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Cortical vascular abnormalities in the syndrome of celiac disease epilepsy bilateral occipital calcifications and folate deficiency.

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offspring at risk in the present study will also be valuable.
This work was supported by National Institutes of‘ Health grants
AG08017, AGo7584, and AGO6781 and Veterans Administration
medical research funds.
Drs D. Nochlin and S. M. Sumi performed the neuropathological
studies and P. McLean, J. Thompson, M. Pfanschmidt, and N. Chinn
provided valuable clinical assistance.
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Cortical Vascular
Abnormalities in the
Syndrome of Celiac
Disease, Epilepsy, Bilateral
Occipital Calcifications, and
Folate Deficiency
Annie M. E. Bye, MBBS, FRACP,*
Frederick Andermann. MD. FRCp(C),$
Yves Robitaille, MD,S M . Oliver, MBBS,S
T. Bohane, MBBS, FRACP;I
Eva Andermann, MD, PhD, FCCMG$
The pathological changes in the syndrome of celiac disease, folate deficiency, bilateral occipital calcifications,
and intractable epilepsy have not been previously described. A child with this disorder had a field defect
correlating with active lateralized epileptic discharges
and asymmetrical lesions. After resection of the right
occipital lobe she W ~ seizure
free for 4 years. A cortical
vascular abnormality with patchy pial angiomatosis, fibrosed veins, and large jagged microcalcifications was
found. These pathological abnormalities were similar
though not identical to those found in the Sturge-Weber
Bye AME, Andermann F, Robitaille Y , Oliver M,
Bohane T, Andermann E. Cortical vascular
abnormalities in t h e syndrome of celiac disease,
epilepsy, bilateral occipital calcifications, and
folate deficiency. Ann Neurol 1993;34:399-401
In 1989, a patient with bilateral intracranial calcifications thought to have Sturge-Weber syndrome (SWS)
without nevus flammeus was reported El). Because of
intractable epilepsy, a right occipital resection was performed with an excellent result. The original diagnosis
was questioned; subsequent investigations showed low
folic acid levels and led to a diagnosis of celiac disease.
She w a shown to have the previously recognized entity of bilateral occipital calcifications, folic acid deficiency, and celiac disease [Z-4).
The purpose of this report is to describe the patho-
From the “Neurology and tGastrocnterology Departments, Prince
of Wales Children’s Hospital, Sydney, Australia, the +Department of
Neurology and Neurosurgery, hkGill University, and the Montreal
Neurological Institute and Hospital, Montreal, Quebec, Canada.
Received Mar 15, 1993, and in revised form Apr 16. Accepted for
publication Apr 19, 1993.
Address corrcspondeiice to Dr Andermann, Montreal Neurological
Hospital, 1801 University Sr, Montreal, Quebec, Canada H3A 2B4.
Copyright Q
1993 by t h e American Neurological Association 399
logical substrate of this syndrome consisting of patchy
pial angiomatosis and fibrosis of small veins in addition
to the calcifications. These abnormalities, though distinct, resemble those of SWS and of occipital calcifications due to antifolate and x-ray treatment in children
with leukemia [ S ] .
Case History
A girl developed focal seizures at the age of 4 years. At 12
years she had intractable complex partial seizures with visual
symptomatology and infrequent secondary generalization.
Her mentation was slowed and she had a left homonymous
inferior quadrantanopia. She did not have a nevus flammeus.
Interictal electroencephalograms (EEGs) showed epileptogenic activity from the right temporal region and bilateral
slow activity with right-sided predominance.
Skull x-ray films at 4 years showed occipital calcifications
with a tram track appearance. Progressive increase of the
bilateral occipital calcification was found on three computed
tomography (CT) scans obtained between the ages of 4 and
12 years (Fig 1A). Adjacent low-density areas, more marked
on the right,.were seen on the latter scan. Angiographic findings were normal. T1-weighted magnetic resonance images
(MRIs) obtained at age 14 (Fig 1B) showed high-intensity
signals in white matter close to the abnormal cortex and to
the areas of void signal corresponding to the calcifications.
She had poor memory, language, and visual perceptive
function, implicating parietooccipital areas bilaterally. On
the Wechsler Intelligence Scale for Children-Revised
(MISC-R), her verbal I Q was 81; performance IQ, 75; and
full-scale lQ, 77.
An extensive resection of the right lateral occipital cortex
was carried out. It led to a minor increase in the visual field
defect. In the first 18 months after the operation, she had
seven brief seizures and over the next 4 years was seizure
free. A CT scan made 4 years after surgery showed no increase in the remaining calcifications.
Gastroenteralogical Investigations
The patient had a gastrointestinal (GI) assessment because
of persistent folate and iron deficiency, associated with a mild
anemia, detected during her preoperative work-up. She had a
long-standing history of pot belly and poor appetite, delayed
puberty, and three fractures following trivial in juries. She
was underweight for height and in the 25th percentile for
weight. The vitamin BI2 level was 650 pgiml (normal:
190-1,000 pgiml), antigliadin antibodies were 182 arbitrary
units (normal: < 2 5 ) , and an upper GI barium series showed
an increase in duodenal folds consistent with a mucosal abnormality. Examination of a small-bowel biopsy specimen
demonstrated partial villous atrophy with questionable presence of intracellular vacuolation, suggesting lipid entrapment
within enterocytes. She was maintained on a normal diet and
a small-bowel biopsy was repeated 6 weeks later. Marked
villous atrophy with hyperplastic crypts and plasma cell infiltrate without vacuolation of enterocytes was found, consistent with a histological diagnosis of celiac disease. Antigliadin
antibodies were now 78.2 arbitrary units. She did not have
biochemical or radiological evidence of vitamin D, A, and K
deficiency, but the vitamin E level was significantly depressed
Annals of Neurology
Fig 1 . (A)Computed tomogram obtained at age 12: bilateral occipital calcifications with hypodensity anterior to them, particukwh o n the right. (BJ Magnetic resonance image obtained at
age 14: void signal corresponding to the calcifications and abnormal signal in white matter anterior to these, suggesting gliosis
(right is left on image).
Vol 34 N o 3 September 1093
at less than 1 mM/liter (normal: 8-30 mM/liter). Results of
lipid studies were normal. There was no clinical evidence of
vitamin E deficiency.
A gluten-free diet was commenced together with folate,
vitamin E, and iron supplementation. Appetite and general
well-being increased and weight reached the 50th to 75th
Hematological indices, plasma, iron, and folate became
normal. A follow-up small-bowel biopsy performed 1 year
later while on a gluten-free diet confirmed a significant improvement in her mucosal abnormality.
Pathological Findings
All brain tissues excised during surgery were submitted.
Numerous sections were stained with hematoxylin-eosin,
Uuver-Barrera, and Weigert’s stain for elastic fibers. There
were a few foci of pial angiomatosis, which were less extensive than in classic SWS (Fig 2A). They were mostly localized
over pathological cortex and separated by wide segments of
normally vascularized leptomeninges. They consisted of
groups of small veins, which were frequently entrapped
within bands of collagen resembling scar tissue. Few pial
veins displayed heavily calcified walls surrounding a wide cuff
of intimal fibrosis, which almost occluded the lumen (Fig
2A). The larger veins that were part of the pial angiomatosis
displayed prominent, dome-shaped endothelial cells; their cytoplasm was strongly immunoreactive for factor VIII antigen.
Although there were numerous isolated microcalcifications
with laminated cores that spared Local neuronal architecture,
the cortical lamination was otherwise extensively blurred by
coalescent clusters of large calcifications with jagged edges,
without laminar distribution, to the point where the architectural features of the normal parietooccipital cortex had been
completely lost (Fig 2B).
In the cortical neuropil there were many small, severely
sclerosed veins. Some of these showed evidence of multiscgmental dissection of intravascular tissues, with occasional
lymphocytic perivascular cuffing (Fig 2C). There was no fibrinoid necrosis, or smooth muscle cell hyperplasia. Several
veins were heavily calcified and had severely stenosed lumina
(Fig 2D). The superficial and intermediate white matter was
irregularly atrophic, and harbored many macrophages amid
areas of poorly demarcated pallor of myelin. The cortex and
white matter showed no sign of neuronal migration disorder
and there was no cortical or white matter cavitation. Superficial and intermediate white matter displayed advanced
wallerian degeneration, with deposition of abundant macrophages. Blank slides submitted to immunocytochemical analysis using the classic peroxidase-antiperoxidase method with
glial fibrillary acidic protein (GFAP) and factor VIII antibodies revealed moderate degrees of reactive gliosis, mostly localized to the edges of the cortical microcalcifications and
white matter atrophy.
Like many patients described in the literature [S- lo},
this girl was first considered to suffer from SWS with
bilateral calcifications but without nevus flammeus.
While patients with SWS and bilateral calcifications
certainly exist and patients with SWS without nevus
flammeus may also be seen, the association of both
these features must be unusual. In 1985 we described
the syndrome of epilepsy and bilateral occipital cakifications as a distinct entity, different from SWS {21, and
in 1988 we stressed the folic acid deficiency that may
be present 131 and the relationship to the celiac disease
that can be demonstrated in many of these patients.
Recently there was a veritable explosion of interest
in this condition. The largest series of patients have
been from Italy (Gobbi and colleagues 111) from the
Bologna School, Magaudda and the group from Verona [12), Gobbi and the Italian working group on
celiac disease and epilepsy { 131). The large number of
Italian patients seems related to the fact that the incidence of celiac disease is particularly high in Italy (C. A.
Tassinari, personal communication, 1992). The reason
for this is unclear. Furthermore, Ambrosetto and his
colleagues El41 showed that occipital seizures associated with celiac disease but without cerebral calcifications may be an early manifestation of the disorder,
with the calcifications developing later. Hypodensity
on CT and abnormal MRI signal, usually anterior to
the calcifications, have been described and the clinical
patterns of the seizures analyzed C11-131. Occipital
lesions may lead not only to occipital but also to temporal EEG epileptic discharges 1151; this pattern has
also been found in some patients with celiac disease
and occipital calcifications [2, 13f. Affected patients
may have other partial seizures as well 1131, perhaps
related to the development of calcifications more anteriorly, particularly in frontal regions 113-161. Generalized epilepsies may also occur I1 31. The attacks may be
relatively easily controlled or remain intractable. Our
previously described 4 patients and many of those reported by other authors were not considered to require
a surgical approach.
A gluten-free diet led to a clear decrease in seizures
in some of the patients reported by Gobbi and colleagues { 131. In our patient, in addition to the surgical
resection, a diet with folate supplementation led to
general improvement and this may have been a factor
in seizure control as well.
The disorder is sporadic for the most part, with the
exception of the two siblings with intracranial hernangiomatosis who seemed to have had this disease, as described by Tateno and coauthors 1161. One died due
to aplastic anemia; the other had, in addition, macular
degeneration. The parents were first cousins; this raises
the possibility of autosomal recessive inheritance but
the absence of other familial cases renders this unlikely. At autopsy the older brother was found to have
“multiple venous hemangiomas in the deep layers of
the cortex and subcortical white matter” {lb). The
walls of the vessels were calcified and there were also
calcium deposits between vessels. The white matter
surrounding these areas showed increased glial cells
Brief Communication: Bye et al: Celiac Disease, Epilepsy, Occipital Calcification 401
and demyelination. Taly and associates {S) in 1987 described tissue removed during surgical treatment of
epilepsy from a patient wrongly diagnosed as having
SWS without nevus flammeus who probably had this
syndrome. They described vascular charges but no pial
angiomatosis; this is difficult to recognize pathologically although it is easily seen by the surgeon at operation (T. B. Rasmussen, personal communication, 1985).
The morphological changes in our patient were distinct from those reported in SWS patients; they usually
have better preserved cortical architecture and frequently laminar distribution of microcalcifications,
which tend to be round and smaller than those observed in the present syndrome. Neuritic calcosiderosis appears more prominent in SWS. However, in the
late stages of SWS, more extensive neuronal loss and
larger calcifications have also been recorded.
Thus, patients with celiac disease, occipital calcifications, folate deficiency, and epilepsy, like those with
SWS, have a vascular abnormality underlying the lesion. It involves mainly small veins and bears a certain
resemblance to the pathological changes found in
SWS where folate deficiency has, to OUT knowledge,
not been described. Folate deficiency due to antifolate
agents and x-ray therapy in leukemic children E5) may
also lead to occipital cortical calcifications but it is not
clear whether similar vascular changes occur in that
situation as well. Because of the pathological similarity,
folate metabolism in patients with SWS and in parents
is currently under study. This may lead to better understanding of the presently unknown mechanisms of that
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Sturge-Weber syndrome. Aust Paediatr J 1989;25:103-105
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and cerebral calcifications. Lancet 1992;340439-443
14. Ambrosetto G, Antonini L, Tassinari A . Occipital lobe seizures
related to clinically asymptomatic celiac disease in adulthood.
Epilepsia 1392;33:476-481
15. Palmini A: Andermann F, Dubeau F, et al. Occipito-temporal
epilepsies. Evaluation of selected patients requiring depth electrode studies and rationale for surgical approaches. Epilepsia
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multiple intracranial haemangiomatosis with calcification. Neurology 1985;232 : 112-1 14,
Fzg 2 (A)Area of extenrzvely jibroseid subarachnozd space tn
u h c h u network of tmall zeiiis z~ entrapped I n the left upper
corner, u markedly calufied Jmall tein zmmedtately abuts the
arachnozd membrane (Bi Severe mtzilzdf fibroszs and stenoszs of
an antracortzcal small vezn. which zs surrounded by nnmerOuJ
haphazardly scattered microcalLzficatzon\ smera) of u hzch appeared to haw coalesced to form much larger,jagged culctficat i o m All nezdwns t n ~uch
focz were usuafh ertterely degenerated
and replaced by few hypertrophic reactive astrocytej (C) iZ/lidcortical I zeu of two aberrant Jmallfibrosed veins, whose walls appear t o have been dissected uzthout injammatoy cbangeJ They
uere suwoundd by scattered mm+ocalcz/icationsAdjacent pyramz&l t c l h were extensiwly disawayed. (0)A snzall cortical wzn
that ZJ heavzly calcified and weref1 stenosed (All hematoxylineoJzn x 123 before 31 reductzon )
Brief Communication: Bye et al: Celiac D~sedse,Epilepsy, Occipital Calcification 403
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occipital, syndrome, vascular, cortical, deficiency, calcification, celiac, abnormalities, disease, bilateral, epilepsy, folate
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