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Ital J Neurol Sci (1998) 19:180-183 © Springer-Verlag 1998
D. Intiso • R. Cioffi • P. Di Viesti • P. Simone • P. Tonali
Bilateral periventricular nodular heterotopia associated with coeliac
disease and palatoschisis
Received: 11 February 1997 /Accepted in revised form: 24 March 1998
Abstract Periventricular nodular heterotopia (PNH) is con-
sidered a distinct entity in relation to the other forms of neu-
ronal migration disorders (NMD), because PNH patients usu-
ally have normal neurological and mental examination results.
We report the case of a 48-year-old woman with bilateral
periventricular nodular heterotopia associated with epilepsy,
coeliac disease, palatoschisis and other dysmorphic features.
Her intelligence quotient (I.Q.) and the results of a neurologi-
cal examination were normal, but she suffered from a drug-re-
sistant epileptic syndrome characterised by predominantly
generalised and sporadic partial seizures. It has recently been
suggested that an X-linked dominant inheritance may play a
role in bilateral periventricular nodular heterotopia, and it is
thought that a genetic defect is probably responsible for coeli-
ac disease. In our patient, a genetic disorder may have pro-
duced both diseases and the dysmorphic syndrome, although
the coexistence of PNH, epileptic seizures, coeliac disease and
palatoschisis could be coincidental. Further observations are
needed to ascertain whether the simultaneous presence of
these disorders is simply an unusual association of unrelated
pathologies or a new and distinct pathological entity.
Key words Periventricular neuronal heterotopia • Coeliac
disease • Epilepsy • Palatoschisis
D. Intiso ([g~) • R. Cioffi • R Di Viesti • R Simone • R Tonali
Division of Neurology
I.R.C.C.S "Casa Sollievo della Sofferenza"
Viale dei Cappuccini, 1-71013 San Giovanni Rotondo (FG), Italy
R Tonali
Institute of Neurology
Catholic University, "S. Cuore"; Roma, Italy
Introduction
Bilateral periventricular nodular heterotopia (PNH) is con-
sidered a clinical and pathological entity that is distinct
from the other neuronal migration disorders (NMD) [1, 2].
Friede [3] suggested that the various forms of NMD may
represent different degrees of severity of a single disorder
due to a radial glial fibre defect occurring when neuroblasts
migrate from the periventricular germinal centres to the
cortical regions. However, the causes of the alteration are
still unknown. Some reports have recently suggested that a
genetic disturbance may underlie the PNH affecting only
women [4, 5]. The PNH patients described in the literature
have generally had normal clinical and neurological exam-
ination results, and none presented with any concomitant
disorders other than seizures [6]. However, a family with
PNH and peculiar dysmorphic features has been recently
reported [7]. We describe the case of a woman simultane-
ously affected by periventricular nodular heterotopia,
epileptic seizures, coeliac disease and palatoschisis.
Case report
A 48-year-old Caucasian woman with no family history of
epilepsy, mental retardation or tuberous sclerosis was born
at term after an uncomplicated delivery. Her acquisition of
developmental milestones was normal, and she successful-
ly completed primary school. Generalised tonic-clonic
epileptic seizures first appeared when she was 14 years old,
with a frequency of 3-6 attacks per month. Initial treatment
with phenobarbital (100 rag/day) had no effect on the
seizures, nor did subsequent treatment at higher doses of up
to 200 mg daily. She started to experience sporadic partial
seizures characterised by sudden vacancy, unresponsive-
ness and orofacial automatisms. After the addition of car-
bamazepine (1200 mg/day) and vigabatrin (1500 mg/day),
D. Intiso et al.: Periventricular nodular heterotopia and coeliac disease
the frequency of the generalised attacks decreased by 50%,
but the partial seizures remained unchanged.
At the time the patient first came to our observation, she
was experiencing 1-3 epileptic episodes per month. A gen-
eral physical examination revealed short stature (137 cm),
a body weight of 45 kg, kyphoscoliosis, cleft palate, drum-
stick fingers and a heart murmur. No tuberous sclerosis
stigmata were found. The results of a neurological exami-
nation were normal and her full Wechsler Adult
Intelligence Scale (WAIS) evaluation score was 90.
Complete blood and urine analyses revealed no abnor-
malities other than hypocalcemia, hypomagnesemia and
high serum parathyroid hormone levels. To check for mal-
absorption, the patient underwent gastroscopy and small
bowel biopsy; microscopic examination showed a blunting
and flattening of the mucosal surface ~md dense inflamma-
tory cells infiltration in the lamina propria. The presence of
autoantibodies against gluten and smooth muscle cells con-
firmed the diagnosis of coeliac disease. She had a normal
46,XX female karyotype.
The results of chest radiography were normal, whereas
spinal radiography revealed kyphoscoliosis, spondylosis
and extensive demineralisation. The electrocardiogram
(ECG) was normal but echocardiography revealed mild re-
gurgitation of the mitral valve and aortic enlargement. We
could record only interictal electroencephalograms (EEGs),
which showed a normal alpha rhythm intermingled with
diffuse irregular theta rhythms in both cerebral hemi-
spheres; no abnormal focal electrical activity was observed
in either the temporal or the occipital regions.
An Hm-PAO SPECT scan revealed normal cerebral per-
fusion. In particular, the heterotopic nodules had a perfusion
pattern that was similar to that of the white matter. The re-
sults of brain computed tomography (CT) were normal.
Magnetic resonance imaging (MRI) was carried out using a
0.5 Tesla superconductive magnet (Toshiba MRT/A) and, by
means of the spin echo (SE) technique, sagittal and axial
Tl-weighted (TR 500 ms; TE 20 ms) and T2-weighted (TR
2800 ms; TE 30-120 ms) images were obtained. The MR ex-
am showed several subependymal nodules slightly protrud-
ing into the ventricular lumen throughout the length of the
walls of the lateral ventricles; the nodules were isointense to
grey matter in both the Tl-weighted and T2-weighted im-
ages (Figs. 1 and 2). These MR features were consistent
with periventricular nodular heterotopia. No other abnor-
malities were detected in the cortical or subcortical regions.
The patient was put on a gluten-free diet and started
lamotrigine treatment, the dosage of which was gradually
increased up to 100 mg/day; vigabatrin treatment was slow-
ly tapered and then stopped. During one year of follow-up,
she has experienced only four episodes of generalised
seizures but still complains of sporadic partial attacks.
There is evidence in the literature that a gluten-free diet
seems to decrease the frequency of seizures, at least in pa-
tients with coeliac disease and cerebral calcifications [8];
181
Fig. 1 Axial T2-weighted image showing nodular subependymal
neuronal dislocation surrounding the walls of the lateral ventricles
Fig. 2 Axial T 1-weighted image showing periventricular neuronal
dislocation. Nodular heterotopia gives the external surface of the
lateral ventricles a characteristic wave-like appearance
however, as our patient simultaneously began treatment
with lamotrigine, the decrease in the number of seizures
may have been caused by the addition of this drug.
Discussion
We believe that this is the first description of a case of PNH
associated with seizures, coeliac disease and palatoschisis.
Patients with seizures and coeliac disease have previously
been described in the literature, but the neuroimaging find-
ings have generally consisted of calcifications in the
182
frontal, temporal and parietal regions [8, 9]. This associa-
tion of epilepsy, coeliac disease and cerebral calcifications
has been considered to be a new syndrome, although many
questions remain unanswered particularly with regard to
the origin of the epilepsy [9]. Furthermore, although
hypocalcemia associated with coeliac disease can deter-
mine neuronal hyperexcitability, it is not known whether
coeliac disease is able to produce or facilitate seizures.
The causes of the seizures occurring in patients with
PNH and other types of NMD, as well as their underlying
pathophysiological mechanisms, are also unknown. Morell
et al. [10] found epileptiform discharges arising from het-
erotopic neurons regardless of the activity in the overlying
cortex, which suggests that neuronal heterotopia may play
an epileptogenic role. PNH patients may have partial or
generalised seizures, although partial epilepsy has been
predominantly reported [1, 6]; on the other hand, patients
with coeliac disease without cerebral calcification com-
plain of generalised epilepsy. In our patient, the seizures
may be a consequence of coeliac disease or neuronal het-
erotopia, or both.
Further considerations can be made concerning the ori-
gin of these disorders. It has been suggested that a defect in
the radial glial fibres may induce migrational arrest in
many NMDs, but the underlying mechanism is unknown
[11, 12]. Environmental factors and genetic defects could
produce this alteration, and some reports have recently sug-
gested an X-linked dominant inheritance of PNH with a
maximum load of 3.65 for markers in distal Xq28 [5, 13].
Unfortunately, our patient had no siblings, so we were un-
able to identify others in her family suffering from neuronal
heterotopias. The etiology of coeliac disease is also un-
known, although genetic factors seem to play an important
role [14].
The association of PNH, coeliac disease and seizures in
our patient could therefore be the expression of multisys-
temic abnormalities produced by a genetic disturbance, al-
though their simultaneous presence may simply be coinci-
dental. Given the known high prevalence of coeliac dis-
ease, such patients should perhaps undergo electrophysio-
logical and neuroimaging investigations in order to evalu-
ate the risk of coincidence with seizures and brain abnor-
malities. The results of neurological and mental examina-
tions in PNH patients are generally normal [2, 6], but
Musumeci et al. [7] have recently reported the case of a
family with PNH, mental retardation and dysmorphic fea-
tures suggesting a well-defined and probably genetic clini-
cal entity, characterised by an X-linked dominant inheri-
tance.
Our patient had PNH, epilepsy and clinical features
consisting of palatal cleft, short stature, low body weight,
drum-stick fingers and aortic enlargement. She could there-
fore be affected by a complex dysmorphic syndrome of
which the periventricular nodular heterotopia may be only
a further aspect. The karyotype analysis was normal, but
D. Intiso et al.: Periventricular nodular heterotopia and coeliac disease
this finding is not sufficient on its own to exclude dysgenic
diseases. On the other hand, her short stature and low body
weight could be the result of malabsorption and not simply
the consequence of hypocalcemia, hypomagnesemia and a
high level of serum parathyroid hormone. Since the disease
of our patient did not show a progressive course, we clini-
cally excluded the most common metabolic diseases.
Further observations are needed to confirm whether
periventricular heterotopia, epilepsy, coeliac disease and
palatoschisis simply constitute an unusual coincidental as-
sociation or whether they represent a clinical and patholog-
ical entity due to a genetic or environmental disturbance.
Sommario Nell'ambito dei disordini della migrazione
neuronale (NMD) la eterotopia neuronale periventricolare
(PNH) ~ stata individuata come una distinta entitd clinica.
I pazienti con questa forma di eterotopia neuronale gene-
ralmente presentano uno sviluppo intellettivo e un esame
neurologico normale. Riportiamo un caso di PNH bilatera-
le associato a crisi comiziali, malattia celiaca e palato-
sch[si. La paziente che descriviamo aveva 48 anni e mo-
strava Q.I. ed esame neurologico normale e soffriva di una
sindrome epilettica caratterizzata prevalentemente da crisi
generalizzate e crisi parziali sporadiche, resistenti al trat-
tamento farmacologico. Recentemente nei pazienti con
PNH ~ stata riscontrata un' ereditarietd X-linked dominan-
te. Anche per la malattia celiaca ~ stata ipotizzata una
eziologia di tipo genetico, per cui la coesistenza delle due
malattie e degli aspetti clinici dismorfici nella nostra pa-
ziente potrebbe essere dovuta ad un disturbo genetico.
D'altro canto, il quadro clinico osservato potrebbe essere
espressione solamente di un' associazione casuale.
Ulteriori osservazioni potranno chiarire se la coesistenza
di questi disturbi rappresenta solo un' insolita associazione
di indipendenti patologie o una nuova distinta entitd clini-
ca.
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