionnelles du Système Nerveux, Unité
Neuropédiatrique, CHU Amiens Nord, Place Victor Pauchet, 80054
Amiens, France. E-mail: Fabrice.Wallois@sa.u-picardie.fr
Epilepsia, 43(10):1268–1272, 2002
Blackwell Publishing, Inc.
© International League Against Epilepsy
1268

Page 2

piezoelectric device encircling the ribcage, a nasal ther-
mistance, and an electrocardiogram. The VNS signal was
monitored by means of two electromyographic surface
electrodes placed over the position of the vagal elec-
trodes used for stimulation. The nasal thermistance
moved during the recording and did not give reliable
values over the whole recording period. Nevertheless,
when both traces were recorded, the signal from the pi-
ezoelectric device was superimposable on that of the
nasal thermistance, which indicated accurate ventilatory
monitoring.
The following reproducible markers were used in the
data analysis: beginning of inspiration, peak inspiratory
velocity (PIV), and peak expiratory velocity (PEV).
From pilot evaluations, PIV and PEV did indeed reflect
inspiratory and expiratory peak flows. The following
time intervals were measured by using these markers:
T1, interval between the beginning of inspiration and
PIV; T2, interval between the PIV and PEV; and T3,
interval between PEV and the beginning of inspiration.
Instantaneous respiratory frequency was taken as (T1 +
T2 + T3)/60.
Breath-by-breath analysis was performed by using
percentage changes, relative to control values, averaged
from the three respiratory cycles immediately preceding
the onset of the stimulus. Mean changes in ventilatory
parameters were assessed by using values calculated
within 10-s intervals. Eighty periods of VNS stimulation
were examined for this purpose during sleep periods, free
of body movement. Differences between control and
stimulation periods were tested by using analysis of vari-
ance, followed by post hoc PLSD (Protected Least
Square Differences) Fisher corrections (StatView+ pack-
age).
Every period of VNS was tightly linked to a period of
respiratory disturbance, which lasted for the entire period
of stimulation. These respiratory modifications were
characterized by an immediate decrease in the amplitude
of both inspiratory and expiratory movements, as esti-
mated from the piezoelectric trace and also as observed
on nasal thermistance. At the same time, respiratory fre-
quency increased (+16.0 ± 2.9%; p < 0.001) secondary to
decreases in all the intermediate times (T1, –18.1 ±
3.7%; p < 0.003; T2, –14.8 ± 2.1%; p < 0.0001; T3,
–20.4 ± 3%; p < 0.007). This early period lasted for
∼10 s.
After this, the amplitude of respiration progressively
returned to control values over the next 50 s. Neverthe-
less, respiratory frequency remained at a steady, in-
creased value. It was only after a few seconds at the end
of VNS stimulation that respiratory frequency and am-
plitude returned to prestimulation values.
It should be noted that respiratory disturbances were
observed throughout the sleep period, but were less eas-
ily distinguishable during wakefulness because of inces-
sant movement of the child. In this child, the occurrence
of CSWSS prevented any distinction between sleep
stages within the EEG recordings, because interictal ac-
tivity was not sufficiently suppressed to ascertain wheth-
er the child was in a rapid eye movement (REM) or
non-REM (NREM) sleep period. No change was noticed
in cardiac frequency (obtained from the RR interval),
global EEG activity, or interspike interval that might be
related to individual periods of VNS.
Before implantation of the stimulator, daytime EEG
presented a stereotypic pattern of paroxysmal activities.
It consisted of a short run of theta waves intermingled
with spikes over a 1-s period, followed by a period of
2–3 s relatively free of abnormalities. Then polyspikes
occurred for 1 s, rapidly followed by spike–waves at 3
Hz. Spike–waves at a more variable frequency persisted
for ∼2 s to several minutes, associated with a loss of
contact. After implantation of VNS, in the different pe-
riods free from seizures, the stereotypic paroxysmal
activities during daytime EEG were modified, being
less numerous and more or less confined to the left
hemisphere. The sequence of theta run followed by a
period free of abnormalities persisted, but polyspikes
or synchronized spike–waves at 3 Hz were no long-
er triggered. Instead, a period of spike–waves at very
varied frequencies occurred for short periods, never ex-
ceeding 15 s.
Our experience underscores the dual influence of VNS
in a case of CSWSS syndrome. This is the first report of
respiratory disorders tightly linked to VNS in a child
with epilepsy. The changes in both respiratory timing
and amplitude were very similar to those previously de-
scribed in animals in response to electrical stimulation of
small myelinated and unmyelinated vagal afferents (3).
As these responses were elicited from the central cut end
of the vagus nerve, they were assumed to result from
direct interactions with respiratory control centers. They
were marked by an earlier onset of both inspiration and
expiration, resulting in shortening of both inspiratory and
expiratory times, as we also observed. Moreover, the
increase in respiratory frequency was associated with a
reduction in the amplitude of the pneumogram, an alter-
ation that appeared to be quite similar to that we ob-
served at the beginning of VNS. Animal studies also
raised the possibility that the reductions in respiratory
flow and the velocity of thoracoabdominal distention
might be due to a reflex restrictive respiratory episode.
Indeed, the stimulation of the central end of vagus nerve
increased the tonic inspiratory activity of the diaphragm,
the intercostal, and the laryngeal muscles, which could
result in stiffening the respiratory tract and the chest.
Finally, the possibility of a direct activation of vagal
efferents should not be definitely ruled out in the present
case.
Conversely, the present preliminary observation high-
LETTERS 1269
Epilepsia, Vol. 43, No. 10, 2002

Page 3

lights the potential benefit of VNS in cases of epilepsy
with CSWSS. Both the reduction in seizure frequency
and the changes in EEG activities indicated that VNS
improved the clinical status of the girl under study. As
an additional argument, her symptoms immediately
worsened during a temporary arrest of the stimulator.
Nevertheless, it remains to be determined whether the
improvements may be ascribed to VNS itself or to the
combination of VNS and FBM. This deserves larger-
scale evaluations to confirm the therapeutic efficacy
of VNS in CSWSS syndrome. In addition, this case
report appears sufficiently demonstrative to propose a
systematic monitoring of respiratory parameters dur-
ing overnight polygraphic recordings in patients treated
with VNS. This should allow a detailed assessment of
the risks of ventilatory disturbances, and their ex-
tent, within the range of the clinical applications of
VNS.
Extrapolating previous animal data to the present and
other findings in humans raises the question whether the
occurrence of discrete alterations of ventilatory param-
eters during VNS might provide a functional indicator of
the activation of small myelinated and/or unmyelinated
vagal fibers, which has been regarded as a contributing
factor to the improvement of epileptic disorders.
REFERENCES
1. Murphy JV. Left vagal nerve stimulation in children with medi-
cally refractory epilepsy: the Pediatric VNS Study Group. J Pedi-
atr 1999;134:563–5.
2. Malow BA, Edwards J, Marzec M, et al. Effects of vagus nerve
stimulation on respiration during sleep: a pilot study. Neurology
2000;55:1450–4.
3. Massion J, Colle J. Influence de la stimulation du nerf vague sur le
diaphragme et sur les muscles intercostaux. Arch Int Physiol Bio-
chem 1960;68:656–68.
**We are greatly indebted to Dr. Plouin for her helpful
comments and criticisms on this manuscript.
Panayiotopoulos Syndrome or Early-onset Benign
Childhood Occipital Epilepsy
To the Editor:
The recent “proposed diagnostic scheme for people
with epileptic seizures and with epilepsy of the Interna-
tional League Against Epilepsy (ILAE) Task Force on
classification” (1) makes a significant contribution by
recognizing Panayiotopoulos syndrome (PS) (2) among
the idiopathic focal epilepsies of childhood in addition to
the “benign childhood epilepsy with centrotemporal
spikes” and the “late-onset childhood occipital epilepsy
(Gastaut type).” They proposed a descriptive name
“early-onset benign childhood occipital epilepsy” at-
tached to an eponym “Panayiotopoulos type (syndrome)” (1).
I wish to draw attention that the descriptive nomen-
clature of PS as “occipital epilepsy,” also previously de-
scribed as “with occipital paroxysms,” may be misleading.
1. Occipital paroxysms in their classic form with
fixation-off sensitivity is a rare finding in PS and
certainly nonspecific (3). Interictal EEG in PS
mainly manifests with multifocal spikes at various
locations, although occipital spikes often (70%)
predominate (2,4,5). EEGs may be normal or with-
out occipital spikes (30%) (2,4,5). In the original
study of Panayiotopoulos (4) of 21 otherwise nor-
mal children with ictal vomiting; occipital spikes
occurred in 12 (57%); the others had extraoccipital
spikes (five), infrequent brief generalized dis-
charges (one), or consistently normal EEG (three)
(4). Subsequent attention was focused on the pre-
dominant group of occipital spikes and occipital
paroxysms, but this is now corrected to include the
group of “extraoccipital spikes or normal EEG.”
The clinical manifestations of PS are the same ir-
respective of EEG localizations.
2. Occipital epilepsy also is incorrect for the follow-
ing good reasons: (a) onset of seizures is mainly
with autonomic symptoms and particularly emesis
(80%) (5). Of occipital symptoms, only deviation
of the eyes may originate from the occipital re-
gions, but this rarely occurs at onset. Visual symp-
toms are exceptional and not consistent in recurrent
seizures; (b) interictal occipital spikes may never
occur, (c) even ictal EEG has documented anterior
onset (6).
3. Characterizing PS as “epilepsy” also is controver-
sial and, in my opinion, unsatisfactory. One third of
children with PS have a single seizure, which by
the operational definition of epilepsy (more than
two seizures) is not epilepsy. Further, PS is not “a
chronic neurological condition characterized by re-
current epileptic seizures” (the current definition of
the ILAE glossary) (7).
All these point out that PS should be classified among
“conditions with epileptic seizures that do not require a
diagnosis of epilepsy,” which is a new concept of the
ILAE proposal to incorporate febrile, benign neonatal,
single seizures, isolated clusters of seizures, and rarely
repeated seizures (oligoepilepsy) (1). PS is a common
clinical phenotype of the benign childhood seizure sus-
ceptibility syndrome (2,5). It manifests with autonomic
seizures and autonomic status epilepticus that in one
third are singular events. Prognosis is excellent even for
those (∼10%) who may initially have many seizures. In-
terictal EEG shows significant variability, even for the
same child. Predominantly PS affects children aged 3–7
years, probably as the result of susceptible emetic and
autonomic centers of this age group (5). PS is a signifi-
cant missing land in pediatric epileptology with immense
LETTERS 1270
Epilepsia, Vol. 43, No. 10, 2002

Page 4

clinical and management implications. Prospective stud-
ies are needed to clarify the many typical and atypical
clinical presentations of PS, their autonomic compo-
nents, and the EEG variations.
Zarko Martinovic
Institute for Mental Health, Department of Epilepsy
and Clinical Neurosciences
Belgrade, Yugoslavia
REFERENCES
1. Engel J Jr. A proposed diagnostic scheme for people with epileptic
seizures and with epilepsy: report of the ILAE Task Force on
Classification and Terminology. Epilepsia 2001;42:796–803.
2. Ferrie CD, Grunewald RA. Panayiotopoulos syndrome: a common
and benign childhood epilepsy [Commentary]. Lancet 2001;357:821–3.
3. Martinovic Z. Panayiotopoulos syndrome. Lancet 2001;358:69.
4. Panayiotopoulos CP. Vomiting as an ictal manifestation of epilep-
tic seizures and syndromes. J Neurol Neurosurg Psychiatry 1988;
51:1448–51.
5. Panayiotopoulos CP. Panayiotopoulos syndrome: a common and
benign childhood epileptic syndrome. London: John Libbey, 2002.
6. Oguni H, Hayashi K, Imai K, et al. Study on the early-onset variant
of benign childhood epilepsy with occipital paroxysms otherwise
described as early-onset benign occipital seizure susceptibility syn-
drome. Epilepsia 1999;40:1020–30.
7. Blume WT, Luders HO, Mizrahi EM, et al. ILAE Commission
report: glossary of descriptive terminology for ictal semiology:
report of the ILAE Task Force on classification and terminology.
Epilepsia 2001;42:1212–8.
Prevention of Refractory Epilepsy
To the Editor:
I was pleased to see Arroyo et al. (1) revisiting the
fundamental questions that my colleagues and I raised 20
years ago (2) i.e., Why does epilepsy become intrac-
table? and Can chronic epilepsy be prevented?
We asked these questions then on the basis of our
earliest prospective studies of the treatment of newly
diagnosed epilepsy in the preceding 10 years, which had
revealed (a) a much better prognosis than had been an-
ticipated on the basis of previous studies in chronic pa-
tients, and (b) most patients with intractability could be
identified within the first 2 years of treatment (3).
Since I reviewed the subject in Epilepsia in 1987 (4),
it is interesting that on the basis of more recent studies
Arroyo et al. are able to support our view that refractory
epilepsy can be a progressive disorder, which, if con-
trolled early, might never develop into a full syndrome
with all its associated sequelae, and that the early initia-
tion of aggressive therapy may improve outcome and
overall quality of life.
There are, however, a number of factors that Arroyo et
al. overlook in their otherwise thoughtful review.
1. They do not mention the subject of compliance
with medication, although in our experience, the
commonest cause of failure of treatment associated
with intractability was poor compliance (3,4).
2. Among many factors that Arroyo et al. (4,5) rightly
identify as increasing the risk of intractability, the
single most important in our own studies was the
number of seizures before the start of treatment.
3. While referring, like ourselves, to the processes of
kindling and secondary epileptogenesis, they omit-
ted what we called the Gowers hypothesis (2,4), his
view that each seizure predisposes to the next,
which is an extension of the kindling phenomenon,
of which Gowers was, of course, unaware.
4. Any discussion of processes of progression, re-
lapse, or intractability should be balanced by a dis-
cussion of processes of remission (5,6).
It is apparent, as Arroyo et al. acknowledged, that
especially in childhood, some epilepsy syndromes appear
to go into remission with or without treatment. The key
to understanding the evolution and prognosis of epilepsy
syndromes lies in the relation of these two competing
processes. To what extent our treatments can prevent the
relapsing processes or enhance the remitting processes is
a central question of our future understanding and man-
agement of epilepsy and its various syndromes.
E. H. Reynolds
Institute of Epileptology
London, Kings College, United Kingdom
REFERENCES
1. Arroyo S, Brodie MJ, Avanzini G, et al. Is refractory epilepsy
preventable? Epilepsia 2002;43:437–44.
2. Reynolds EH, Elwes RDC, Shorvon SD. Why does epilepsy be-
come intractable? Prevention of chronic epilepsy. Lancet
1983;ii:952–4.
3. Elwes RDC, Johnson AL, Shorvon SD, et al. The prognosis for
seizure control in newly diagnosed epilepsy. N Engl J Med 1984;
311:944–7.
4. Reynolds EH. Early treatment and prognosis of epilepsy. Epilepsia
1987;28:97–106.
5. Reynolds EH. The influence of antiepileptic drugs on the natural
history of epilepsy. In: Pisani F, Perucca E, Avanzini G, et al., eds.
New antiepileptic drugs. Amsterdam: Elsevier, 1991:15–9.
6. Reynolds EH. Mechanisms of intractability. In: Wolf P, ed. Epi-
leptic seizures and syndromes. London: John Libbey, 1994:599–
603.
Response: Prevention of Refractory Epilepsy
To the Editor:
We thank Dr. Reynolds for his support of our article,
and we acknowledge the insight and contributions that
their group had in the area of progression of epilepsy a
few years ago. We agree with Dr. Reynolds that a com-
mon cause of failure of the treatment is the patient’s
noncompliance. However, for the purpose of our review,
we considered it understood that noncompliant patients
are not truly refractory.
LETTERS1271
Epilepsia, Vol. 43, No. 10, 2002

Page 5

The number of seizures before the start of treatment
has been found in some but not all studies to be a risk
factor for intractability. In any case, we concur with Dr.
Reynolds in that it appears to be a relevant risk factor. In
a recent article from one of us (1), it was confirmed that
those patients with 20 or more seizures before treatment
had a significantly higher chance of intractability.
Finally, in our text, we discussed the phenomenon of
secondary epileptogenesis and of the possibility that sei-
zures beget seizures. Unfortunately, because of numer-
ous methodologic issues, the evidence that this
phenomenon occurs in humans has been difficult to as-
certain. In this sense, different types of epilepsy might
behave differently. Even in those types that we believe
are progressive (like mesial temporal lobe epilepsy), an
initial and sometimes years-long “honeymoon period” is
often observed, implying that the disease evolution and
not the seizures in themselves might be responsible for
the intractability.
Dr. Santiago Arroyo
Medical College of Wisconsin
Milwaukee, Wisconsin, U.S.A.
REFERENCE
1. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N
Engl J Med 2000;342:314–9.
LETTERS1272
Epilepsia, Vol. 43, No. 10, 2002