Case Reports

Aicardi's syndrome: repor t of an autopsied case and review of the li terature1

Gerald Erenberg , M . D .

The clinical and autopsy findings in a female infant with Aicardi's syndrome are presented. A clinical en-tity consisting of seizures, mental retardation, and cho-rioretinal lacunae, Aicardi's syndrome is found only in females and is associated with agenesis of the corpus callosum. Vertebral anomalies may also occur. Al-though the time of developmental arrest appears to be within the first trimester of pregnancy, the etiology of this disorder remains unknown.

Index terms: A i c a r d i ' s s y n d r o m e • C o r p u s c a l -

l o s u m

Cleve Clin Q 5 0 : 3 4 1 - 3 4 5 , F a l l 1 9 8 3

In 1 9 6 5 Aicardi et al descr ibed a s y n d r o m e consist ing o f infanti le spasms, menta l retardat ion, a n d mult ip le ocular anomal ie s occurr ing in fe-males with agenes i s o f the corpus cal losum. 1 V e r -tebral a n d rib anomal i e s are o f t e n present , a n d the e l ec t roencepha lograph ic (EEG) abnormal i t i es inc lude asynchrony b e t w e e n the two h e m i -spheres . A p p r o x i m a t e l y 1 0 0 cases o f Aicardi 's s y n d r o m e have n o w b e e n repor ted , 2 a l t h o u g h most have b e e n in the non-Engl i sh l i terature a n d few have b e e n autops ied . 3 T h e fo l l owing case o f Aicardi's s y n d r o m e was seen recent ly at T h e Cleve land Clinic Foundat ion . Diagnos is was m a d e d u r i n g l ife a n d c o n f i r m e d at autopsy.

C a s e r e p o r t The patient was a 3770-g girl born at term on May 19,

1981, to a 29-year-old gravida I para 1 woman in good health. Delivery was by caesarean section because of pre-eclampsia manifested by maternal hypertension. Apgar scores were 9 at one and five minutes. Acrocyanosis and

1 Sect ion on Chi ld N e u r o l o g y , D e p a r t m e n t s of N e u r o l o g y a n d Ped ia t r i c a n d Ado le scen t Medic ine , T h e Cleve land Clinic F o u n d a -t ion. S u b m i t t e d f o r pub l ica t ion May 1983; accep t ed J u n e 1 9 8 3 .

fever developed at four days of age, and sepsis was suspected. All cultures were negative except for cerebrospinal fluid, which grew Streptococcus viridans. Although it was suspected that this represented a contaminant, intravenous antibiotic therapy was continued for 14 days. An initial DPT immu-nization was administered at eight weeks of age. The patient became febrile, and 24 hours later myoclonic seizures de-veloped. She was hospitalized elsewhere, and her EEG showed rare left hemisphere spikes as well as hemisphere asymmetry. The computed tomography (CT) scan of the head was interpreted as indicating possible agenesis of the corpus callosum. TORCH titers were negative; blood and urine amino acid chromatography were normal.

The infantile myoclonic seizures did not respond to phén-obarbital, and valproic acid was substituted. Frequent sei-zures continued and were unresponsive to combinations of adrenocorticotropic hormone, diazepam, clonazepam, and ethosuximide. She was first seen at the Cleveland Clinic on January 26, 1982, at the age of eight months. The head circumference was below the third percentile, and the pa-tient was markedly hypotonic with little spontaneous move-ment. Hyperreflexia and extensor toe responses were pre-sent bilaterally. She showed little awareness of her surround-ings, exhibited no head control, and was unable to sit or support weight.

The patient's seizures did not respond to treatment with nitrazepam, carbamazepine, or phenytoin. Lethargy, feed-ing difficulties, and inadequate weight gain were ongoing problems. She was hospitalized in July and again in August 1982 in an attempt to improve her seizure control and to investigate methods of improving her nutritional state. Three EEGs performed during these hospitalizations showed bursts of multifocal sharp and slow waves occurring asynchronously in the right and left hemispheres (Fig. 1). The bursts alternated with episodes of suppression lasting two to three seconds. Sleep spindles and vertex sharp tran-sients could be identified.

Cerebrospinal fluid was normal. A CT scan of the head showed agenesis of the corpus callosum and large subarach-noid spaces around the frontal lobes, consistent with hypo-plasia (Fig. 2). Thoracic and lumbar spine roentgenograms were normal with no evidence of skeletal defects. Eye ex-amination revealed a coloboma of the right disc with an area of chorioretinal atrophy surrounding it. The left retina

341

on February 18, 2022. For personal use only. All other uses require permission.www.ccjm.orgDownloaded from

'342 Cleveland Clinic Quarter ly Vol. 50, No. 2

Fig. 1. C o m p u t e d t o m o g r a p h y scan showing agenesis of the corpus callosum. T h e r e is also m a r k e d e n l a r g e m e n t of the subar-achnoid spaces s u r r o u n d i n g the f ron ta l lobes.

showed large areas of chorioretinal atrophy with a spotty, peppery type of pigmentation. The atrophic areas were yellowish, consistent with absence of retinal pigment epithe-lium rather than with inflammatory destruction.

When she was last seen on September 20, 1982, my-oclonic seizures had continued to occur daily, and no devel-opmental progress had been made. Microcephaly, lethargy, hypotonia, and hyperreflexia were again noted.

At 17 months of age she w as found pale and unresponsive in bed. Resuscitative attempts were unsuccessful.

Autopsy f indings T h e autopsy was p e r f o r m e d at University Hos-

pitals of Cleveland. Multiple sections t h rough both lungs showed a d i f fuse suppura t ive exuda te filling the bronchioles and alveoli, amidst rem-nants of vegetable ma t t e r and skeletal muscle fibers. N u m e r o u s gram-posit ive cocci were iden-tified and t h o u g h t to be indicative of aspiration p n e u m o n i a . T h e brain was r emarkab l e for polymicrogyria in the f ronta l lobes involving both supraorbi ta l and parietal surfaces, and dem-ons t ra ted microscopically by abor t ive sulci and

th inn ing of the cerebra l cor tex . T h e r e was partial agenesis of the corpus callosum with preservat ion of the an te r io r por t ion {Fig. 3). T h e lateral ven-tricles were displaced laterally and s t re tched ver-tically. T h e cingulate gyrus was absent . He te ro-topia was seen in the f ronta l h o r n on the left. An addit ional abnormal i ty was the comple te disor-ganization of the layers in the lateral geniculate body. Permission to examine the eyes was re-fused.

Discussion T h e Table lists the clinical and ana tomic abnor -

malities that character ize Aicardi 's syndrome. Several fea tures universally present in all case repor t s a n d reviews 3 - ' a re female sex, seizures, mental r e ta rda t ion , ocular anomalies, and partial or comple te agenesis of the corpus callosum. O t h e r abnormal i t ies occur in varying percent -ages in pat ients with this syndrome. Most pat ients die within the first decade of life.

Sex of patient: Except for one repor t , 8 only females have been r epo r t ed to have Aicardi 's syndrome. T h e validity of the single case r epo r t of a male has been ques t ioned on the basis of whe the r the ocular f indings a re truly those seen in Aicardi 's syndrome." It has been postulated that this synd rome is caused by a single dominant gene muta t ion on the X chromosome. 4 T h e gene possibly arises as a muta t ion e i ther in the mater -nal oocyte o r pa ternal X-carrying sperm, a n d the condi t ion is lethal in the male fetus.

Family history: T h e r e have been no repor t s of Aicardi 's syndrome occur r ing in m o r e than one m e m b e r of a family. T h e absence of a familial pa t te rn has impor t an t implications for family counsel ing since the re is no increased risk of the condi t ion r ecu r r ing in a f fec ted families.

Seizures: All pat ients have presen ted for med-ical a t tent ion because of seizures. Seizures begin within the first few mon ths of life. Combina t ions of general ized tonic-clonic seizures and infant i le myoclonic seizures have been universal a n d a re usually resistant to t r e a t m e n t with antiepileptic drugs . T h e types of seizures are not diagnostic, bu t Aicardi 's synd rome should be considered in a female infant with infanti le myoclonic seizures of unknown etiology.

Mental retardation: Severe menta l re ta rda t ion with delayed psychomotor deve lopment has been present in all r e p o r t e d cases. Th i s re ta rda t ion is accompanied by marked hypotonia .

Ocular anomalies: T h e ocular manifestat ions may be varied, but chorioret inal lacunae a r e

on February 18, 2022. For personal use only. All other uses require permission.www.ccjm.orgDownloaded from

I [second

H J 200>i V

Fig . 2. Burs t s o f mul t i foca l s h a r p a n d slow waves o c c u r r i n g a s y n c h r o n o u s l y in the r i gh t a n d left h e m i s p h e r e s . T h e s e a l t e r n a t e wi th ep i sodes of supp re s s ion .

F ig . 3 . A b s e n c e of t h e c o r p u s ca l losum (arrow). T h e gross spec imen is a p p r o x i m a t e l y t h e s a m e level as s h o w n o n t h e C T scan in Figure 2.

343

on February 18, 2022. For personal use only. All other uses require permission.www.ccjm.orgDownloaded from

'544 Cleveland Clinic Quarterly

Table. F i n d i n g s i n A i c a r d i ' s s y n d r o m e

Females only Lack of family his tory Seizures of early onset Mental r e t a rda t ion Chor io re t ina l lacunae Ver t eb ra l anomal ies Agenesis o f the co rpus callosum Cortical he te ro top ias Hypsa r rhy thmic pa t t e rn on EEG Asynchronous burs t suppression on EEG

thought to be characteristic, if not pathogno-monic, of this disorder.9 The lacunae vary in size, have various amounts of pigment around their borders, are multiple in number, and usually occur bilaterally. The alterations appear to be in the retinal pigment epithelium and the underly-ing choroid. The retina itself is normal, and the electroretinogram has been normal or minimally altered in the few cases in which it has been recorded. Less common anomalies include colo-bomas of the choroid and optic nerve, gliosis of the optic disc, persistent pupillary membrane, and microphthalmia.

Skeletal abnormalities: Although a frequent feature of Aicardi's syndrome, bony anomalies are not universally present. Abnormalities of the vertebral bodies are the most common and in-clude hemivertebrae, fused vertebrae, variations in vertebral size, and spina bifida. Hand, finger, and costovertebral anomalies have also been re-ported, but there are no reports of long-bone abnormalities.

Radiographic studies: Total or partial agenesis of the corpus callosum is seen in all cases. This anomaly was initially diagnosed by pneumoen-cephalography, but the CT scan has established this finding in more recent cases.10 Intracranial calcifications are not seen, but there have been case reports of Aicardi's syndrome in association with choroid plexus papillomas.11 All autopsy cases have demonstrated cortical heterotopias as well, but heterotopias are often not diagnosable by radiographic studies.

Electroencephalographic findings: The combi-nation of EEG findings seen in patients with Aicardi's syndrome is suggestive of the diagno-sis, but there is no pathognomonic pattern.5 The most frequent features include a hypsarrhythmic pattern manifested by widespread spikes of irreg-ular rates and by high voltage slow waves replac-ing the normal background. The background is also characterized by a burst-suppression pattern

Vol. 50, No. 2

with burst and suppression portions of approxi-mately equal duration. T h e most striking feature, when present, is a variable degree of asynchrony between the activity of the two hemispheres. In its most dramatic form, brain wave activity is completely asynchronous with the burst-suppres-sion pattern shifting randomly between the two hemispheres. Normal sleep characteristics with spindles and vertex transients may be present or absent.

Labora tory studies: N o studies other than EEGs or neuroimaging have been of value in diagnos-ing Aicardi's syndrome.7 With rare exception, cerebrospinal fluid studies have been normal. No abnormalities have been found in routine blood or urine studies. Generalized aminoaciduria has been reported occasionally, but is of doubtful significance. Many unsuccessful attempts have been made to implicate an intrauterine infec-tion.12 Multiple negative studies for infectious agents have been directed against toxoplasmosis, cytomegalovirus, herpes, rubella, and syphilis. Results of all chromosomal studies reported have also been normal.

Etiology: The events leading to Aicardi's syn-drome are unknown. The developmental arrest leading to this syndrome is probably between the fourth and twelfth week of gestation. The com-missural plate is formed from the fourth to sev-enth week, and the corpus callosum results from intussusception of this plate during the third month of fetal life. The retinal pigment, the choroidal pigment, and the sclerotomes that form the vertebral bodies all arise between the fourth and fifth week. No toxic agent or teratogenic drug has been found to cause Aicardi's syn-drome. Although there are some superficial sim-ilarities between Aicardi's syndrome and the aftermath of severe intrauterine infections, no infectious etiology has ever been found.12 In ad-dition, agenesis of the corpus callosum and the specific ocular abnormalities do not occur in any of the known intrauterine infections.

It is not known if Aicardi's syndrome is caused by a genetic abnormality. No chromosomal ab-normalities have been found in patients who have had karyotyping performed. Several possible contributing factors can be considered. One pos-sibility is an X-chromosomal-dominant inherit-ance with manifestation in the heterozygote and with a male lethal factor. A gene defect lethal to males has been proposed to explain female pre-ponderance in incontinentia pigmenti and the Goltz syndrome.7 Another possibility is that the

on February 18, 2022. For personal use only. All other uses require permission.www.ccjm.orgDownloaded from

Fall 1983 Aicardi's syndrome 345

syndrome is due to a multiple gene effect with a greatly increased tendency to appear in females. Finally, it is possible that all cases represent new mutations.

Acknowledgments Harold Morris, M. D., interpreted the EEG records, and

Ronald Price, M. D., performed the ophthalmological ex-aminations. The results of the autopsy were kindly supplied by T. C. Nguyen, M. D., and Uros Roessman, M. D., of Case Western Reserve University.

References 1. Aicard i J , L e f e b v r e J , Ler ique-Koech l in A. A new s y n d r o m e :

spasm inf lexion, callosal agenesis, ocu la r abnormal i t i e s . Elec-t r o e n c e p h a l o g r Clin Neurophys io l 1965; 1 9 : 6 0 9 - 6 1 0 .

2. Aicardi J . Aicardi s y n d r o m e in a male in fan t (letter). J Ped ia t r 1980; 9 7 ; 1 0 4 0 - 1 0 4 1 .

3. d e j o n g J G Y , Del leman J W , H o u b e n M, Manscho t W A , de-M i n j e r A, Mol J . Agenesis of t he c o r p u s cal losum, infant i le spasms, ocular anomal ies (Aicardi ' s syndrome) ; clinical a n d pathological f indings . N e u r o l o g y 1976; 2 6 : 1 1 5 2 - 1 1 5 8 .

4. Dennis J , Bower BD. T h e Aicardi s y n d r o m e . Dev Med Chi ld N e u r o l 1972; 1 4 : 3 8 2 - 3 9 0 .

5. Fariel lo RG, C h u n R W M , D o r o J M , Buncic R, P r i cha rd JS. EEG recogni t ion of Aicardi ' s s y n d r o m e . A r c h N e u r o l 1977; 3 4 : 5 6 3 - 5 6 6 .

6. Denslow G T , R o b b RM. Aicardi ' s s y n d r o m e : a r e p o r t of f o u r cases a n d review of t h e l i t e ra ture . J Ped ia t r O p h t h a l m o l S t rab i smus 1979; 1 6 : 1 0 - 1 5 .

7. Ber ton i J M , von Loh S, Allen RJ. T h e Aicard i ' s s y n d r o m e : r e p o r t of 4 cases a n d review of t he l i t e ra tu re . A n n N e u r o l 1979; 5 : 4 7 5 - 4 8 2 .

8. C u r a t o l o P, Libut t i G, Dallapiccola B. Aicardi s y n d r o m e in a male in fan t . J Ped ia t r 1980; 9 6 : 2 8 6 - 2 8 7 .

9. Hoy t CS, Billson F, O u v r i e r R, Wise G. O c u l a r f ea tu re s of Aicardi ' s s y n d r o m e . Arch O p h t h a l m o l 1978; 9 6 : 2 9 1 - 2 9 5 .

10. R o t h n e r AD, Duchesneau PM, Weins te in M. Agenes is of t he c o r p u s callosum revea led by c o m p u t e r i z e d t o m o g r a p h y . Dev Med Chi ld N e u r o l 1976; 1 8 : 1 6 0 - 1 6 6 .

11. T a c h i b a n a H , Matsui A, Takesh i t a K, T a m a i T . Aicard i ' s s y n d r o m e with mul t ip le papi l loma of cho ro id plexus. Arch N e u r o l 1982; 39 : 194 .

12. Willis J , Rosman N P . T h e Aicardi s y n d r o m e versus congeni ta l infect ion: d iagnost ic cons idera t ions . J Ped ia t r 1980; 9 6 : 2 3 5 -239 .

on February 18, 2022. For personal use only. All other uses require permission.www.ccjm.orgDownloaded from