Saturday 22 August
No 8817
1992
ORIGINAL ARTICLES
Coeliac disease, epilepsy, and cerebral calcifications
There have been anecdotal reports of an association between coeliac disease and epilepsy with cerebral calcifications that resemble those of the Sturge-Weber syndrome. A series of patients who had epilepsy with calcifications, in whom coeliac disease (CD) was incidentally observed, prompted us
to
study this association.
43 patients (15 male, age range 4·6-30·7 years) were selected from two series. 31 patients with cerebral calcifications of unexplained origin and epilepsy (series A) underwent intestinal biopsy. 12 patients with CD and epilepsy (series B) underwent computed tomography. Antibodies to gluten, folic acid serum concentrations, were measured, and H LA typing was done in most patients. 24 of the series A patients were identified as having CD on the basis of a flat intestinal mucosa (15/22 with a high concentration of serum antigluten), and 5 series B patients showed cerebral calcifications, giving a total of 29 cases with the combination of CD, epilepsy, and cerebral calcifications (CEC). In 27 of these CEC patients, calcifications were located in the parieto-occipital regions. Only 2 of the series A patients had gastrointestinal symptoms at the time of intestinal biopsy; most patients had recurrent
diarrhoea, anaemia, and other symptoms suggestive of CD in the first 3 years of life. The epilepsy in CEC patients was poorly responsive to antiepileptic drugs. Gluten-free diet beneficially affected the course of epilepsy only when started soon after
epilepsy onset. Cases of "atypical Sturge-Weber syndrome" (characterised by serpiginous cerebral calcifications and epilepsy without facial port-wine naevus)
should be reviewed, and CD should be ruled out in all cases of epilepsy and cerebral calcifications of
unexplained origin. Lancet 1992; 340: 439-43.
Introduction There has been considerable interest in the association of coeliac disease (CD) with neurological disorders, especially an increased frequency of epilepsy (up to 5 %). I-’ Moreover, anecdotal reports have described an association of CD with epilepsy and cerebral calcifications like those seen in the
Sturge-Weber syndrome (SWS). Atypical (without facial naevus) SWS with epilepsy has also been reported.7,8 Unfortunately CD was not assessed in those patients, and there is no reason to regard the cases of cerebral calcification without facial port-wine angioma as "atypical SWS". An unexpected series of patients who had cerebral calcifications with epilepsy in whom CD was incidentally observed prompted us to study the association between CD and epilepsy. Patients and methods Patients 43 patients (15 male, 28 female; mean [SD] age 16[6’6] years [range 4-6-30 7]) were selected retrospectively from those attending
ADDRESSES Divisione di Neuropsichiatria Infantile (F. Bouquet, MD) and Clinica Pediatrica dell’Universitá (A Ventura, MD), Istituto per l’Infanzia, Trieste; Servizio di Neuropsichiatria Infantile, Reggio Emilia (G Gobbi, MD); Clinica Pediatrica, II Facolta’ di Medicina e Chirurgia, Universitá di Napoli (L Greco, MD); Divisione di Pediatria, Ospedale Maggiore, Bologna (A Lambertini, MD, M. G Zaniboni, MD), and Divisione de Neurologia, II Cattedra di Neurologia, Ospedale Bellaria, Universitá di Bologna (C A Tassinari, MD). Correspondence to Dr Giuseppe Gobbi, Servizio di Neuropsichiatria Infantile, USL 9, Via Amendola 2, 42100 Reggio Emilia, Italy
440
the
departments of Working Group members over 6 months from series. Series A consisted of 31 patients with epilepsy and cerebral calcifications of unexplained origin attending various neurological departments. 13 of these patients have previously been reported. 5,6,11-11 Series B consisted of 12 patients with CD (according to the 1979 European Society for Pediatric Gastroenterology and Nutrition criteria)12 and epilepsy attending paediatric and gastrointestinal departments. Patients with other causes of cerebral calcifications (encephalitis, purulent meningitis, leukaemia, chemotherapy, neonatal haemorrhage, congenital infection, and disturbances of calcium and phosphorus metabolism) were two
excluded. Patients who had tuberous sclerosis and SWS with with
port-wine facial naevus were also excluded but 3 patients complete SWS underwent intestinal biopsy as control cases. Methods Series A
patients underwent full gastrointestinal evaluation, including biopsy of the small intestine, for diagnosis of CD. 19 patients had a xylose afterload test and 28 had assessment of antibodies to gluten. Serum folic acid was measured in 26 patients. HLA typing was available for 22 patients. Individuals with unequivocal flat mucosa on biopsy were prescribed a gluten-free diet. Patients from series B underwent neurological examination, including computed tomographic (CT) scanning and electroencephalography (EEG). Written informed consent was obtained before the study from all patients or their parents. Small-bowel biopsy was performed with a Watson-Crosby capsule at the level of the Treitz ligament. Morphology was scored according to Dunnill and Whitehead’s criteria.13 Crypt hyperplasia and unequivocal flat mucosa were regarded as markers of CD. Antigliadin IgG and IgA were assessed by enzyme-linked immunosorbent asay (Alfa-Gliatest, Eurospital Pharma, Trieste, Italy). Cerebral CT scan was done according to standard techniques: images were reassessed by a peer-review committee of the Italian Working Group. EEG recordings accorded with the 10-20 International System of electrode placement.14 Psychomotor development was assessed by the Wechsler scale (children and adults) or other methods (eg, Brunet Lezine adapted for age test) appropriate to the age of the subject. Epilepsy was classified according to the 1981 and 1989 criteria of the International League Against Epilepsy.15,16 The SPSS-PC+ computer package was used for statistical analysis. Data are shown as mean (SD).
Results
gastrointestinal complaints. 1
This group consisted of 8 male and 21 female years
a
CEC
Note impressive bilateral occipital cortical-subcortical calcifications. Asterisk denotes front right
diagnosis did not differ between the two series: 17% were underweight and 27% were short in stature. Gut-The gastrointestinal fmdings of the CEC patients are as
follows: —
Gut complamts at diagnosis Reported complaints up to age
No of CD cases/no tested Series A Series B
2*/24
5t/5
Recurrent diarrhoea Meteorism Anaemia Recurrent aphthous stomatitis Previous diagnosis of CD
21/24 14/24 7/24 4/24
5/5 5/5 1/5 1/5
(GFD stopped or not done)
9/24
..
Abnormal antibodies to gluten at
diagnosis
folate at diagnosis Xylose afterload test at diagnosis GFD = gluten-free diet Low
serum
15/22 17/19 10/16
1/2 _
.
5/5
*Mild recurrent diarrhoea tchronic diarrhoea, failure to thrive, abdominal distension, anaemia
(CEC)
(15-5 [6-2]
of cerebral calcifications in
3 yr
24 of the series A patients had unequivocal CD. 5 of the series B patients showed cerebral calcifications on the CT scan. Thus, there were 29 patients with CD, epilepsy, and cerebral calcifications (CEC, group 1), 7 with CD and epilepsy without cerebral calcifications (group 2), and 7 with epilepsy and cerebral calcifications without CD (group 3). The 3 control patients had normal mucosa and no
Group
Fig 1-Typical pattern patient.
patients
[range 4-4-30-0]).
Cerebral calcifications-Calcifications identified at age 12-9 (3-6) years (4-20). Bilateral Unilateral Total PO parieto-occipital
PO 20 3
23
on
CT
scan were
PO + other*
Othert
3 1 4
1 1 2
=
*PO extended to frontal regions tParasellar region and lenticular nuclei
Fig 1 shows the typical pattern of calcifications, and individual locations are depicted in fig 2. CD-Age at diagnosis of CD was 14-8 (7-0) years (4-32) in the series A patients and 19-2 (7-2) years (8-28) in the series B patients. The distribution of weight and height centiles at
HLA typing, performed in 16 cases, showed that 15 had the DQw2 phenotype (table I).
Neurological features at onset of epilepsy-In all CEC patients epilepsy started before the diagnosis of CD at 64 (4-5) years (1-14). In 2 infants epilepsy had started in the first year of life, in 16 from 1 to 6 years, and in 7 from 7 to 14 years. 5 had generalised epilepsy; the other 24 had partial epilepsy, of whom 19 had occipital seizures and 5 had other types of partial seizure. 20 of the 29 cases showed focal abnormalities on EEG and 5 showed generalised abnormalities. EEG was normal in 4 patients. Mental development was normal for age in 23 patients. There were no neurological signs at clinical examination. Neurological course -1 (7’1) years (4’0-27’0) elapsed from the onset of epilepsy to the identification of CD with
441
TABLE H—FACTORS RELATED TO SEIZURE COURSE t
*Seizure frequency mcreased more than 50% tSeizure frequency decreased more than 50%. GFD = gluten-free diet
Epilepsy worsened (seizure frequency increased more than 50%) in 1 and was unchanged in 9. The chances of seizures stopping after the diet did not seem to be related to age at onset of epilepsy, but was significantly inversely related to the duration of epilepsy before and to the age at the beginning of the gluten-free diet (table n). In the 6 patients in whom seizures stopped after the diet the seizure frequency before the diet was more than 1 a year in 2 (followed up for 4 years), more than 1 a week in 3 (followed up for 6, 7, and 12 months), and more than 1 a day in 1 (followed up for 10 months). At onset of epilepsy, mental development was normal in 23 cases, impaired in 3, unknown in 3. At the beginning of the gluten-free diet mental development was normal in 10 patients, impaired in 13, and unknown in 6. Not enough time elapsed on the gluten-free diet to check mental development after the diet.
Group 2 Fig 2-Location of cerebral calcifications in 29 CEC patients (schematic representation). the consequent start of a gluten-free diet. At the time of intestinal biopsy, seizures were drug resistant in 25 cases despite antiepileptic treatment: seizures stopped in only 4 cases. In particular, among 19 cases with partial epilepsy and occipital lobe seizures the evolution was benign in 3 whereas the seizures persisted unchanged despite antiepileptic treatment in 8. In the remaining 8 cases of partial epilepsy with occipital lobe seizures, the evolution was characterised by an apparently benign onset with progressive severity as already described.17 The seizures were drug resistant in all 5 cases affected by other types of partial epilepsy and in all cases but 1 with generalised epilepsy. After the diagnosis of CD, all patients were prescribed a gluten-free diet. 20 had a minimum of 6 months’ follow-up (mean 25-4 months; range 6-72). Mean duration of epilepsy before the diet of these 20 cases was 7-3 years (range 0-1-19-1). The frequency of seizures at the beginning of the diet was more than 1 a day in 7 patients, more than 1 a week in 7, more than 1 a month in 3, and more than 1 a year in 3. In 3 cases, duration of follow-up was less than 1 year: seizure frequency in these cases was more than
day in 1 patient, and more than 1 a month in 2. improved (frequency decreased by more than 50%) in 4 patients and stopped in 6 after the gluten-free diet. 1
a
Seizures
TABLE I-HLAANTIGENS IN THE3GROUPS OFPATIENTS
This group consisted of 3 male and 4 female patients (10-7 years old [8 months-19 years]). No abnormality was found on the CT scan. CD was diagnosed at age 4-5 (45) years (1-12). Antigluten IgA and IgG assessed in 2 patients at diagnosis were positive. Folic acid serum concentration was measured only in 1 patient, and was below normal range. Xylose afterload blood concentration was below normal range in 4 patients and normal in the others. Weight was equal to or below the 3rd centile in 2 patients, between the 4th and 25th centile in 3, and over the 25th centile in the remaining 2. For height the data are 2, 2, and 3, respectively. At the time of the study, all patients were on a gluten-free diet and had no clinical gastrointestinal signs. Epilepsy started at age 4-8 (3-9) years (8 months to 10 years). In 5, seizures started before the diagnosis of CD. Unlike those in group 1, seizures were usually generalised (6/7)-eg, absences and/or tonic clonic seizures. Psychomotor development was normal in 5 patients and severely compromised in 2. Follow-up over 6 months was possible in 4 of the 5 patients in whom epilepsy had started before diagnosis of CD. In all 7 patients of this group, course of the seizures was
[6’1]
benign.
Group 3 There were 4 male and 3 female patients (15-5 [4.0] years old [range 8-21]) in this group. CT scan disclosed impressive cortical subcortical serpiginous calcifications in all cases; they were located in the parieto-occipital regions in all cases and were also bilateral in 5. Cerebral calcifications were diagnosed at 9-9 (2-2) years (7-5-14).
442
judged by intestinal biopsy, all patients had normal Antigluten IgA and IgG were normal in all In 3 of 6 patients in whom serum folic acid was patients. were below normal range; xylose concentrations measured, afterload test was normal in all 6 tested patients. HLA typing was done in 6 patients (table 1). No patient had either a history of diarrhoea or diarrhoea at the time of the intestinal biopsy nor did any patient have a history of gut signs. Weight was above the 25th centile in 6 of 7 and below the 3rd in 1. Height was above the 25th in 4 and below the 3rd in 3. Epilepsy started at age 5-9 (4-6) years (8 months-12 years). 2 patients had generalised seizures, whereas 5 had partial seizures. At onset of epilepsy, seizure frequency was As
mucosa.
variable. The EEG findings pointed to generalised abnormalities in 2 patients and focal abnormalities in 4. EEG was normal in 1 patient. Psychomotor development was slightly delayed in 4 patients at onset. Course of epilepsy varied: after 9-5 (5-0) years (2-16) the seizures persisted unchanged in 3 patients, improved in 2, and worsened in the other 2. Psychomotor development deteriorated in all these cases.
Discussion The
typical radiological pattern of SWS
consists of
sinuous, garland-shaped, double-contoured calcifications often with
hypoplastic convolutions (microgyria), most frequently involving the occipital and parietal area of one side.18 Few reports have pointed to an association between this type of cerebral calcifications and CD. 3--5,9,10 The association of CD with epilepsy and cerebral calcification is unlikely to be coincidental since there is no reason for there to be a higher frequency of CD in subjects with cerebral calcifications than in the normal population. CD may be symptomless in teenagers and young adults. Our series had a mean age at biopsy of 14-8 years, and many of these patients could be regarded as having symptomless disease. Most such cases may be missed, as evidenced by our findings that many patients had histories of serious gastrointestinal complaints and that diagnosis of CD had been suggested by the paediatricians during infancy in some.
The finding that 17 of 19 patients had very low serum folate at the time of intestinal biopsy was unexpected for "symptom-free" coeliac patients, compared with a series of young adultsl9 and a group of symptom-free familial cases.2o It is difficult to establish whether our CEC patients had SWS. The clinical course of the disease and epilepsy in our cases differ from those of typical SWS.21 Moreover, there was no choroid plexus enlargement nor local or diffuse brain atrophy, which are common CT and magnetic resonance image findings in SWS. In the few patients who underwent enhanced CT scanning, abnonnal deep cerebral veins, which are often seen in cases of SWS, were not detected. Although none of our patients underwent cerebral biopsy, the 2 published cases with histological examination cannot throw light on this problem: even though histological findings seem to be typical of SWS in case number 3ofIto,22 leptomeningeal angiomatosis was not seen in Taly’s case23 in accordance with a report by others.24 Moreover, in 3 of our patients with complete SWS who underwent intestinal biopsy, mucosa was normal. Thus, we feel that CEC cases do not overlap with SWS and that the cerebral calcifications probably havea different origin. The HLA phenotype data of our CEC patients accord with other reported series25--27 of coeliac patients.
The pathogenetic relation between CD and epilepsy with cerebral calcifications is beyond the limits of this descriptive study; however, we have some suggestions. Neurological impairment and various cerebral calcifications have been found in both iatrogenic folic acid deficiency (ie, methotrexate therapy and radiotherapy)28.29 and in congenital folate malabsorption.3O The calcifications in our series could be related to chronic persistent folic acid deficiency due to unrecognised CD and also to the effect of antiepileptic drugs.31 Drug influence, however, seems less likely because antiepileptic-induced folate deficiency is rare and in some of our patients therapy was started after calcifications had been found. Since CD may be associated with different autoimmune disorders,32-34 we cannot rule out the possibility that cerebral calcifications depend on autoimmune or immune-complex-related endothelial inflammation. If there were such a possibility, the particular cerebral location of the calcifications, which remains unexplained, could be related to a selective vulnerability of the occipital lobe. 35 Finally there may not be any sequential correlation between CD, epilepsy, and cerebral calcifications; this association could be a genetically determined syndrome. In 25 of the 29 CEC patients, seizures were resistant to antiepileptic drugs, whereas seizures stopped in only 4 cases. Awareness of the severe prognosis of epilepsy with mental impairment in patients with serpiginous occipital calcifications has already been suggested by Gobbi et al" and confirmed by Giroud et aF4 (although there is no mention of CD). The part played by inadequately treated CD during the severe course of epilepsy is unknown. We found that in the 6 patients whose seizures stopped after the gluten-free diet, both the mean duration of the epilepsy before the diet and the mean age at the beginning of the diet were significantly lower than in the other 14 patients followed up for 6 months. In particular, these 6 patients were under 13 years with a mean age of 9-1 years. Even though the duration of both epilepsy and CD before the diet was much longer than the duration of the gluten-free diet, these data suggest that if the diet is started near to the onset of epilepsy and early in childhood, it may be effective in controlling seizures. However, a longer follow-up in a much larger series is needed to confirm this hypothesis. It is possible that food practices are important in the incidence of CD, which is higher in some European countries than in others. It would be interesting to know whether countries with a high incidence of CD also have a high incidence of CEC. In the group 2 patients (CD and epilepsy withourcerebral calcifications) CD was diagnosed early so that they went on a gluten-free diet at a mean age of 4-5 years. Although we cannot exclude the possibility that there is a correlation between prompt institution of such a diet and the absence of calcifications, the epileptic seizures in this group were very different from those in the CEC group. In particular, most of them had only generalised seizures similar to those of the idiopathic generalised epilepsies starting in childhood. Therefore, we presume that the association between epilepsy and CD in these cases is coincidental. The group 3 patients (epilepsy with cerebral calcifications without flat mucosa) had several similarities with the CEC group with respect to location of calcifications, seizures, and HLA phenotype, consistent with a diagnosis of CD.25-27 Because several cases of CD with "patchy" intestinal mucosal lesions or late-onset enteropathy have been reported,36 we speculate that some of our group 3 patients
443
could have had CD even though they had a normal intestinal biopsy. That 3 of the 6 tested cases had low serum folic acid also points to a diagnosis of CD. We believe that the CEC association is probably more common
than is
thought.
All
cases
previously reported
as
"atypical SWS" because of the absence of port-wine angioma, should be reviewed, in view of the possible association with CD. We also recommend that paediatric neurologists should rule out CD in all cases of epilepsy and cerebral calcifications of unexplained origin, especially when the epilepsy is characterised by occipital seizures and the calcifications located bilaterally in the posterior regions. Because gastrointestinal signs are often missing, paediatric neurologists might be the only ones to discover CD in these patients. Even though the efficacy of the gluten-free diet in controlling epileptic seizures in these cases has to be proven by a longer follow-up in a larger series of patients, the efficacy of the gluten-free diet seems to be inversely related to the duration of epilepsy before the diet and to the age at the beginning of the diet. We thank Mrs Carla Pini for her kind cooperation, and Mrs Anne Collins for revising the English text.
Members of the Italian Working Group are: Dr P. Ambrosetto, Clinica Neurologica, Universitá Bologna; Dr F. Balli, and Dr V. Galli, Clinica Pediatrica, Universitá Modena; Dr P. A. Battistella, Dr C. Boniver, and Dr F. Donzelli, Dipartimento Pediatria, Universitá Padova; Dr P. A. Bianchi, Dr N. Molteni, and Dr M. T. Bardella, Patologia Medica III, Universitá Milano; Dr E. Del Giudice and Dr F. Correale, Clinica Pediatrica, Universitá Napoli; Dr G. Della Cella, Divisione Pediatria, Ospedali Riuniti, Chiavari; Dr P. G. Garofalo, Dr C. Durisotti, and Dr C. Filati, Divisione Neurologia, Ospedale Civile Vicenza; Dr A. M. Giunta, Clinica Pediatrica II, Università Minalo; Dr A. Miano, Divisione Pediatria, Ospedale Bufalini Cesena; Dr A. Pascotto and Dr G. Coppola, Istituto Neuropsichiatria Infantile, Universitá Napoli; Dr L. Piattella and Dr N. Zamponi, Divisione Neuropsichiatria Infantile, Ospedale Salesi Ancona; Dr P. Santanelli, Clinica Neurologica, Universitá Napoli; Dr E. Veneselli, Divisione Neuropsichiatria Infantile, Istituto Gaslini, Universitá Genova; Dr F. Viani and Dr A. Van Lierde, Centro Regionale Studio Epilessia, Milano, Italy; Dr G. P. Corazza, Patologia Medica, Università Bologna.
REFERENCES
JM, Chapman RG, Colin Jones DG, Eade O, Smith CL. Increased prevalence of epilepsy in coeliac disease. Gut 1977; 18: A 943. 2. Chapman RG, Laidlow JM, Colin Jones DG, Eade OE, Smith CL. Increased prevalence of epilepsy in coeliac disease. BMJ 1978; 2: 250-51. 3. Sammaritano M, Andermann F, Melanson D, Guberman A, Tinuper P, Gastaut H. The syndrome of intractable epilepsy, bilateral occipital calcifications and folic acid deficiency. Neurology 1988; 38 (suppl 1): 239. 4. Garwicz S, Mortensson W. Intracranial calcifications mimicking the Sturge-Weber syndrome (a consequence of cerebral folic acid deficiency?). Pediatr Radiol 1976; 5: 5-9. 5. Molteni N, Bardella MT, Baldassarri AR, Bianchi PA. Celiac disease associated with epilepsy and intracranial calcifications: report of two patients. Am J Gastroenterol 1988; 83: 992-94. 6. Della Cella G, Beluchi C, Cipollina F. Intracranial calcificationsepilepsy—celiac disease: description of a case. Med Surg Pediatr 1991; 13: 427-30. 7. Ambrosetto P, Ambrosetto G, Michelucci R, Bacci A. Sturge Weber syndrome without port-wine facial nevus. Child’s Brain 1983; 10: 387-92. 8. Battistella PA, Casara GL, Carollo C, Cattelan C, Condini A, Pardatscher K. Calcificazioni cerebrali bilaterali senza angiomatosi cutanea: forma atipica della malattia di Sturge Weber. Riv Ital Ped (IJP) 1986; 12: 417-18. 9 Zaniboni MG, Lambertini A, Gobbi G, et al. Celiac disease and epilepsy with occipital calcifications: an uncasual association. In: Banchini G, Gaundalini S, De Angelis GL, Walker-Smith JA, eds. Proceedings of the 1st British Italian Pediatric Gastroenterology Meeting, 1989 Sept 22-23; Parma (Italy): 54. Humana Italia Sp. A, Milano. 10. Ventura A, Bouquet F, Sartorelli C, Barbi E, Torre G, Tommasini G. Coeliac disease, folic acid deficiency and epilepsy with cerebral calcifications. Acta Paediatr Scand 1991; 80: 559-62. 11. Del Giudice E, Pelosi L, Romano A, et al. Unexplained bilateral occipital calcification and reduced vision. Neuropediatrics 1984; 15: 218-19. 1. Laidlow
12. McNeish AS, Harms HK, Rey J, Shmerling DH, Visakorpi JK, Walker Smith JA. The diagnosis of coeliac disease. Arch Dis Child 1979; 54:
783-86. 13. Dunnill MS, Whitehead R. A method for the quantification of small intestinal biopsy specimen. J Clin Pathol 1972; 25: 243-45. 14. Jasper H. Report of committee on methods of clinical exam in EEG. EEG Clin Neurophysiol 1958; 10: 370-75. 15. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia
1981; 22: 489-501. 16. Commission
17.
on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilesies and epileptic syndromes. Epilepsia 1989; 30: 389-99. Gobbi G, Sorrenti G, Santucci M, et al. Epilepsy with bilateral occipital calcifications: a benign onset with progressive severity. Neurology 1988;
38: 913-20. 18. Maki Y, Samba A. Computed tomography of Sturge-Weber disease. Child’s Brain 1979; 5: 51-61. 19. Logan RFA, Tucker G, Rifkind EA, Heading RC, Ferguson A. Changes in clinical features of coeliac disease in adults in Edinburgh and the Lothians 1960-79. BMJ 1983; 286: 95-97. 20. Auricchio S, Mazzacca G, Tosi R, Visakorpi JK, Maki M, Polanco I. Coeliac disease as a familial condition: identification of asymptomatic coeliac patients within family groups. Gastroenterol Int 1988; 1: 25-31. 21. Alexander GL. Sturge-Weber syndrome. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. Amsterdam: Elsevier, 1972: 223-39. 22. Ito M, Sato K, Ohnuki A, Uto A. Sturge-Weber disease: operative indications and surgical results. Brain Dev (Tokyo) 1990; 12: 473-77. 23. Taly AB, Nagaraja D, Das S, Shankar SK, Pratibha NG. Sturge-WeberDimitri disease without facial nevus. Neurology 1987; 37: 1063-64. 24. Giroud M, Borsotti JP, Michiels R, Tommasi M, Dumas R. Epilepsie et calcifications occipitales bilatérales: 3 cas. Rev Neurol 1990; 4: 288-92. 25. De Marchi M, Carbonara A, Ansaldi N, et al. HLA-DR3 and DR7 in coeliac disease: immunogenetic and clinical aspects. Gut 1983; 24: 706-12. 26. Tosi R, Vismara D, Tanigaki N, et al. Evidence that coeliac disease is primarily associated with DC locus allelic specificity. Clin Immunol Immunopathol 1983; 28: 395-404. 27. Corazza GR, Tabacchi P, Frisoni M, Prati C, Gasbarrini G. DR and non-DR Ia allotypes are associated with susceptibility to coeliac disease. Gut 1985; 26: 1210-13. 28. Young LW, Jequier S, O’Gorman AM. Intracerebral calcifications in treated leukemia in a child. Am J Dis Child 1977; 131: 1283-85. 29. Namaguchi Y, Hoffman IC, Jones IP. Basal ganglia calcifications as a late radiation effect. Am J Roentgenol 1975; 123: 27-28. 30. Corbeel L, Van den Berghe G, Van Tornout J, Jaeken J, Eeckeels R. Congenital folate malabsorption. Eur J Pediatr 1985; 143: 284-90. 31. Reynolds EH. Anticonvulsants, folic acid, and epilepsy. Lancet 1973; i: 1376-78. 32. Copper BT, Holmes GKT, Cooke WT. Coeliac disease and immunological disorders. BMJ 1978; 1: 537-42. 33. Burgin-Wolff A, Gaze H, Hadziselimovic F, et al. Antigliadin and antiendomysium antibody determination for coeliac disease. Arch Dis Child 1991; 66: 941-47. 34. Maki M, Hallstrom O, Marttinen A. Reaction of human non-collagenous polypeptides with coeliac disease autoantibodies. Lancet 1991; 338: 724-25. 35. Hauser RA, Lacey M, Knight MR. Hypertensive encephalopathy: magnetic resonance imaging demonstration of reversible cortical and white matter lesions. Arch Neurol 1988; 45: 1078-83. 36. Maki M, Holm K, Kosmies S, Hallstrom O, Visakorpi JK. Normal small bowel biopsy followed by coeliac disease. Arch Dis Child 1990; 65: 1137-41.
From The Lancet Heavy-metal hazard Two samples of curry powder were found to contain 40 and 85 parts per million of lead, which comes from rubbing tumeric root with chromate of lead to improve its colour. This is an old offence, but the increased use of curry powder to give flavour and variety to war-time diet has brought it into importance. An occasional curry containing this small quantity of lead might not matter much, but in households where a curry once or more a week has become customary the danger of chronic lead poisoning cannot be overlooked. The practice of "improving" tumeric with chromate of lead should be stopped immediately. (July 4, 1942)
No 8817
1992
ORIGINAL ARTICLES
Coeliac disease, epilepsy, and cerebral calcifications
There have been anecdotal reports of an association between coeliac disease and epilepsy with cerebral calcifications that resemble those of the Sturge-Weber syndrome. A series of patients who had epilepsy with calcifications, in whom coeliac disease (CD) was incidentally observed, prompted us
to
study this association.
43 patients (15 male, age range 4·6-30·7 years) were selected from two series. 31 patients with cerebral calcifications of unexplained origin and epilepsy (series A) underwent intestinal biopsy. 12 patients with CD and epilepsy (series B) underwent computed tomography. Antibodies to gluten, folic acid serum concentrations, were measured, and H LA typing was done in most patients. 24 of the series A patients were identified as having CD on the basis of a flat intestinal mucosa (15/22 with a high concentration of serum antigluten), and 5 series B patients showed cerebral calcifications, giving a total of 29 cases with the combination of CD, epilepsy, and cerebral calcifications (CEC). In 27 of these CEC patients, calcifications were located in the parieto-occipital regions. Only 2 of the series A patients had gastrointestinal symptoms at the time of intestinal biopsy; most patients had recurrent
diarrhoea, anaemia, and other symptoms suggestive of CD in the first 3 years of life. The epilepsy in CEC patients was poorly responsive to antiepileptic drugs. Gluten-free diet beneficially affected the course of epilepsy only when started soon after
epilepsy onset. Cases of "atypical Sturge-Weber syndrome" (characterised by serpiginous cerebral calcifications and epilepsy without facial port-wine naevus)
should be reviewed, and CD should be ruled out in all cases of epilepsy and cerebral calcifications of
unexplained origin. Lancet 1992; 340: 439-43.
Introduction There has been considerable interest in the association of coeliac disease (CD) with neurological disorders, especially an increased frequency of epilepsy (up to 5 %). I-’ Moreover, anecdotal reports have described an association of CD with epilepsy and cerebral calcifications like those seen in the
Sturge-Weber syndrome (SWS). Atypical (without facial naevus) SWS with epilepsy has also been reported.7,8 Unfortunately CD was not assessed in those patients, and there is no reason to regard the cases of cerebral calcification without facial port-wine angioma as "atypical SWS". An unexpected series of patients who had cerebral calcifications with epilepsy in whom CD was incidentally observed prompted us to study the association between CD and epilepsy. Patients and methods Patients 43 patients (15 male, 28 female; mean [SD] age 16[6’6] years [range 4-6-30 7]) were selected retrospectively from those attending
ADDRESSES Divisione di Neuropsichiatria Infantile (F. Bouquet, MD) and Clinica Pediatrica dell’Universitá (A Ventura, MD), Istituto per l’Infanzia, Trieste; Servizio di Neuropsichiatria Infantile, Reggio Emilia (G Gobbi, MD); Clinica Pediatrica, II Facolta’ di Medicina e Chirurgia, Universitá di Napoli (L Greco, MD); Divisione di Pediatria, Ospedale Maggiore, Bologna (A Lambertini, MD, M. G Zaniboni, MD), and Divisione de Neurologia, II Cattedra di Neurologia, Ospedale Bellaria, Universitá di Bologna (C A Tassinari, MD). Correspondence to Dr Giuseppe Gobbi, Servizio di Neuropsichiatria Infantile, USL 9, Via Amendola 2, 42100 Reggio Emilia, Italy
440
the
departments of Working Group members over 6 months from series. Series A consisted of 31 patients with epilepsy and cerebral calcifications of unexplained origin attending various neurological departments. 13 of these patients have previously been reported. 5,6,11-11 Series B consisted of 12 patients with CD (according to the 1979 European Society for Pediatric Gastroenterology and Nutrition criteria)12 and epilepsy attending paediatric and gastrointestinal departments. Patients with other causes of cerebral calcifications (encephalitis, purulent meningitis, leukaemia, chemotherapy, neonatal haemorrhage, congenital infection, and disturbances of calcium and phosphorus metabolism) were two
excluded. Patients who had tuberous sclerosis and SWS with with
port-wine facial naevus were also excluded but 3 patients complete SWS underwent intestinal biopsy as control cases. Methods Series A
patients underwent full gastrointestinal evaluation, including biopsy of the small intestine, for diagnosis of CD. 19 patients had a xylose afterload test and 28 had assessment of antibodies to gluten. Serum folic acid was measured in 26 patients. HLA typing was available for 22 patients. Individuals with unequivocal flat mucosa on biopsy were prescribed a gluten-free diet. Patients from series B underwent neurological examination, including computed tomographic (CT) scanning and electroencephalography (EEG). Written informed consent was obtained before the study from all patients or their parents. Small-bowel biopsy was performed with a Watson-Crosby capsule at the level of the Treitz ligament. Morphology was scored according to Dunnill and Whitehead’s criteria.13 Crypt hyperplasia and unequivocal flat mucosa were regarded as markers of CD. Antigliadin IgG and IgA were assessed by enzyme-linked immunosorbent asay (Alfa-Gliatest, Eurospital Pharma, Trieste, Italy). Cerebral CT scan was done according to standard techniques: images were reassessed by a peer-review committee of the Italian Working Group. EEG recordings accorded with the 10-20 International System of electrode placement.14 Psychomotor development was assessed by the Wechsler scale (children and adults) or other methods (eg, Brunet Lezine adapted for age test) appropriate to the age of the subject. Epilepsy was classified according to the 1981 and 1989 criteria of the International League Against Epilepsy.15,16 The SPSS-PC+ computer package was used for statistical analysis. Data are shown as mean (SD).
Results
gastrointestinal complaints. 1
This group consisted of 8 male and 21 female years
a
CEC
Note impressive bilateral occipital cortical-subcortical calcifications. Asterisk denotes front right
diagnosis did not differ between the two series: 17% were underweight and 27% were short in stature. Gut-The gastrointestinal fmdings of the CEC patients are as
follows: —
Gut complamts at diagnosis Reported complaints up to age
No of CD cases/no tested Series A Series B
2*/24
5t/5
Recurrent diarrhoea Meteorism Anaemia Recurrent aphthous stomatitis Previous diagnosis of CD
21/24 14/24 7/24 4/24
5/5 5/5 1/5 1/5
(GFD stopped or not done)
9/24
..
Abnormal antibodies to gluten at
diagnosis
folate at diagnosis Xylose afterload test at diagnosis GFD = gluten-free diet Low
serum
15/22 17/19 10/16
1/2 _
.
5/5
*Mild recurrent diarrhoea tchronic diarrhoea, failure to thrive, abdominal distension, anaemia
(CEC)
(15-5 [6-2]
of cerebral calcifications in
3 yr
24 of the series A patients had unequivocal CD. 5 of the series B patients showed cerebral calcifications on the CT scan. Thus, there were 29 patients with CD, epilepsy, and cerebral calcifications (CEC, group 1), 7 with CD and epilepsy without cerebral calcifications (group 2), and 7 with epilepsy and cerebral calcifications without CD (group 3). The 3 control patients had normal mucosa and no
Group
Fig 1-Typical pattern patient.
patients
[range 4-4-30-0]).
Cerebral calcifications-Calcifications identified at age 12-9 (3-6) years (4-20). Bilateral Unilateral Total PO parieto-occipital
PO 20 3
23
on
CT
scan were
PO + other*
Othert
3 1 4
1 1 2
=
*PO extended to frontal regions tParasellar region and lenticular nuclei
Fig 1 shows the typical pattern of calcifications, and individual locations are depicted in fig 2. CD-Age at diagnosis of CD was 14-8 (7-0) years (4-32) in the series A patients and 19-2 (7-2) years (8-28) in the series B patients. The distribution of weight and height centiles at
HLA typing, performed in 16 cases, showed that 15 had the DQw2 phenotype (table I).
Neurological features at onset of epilepsy-In all CEC patients epilepsy started before the diagnosis of CD at 64 (4-5) years (1-14). In 2 infants epilepsy had started in the first year of life, in 16 from 1 to 6 years, and in 7 from 7 to 14 years. 5 had generalised epilepsy; the other 24 had partial epilepsy, of whom 19 had occipital seizures and 5 had other types of partial seizure. 20 of the 29 cases showed focal abnormalities on EEG and 5 showed generalised abnormalities. EEG was normal in 4 patients. Mental development was normal for age in 23 patients. There were no neurological signs at clinical examination. Neurological course -1 (7’1) years (4’0-27’0) elapsed from the onset of epilepsy to the identification of CD with
441
TABLE H—FACTORS RELATED TO SEIZURE COURSE t
*Seizure frequency mcreased more than 50% tSeizure frequency decreased more than 50%. GFD = gluten-free diet
Epilepsy worsened (seizure frequency increased more than 50%) in 1 and was unchanged in 9. The chances of seizures stopping after the diet did not seem to be related to age at onset of epilepsy, but was significantly inversely related to the duration of epilepsy before and to the age at the beginning of the gluten-free diet (table n). In the 6 patients in whom seizures stopped after the diet the seizure frequency before the diet was more than 1 a year in 2 (followed up for 4 years), more than 1 a week in 3 (followed up for 6, 7, and 12 months), and more than 1 a day in 1 (followed up for 10 months). At onset of epilepsy, mental development was normal in 23 cases, impaired in 3, unknown in 3. At the beginning of the gluten-free diet mental development was normal in 10 patients, impaired in 13, and unknown in 6. Not enough time elapsed on the gluten-free diet to check mental development after the diet.
Group 2 Fig 2-Location of cerebral calcifications in 29 CEC patients (schematic representation). the consequent start of a gluten-free diet. At the time of intestinal biopsy, seizures were drug resistant in 25 cases despite antiepileptic treatment: seizures stopped in only 4 cases. In particular, among 19 cases with partial epilepsy and occipital lobe seizures the evolution was benign in 3 whereas the seizures persisted unchanged despite antiepileptic treatment in 8. In the remaining 8 cases of partial epilepsy with occipital lobe seizures, the evolution was characterised by an apparently benign onset with progressive severity as already described.17 The seizures were drug resistant in all 5 cases affected by other types of partial epilepsy and in all cases but 1 with generalised epilepsy. After the diagnosis of CD, all patients were prescribed a gluten-free diet. 20 had a minimum of 6 months’ follow-up (mean 25-4 months; range 6-72). Mean duration of epilepsy before the diet of these 20 cases was 7-3 years (range 0-1-19-1). The frequency of seizures at the beginning of the diet was more than 1 a day in 7 patients, more than 1 a week in 7, more than 1 a month in 3, and more than 1 a year in 3. In 3 cases, duration of follow-up was less than 1 year: seizure frequency in these cases was more than
day in 1 patient, and more than 1 a month in 2. improved (frequency decreased by more than 50%) in 4 patients and stopped in 6 after the gluten-free diet. 1
a
Seizures
TABLE I-HLAANTIGENS IN THE3GROUPS OFPATIENTS
This group consisted of 3 male and 4 female patients (10-7 years old [8 months-19 years]). No abnormality was found on the CT scan. CD was diagnosed at age 4-5 (45) years (1-12). Antigluten IgA and IgG assessed in 2 patients at diagnosis were positive. Folic acid serum concentration was measured only in 1 patient, and was below normal range. Xylose afterload blood concentration was below normal range in 4 patients and normal in the others. Weight was equal to or below the 3rd centile in 2 patients, between the 4th and 25th centile in 3, and over the 25th centile in the remaining 2. For height the data are 2, 2, and 3, respectively. At the time of the study, all patients were on a gluten-free diet and had no clinical gastrointestinal signs. Epilepsy started at age 4-8 (3-9) years (8 months to 10 years). In 5, seizures started before the diagnosis of CD. Unlike those in group 1, seizures were usually generalised (6/7)-eg, absences and/or tonic clonic seizures. Psychomotor development was normal in 5 patients and severely compromised in 2. Follow-up over 6 months was possible in 4 of the 5 patients in whom epilepsy had started before diagnosis of CD. In all 7 patients of this group, course of the seizures was
[6’1]
benign.
Group 3 There were 4 male and 3 female patients (15-5 [4.0] years old [range 8-21]) in this group. CT scan disclosed impressive cortical subcortical serpiginous calcifications in all cases; they were located in the parieto-occipital regions in all cases and were also bilateral in 5. Cerebral calcifications were diagnosed at 9-9 (2-2) years (7-5-14).
442
judged by intestinal biopsy, all patients had normal Antigluten IgA and IgG were normal in all In 3 of 6 patients in whom serum folic acid was patients. were below normal range; xylose concentrations measured, afterload test was normal in all 6 tested patients. HLA typing was done in 6 patients (table 1). No patient had either a history of diarrhoea or diarrhoea at the time of the intestinal biopsy nor did any patient have a history of gut signs. Weight was above the 25th centile in 6 of 7 and below the 3rd in 1. Height was above the 25th in 4 and below the 3rd in 3. Epilepsy started at age 5-9 (4-6) years (8 months-12 years). 2 patients had generalised seizures, whereas 5 had partial seizures. At onset of epilepsy, seizure frequency was As
mucosa.
variable. The EEG findings pointed to generalised abnormalities in 2 patients and focal abnormalities in 4. EEG was normal in 1 patient. Psychomotor development was slightly delayed in 4 patients at onset. Course of epilepsy varied: after 9-5 (5-0) years (2-16) the seizures persisted unchanged in 3 patients, improved in 2, and worsened in the other 2. Psychomotor development deteriorated in all these cases.
Discussion The
typical radiological pattern of SWS
consists of
sinuous, garland-shaped, double-contoured calcifications often with
hypoplastic convolutions (microgyria), most frequently involving the occipital and parietal area of one side.18 Few reports have pointed to an association between this type of cerebral calcifications and CD. 3--5,9,10 The association of CD with epilepsy and cerebral calcification is unlikely to be coincidental since there is no reason for there to be a higher frequency of CD in subjects with cerebral calcifications than in the normal population. CD may be symptomless in teenagers and young adults. Our series had a mean age at biopsy of 14-8 years, and many of these patients could be regarded as having symptomless disease. Most such cases may be missed, as evidenced by our findings that many patients had histories of serious gastrointestinal complaints and that diagnosis of CD had been suggested by the paediatricians during infancy in some.
The finding that 17 of 19 patients had very low serum folate at the time of intestinal biopsy was unexpected for "symptom-free" coeliac patients, compared with a series of young adultsl9 and a group of symptom-free familial cases.2o It is difficult to establish whether our CEC patients had SWS. The clinical course of the disease and epilepsy in our cases differ from those of typical SWS.21 Moreover, there was no choroid plexus enlargement nor local or diffuse brain atrophy, which are common CT and magnetic resonance image findings in SWS. In the few patients who underwent enhanced CT scanning, abnonnal deep cerebral veins, which are often seen in cases of SWS, were not detected. Although none of our patients underwent cerebral biopsy, the 2 published cases with histological examination cannot throw light on this problem: even though histological findings seem to be typical of SWS in case number 3ofIto,22 leptomeningeal angiomatosis was not seen in Taly’s case23 in accordance with a report by others.24 Moreover, in 3 of our patients with complete SWS who underwent intestinal biopsy, mucosa was normal. Thus, we feel that CEC cases do not overlap with SWS and that the cerebral calcifications probably havea different origin. The HLA phenotype data of our CEC patients accord with other reported series25--27 of coeliac patients.
The pathogenetic relation between CD and epilepsy with cerebral calcifications is beyond the limits of this descriptive study; however, we have some suggestions. Neurological impairment and various cerebral calcifications have been found in both iatrogenic folic acid deficiency (ie, methotrexate therapy and radiotherapy)28.29 and in congenital folate malabsorption.3O The calcifications in our series could be related to chronic persistent folic acid deficiency due to unrecognised CD and also to the effect of antiepileptic drugs.31 Drug influence, however, seems less likely because antiepileptic-induced folate deficiency is rare and in some of our patients therapy was started after calcifications had been found. Since CD may be associated with different autoimmune disorders,32-34 we cannot rule out the possibility that cerebral calcifications depend on autoimmune or immune-complex-related endothelial inflammation. If there were such a possibility, the particular cerebral location of the calcifications, which remains unexplained, could be related to a selective vulnerability of the occipital lobe. 35 Finally there may not be any sequential correlation between CD, epilepsy, and cerebral calcifications; this association could be a genetically determined syndrome. In 25 of the 29 CEC patients, seizures were resistant to antiepileptic drugs, whereas seizures stopped in only 4 cases. Awareness of the severe prognosis of epilepsy with mental impairment in patients with serpiginous occipital calcifications has already been suggested by Gobbi et al" and confirmed by Giroud et aF4 (although there is no mention of CD). The part played by inadequately treated CD during the severe course of epilepsy is unknown. We found that in the 6 patients whose seizures stopped after the gluten-free diet, both the mean duration of the epilepsy before the diet and the mean age at the beginning of the diet were significantly lower than in the other 14 patients followed up for 6 months. In particular, these 6 patients were under 13 years with a mean age of 9-1 years. Even though the duration of both epilepsy and CD before the diet was much longer than the duration of the gluten-free diet, these data suggest that if the diet is started near to the onset of epilepsy and early in childhood, it may be effective in controlling seizures. However, a longer follow-up in a much larger series is needed to confirm this hypothesis. It is possible that food practices are important in the incidence of CD, which is higher in some European countries than in others. It would be interesting to know whether countries with a high incidence of CD also have a high incidence of CEC. In the group 2 patients (CD and epilepsy withourcerebral calcifications) CD was diagnosed early so that they went on a gluten-free diet at a mean age of 4-5 years. Although we cannot exclude the possibility that there is a correlation between prompt institution of such a diet and the absence of calcifications, the epileptic seizures in this group were very different from those in the CEC group. In particular, most of them had only generalised seizures similar to those of the idiopathic generalised epilepsies starting in childhood. Therefore, we presume that the association between epilepsy and CD in these cases is coincidental. The group 3 patients (epilepsy with cerebral calcifications without flat mucosa) had several similarities with the CEC group with respect to location of calcifications, seizures, and HLA phenotype, consistent with a diagnosis of CD.25-27 Because several cases of CD with "patchy" intestinal mucosal lesions or late-onset enteropathy have been reported,36 we speculate that some of our group 3 patients
443
could have had CD even though they had a normal intestinal biopsy. That 3 of the 6 tested cases had low serum folic acid also points to a diagnosis of CD. We believe that the CEC association is probably more common
than is
thought.
All
cases
previously reported
as
"atypical SWS" because of the absence of port-wine angioma, should be reviewed, in view of the possible association with CD. We also recommend that paediatric neurologists should rule out CD in all cases of epilepsy and cerebral calcifications of unexplained origin, especially when the epilepsy is characterised by occipital seizures and the calcifications located bilaterally in the posterior regions. Because gastrointestinal signs are often missing, paediatric neurologists might be the only ones to discover CD in these patients. Even though the efficacy of the gluten-free diet in controlling epileptic seizures in these cases has to be proven by a longer follow-up in a larger series of patients, the efficacy of the gluten-free diet seems to be inversely related to the duration of epilepsy before the diet and to the age at the beginning of the diet. We thank Mrs Carla Pini for her kind cooperation, and Mrs Anne Collins for revising the English text.
Members of the Italian Working Group are: Dr P. Ambrosetto, Clinica Neurologica, Universitá Bologna; Dr F. Balli, and Dr V. Galli, Clinica Pediatrica, Universitá Modena; Dr P. A. Battistella, Dr C. Boniver, and Dr F. Donzelli, Dipartimento Pediatria, Universitá Padova; Dr P. A. Bianchi, Dr N. Molteni, and Dr M. T. Bardella, Patologia Medica III, Universitá Milano; Dr E. Del Giudice and Dr F. Correale, Clinica Pediatrica, Universitá Napoli; Dr G. Della Cella, Divisione Pediatria, Ospedali Riuniti, Chiavari; Dr P. G. Garofalo, Dr C. Durisotti, and Dr C. Filati, Divisione Neurologia, Ospedale Civile Vicenza; Dr A. M. Giunta, Clinica Pediatrica II, Università Minalo; Dr A. Miano, Divisione Pediatria, Ospedale Bufalini Cesena; Dr A. Pascotto and Dr G. Coppola, Istituto Neuropsichiatria Infantile, Universitá Napoli; Dr L. Piattella and Dr N. Zamponi, Divisione Neuropsichiatria Infantile, Ospedale Salesi Ancona; Dr P. Santanelli, Clinica Neurologica, Universitá Napoli; Dr E. Veneselli, Divisione Neuropsichiatria Infantile, Istituto Gaslini, Universitá Genova; Dr F. Viani and Dr A. Van Lierde, Centro Regionale Studio Epilessia, Milano, Italy; Dr G. P. Corazza, Patologia Medica, Università Bologna.
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From The Lancet Heavy-metal hazard Two samples of curry powder were found to contain 40 and 85 parts per million of lead, which comes from rubbing tumeric root with chromate of lead to improve its colour. This is an old offence, but the increased use of curry powder to give flavour and variety to war-time diet has brought it into importance. An occasional curry containing this small quantity of lead might not matter much, but in households where a curry once or more a week has become customary the danger of chronic lead poisoning cannot be overlooked. The practice of "improving" tumeric with chromate of lead should be stopped immediately. (July 4, 1942)
