The corpus callosum, which is the largest white matter structure in the brain of all placental mammals, connects the left and right
cerebral hemispheres. An alteration in its morphology, hypoconnectivity or hyperconnectivity is a common marker of various
neuropsychiatric pathologies. One of these is Aicardi syndrome, which is characterized by a triad of callosal agenesis, infantile
spasms and chorioretinal lacunae. Patients affected by Aicardi syndrome frequently display other malformations together with
congenital defects of the eyes, ribs and vertebrae. Based on the current clinical knowledge, this syndrome is now recognized as
a complex neurodevelopmental disorder that includes neurological and constitutional symptoms. However, literature data have
not yet defined the presence of a particular set of symptoms in psychiatric patients with this condition. The present case is the
first report in which an on-going compulsive behaviour focused on the insistence to order objects has been observed in Aicardi syndrom

A. Anastasia

A. Quartini

BERSANI, Giuseppe

C. Colletti

E. Prinzivalli

F. S. Bersani

G. Valeriani

English

Archivio della ricerca- Università di Roma La Sapienza

359Case reportJournal of Psychopathology 2013;19:359-362SummaryThe corpus callosum, which is the largest white matter structure in the brain of all placental mammals, connects the left and right cerebral hemispheres. An alteration in its morphology, hypocon-nectivity or hyperconnectivity is a common marker of various neuropsychiatric pathologies. One of these is Aicardi syndrome, which is characterized by a triad of callosal agenesis, infantile spasms and chorioretinal lacunae. Patients affected by Aicardi syndrome frequently display other malformations together with congenital defects of the eyes, ribs and vertebrae. Based on the current clinical knowledge, this syndrome is now recognized as a complex neurodevelopmental disorder that includes neurolog-ical and constitutional symptoms. However, literature data have not yet defined the presence of a particular set of symptoms in psychiatric patients with this condition. The present case is the first report in which an on-going compulsive behaviour focused on the insistence to order objects has been observed in Aicardi syndrome.Key wordsAicardi syndrome • Agenesis of the corpus callosum • Seizures • Com-pulsive behaviour • Dysmorphism • Mental and psychomotor develop-mental delayCompulsive behaviour in a patient with Aicardi syndrome. Agenesis of the corpus callosumCondotte compulsive in paziente con sindrome di Aicardi. Agenesia del corpo callosoE. Prinzivalli, A. Quartini, A. Anastasia, F.S. Bersani, C. Colletti, G. Valeriani, G. BersaniU.O.D. Universitaria di Psichiatria, Ospedale “A. Fiorini” di Terracina (LT); DSM LT, Dipartimento di Scienze e Biotecnologie medico-chirurgiche, Università “Sapienza”, Roma, ItalyCorrespondenceEmiliano Prinzivalli, via Firenze, 04019 Terracina (LT), Italy • Tel./Fax +39 0773708006 • E-mail: prinzivalliemiliano@libero.itSyndrome descriptionAlthough it is a relatively rare disease, Aicardi syndrome is estimated to affect thousands of people worldwide. The disorder was first recognized as a distinct syndrome by the French neurologist Jean Aicardi in 1965. It is a rare en-cephalopathic malformation affecting almost exclusively young females and very rarely males with Klinefelter syn-drome (47 XXY karyotype) 1-3. It has therefore been sug-gested that Aicardi syndrome may be the direct result of a de novo dominant mutation in a gene located on the X chromosome, and lethal in hemizygous males 3.The first sign of the disease becomes evident around the age of three months, when young patients begin having infantile spasms. The triad that characterises Aicardi syn-drome includes, in fact, agenesis of the corpus callosum (CC) and pathognomonic chorioretinal lacunae in addi-tion to the above-mentioned “marker”1.Based on current clinical knowledge, the syndrome is now recognized as a complex neurodevelopmental disor-der characterized by additional neurological and consti-tutional symptoms.Indeed, neurological examination may detect microceph-aly, axial hypotonia and appendicular hypertonia with spasticity and deep tendon hyperreflexia as well as a mod-erate-to-severe psychomotor and mental retardation 4. Sei-zures associated with asymmetric spasms, often preceded by partial early-onset epileptic fits in the first three months of life, may also be detected. A third element may be a peculiar EEG pattern characterized by asymmetric activity and asynchronous intercritical paroxysmal anomalies in both hemispheres due to agenesis of the corpus callosum, with an MRI detecting its dysgenesis. Frontal perisylvian polymicrogyria, periventricular and subcortical hetero-topia, gross brain asymmetry, choroid plexus papilloma, ventriculomegaly and intracerebral cysts are also frequent findings.In addition to pathognomonic chorioretinal lacunae, pa-tients affected by Aicardi syndrome present unilateral mi-crophthalmia, coloboma/hypoplasia of the optic nerve, retinal detachment and nystagmus.Craniofacial, vertebral and costal anomalies are also re-ported; these include short philtrum, prominent premax-illa with a consequent reduction in the frontonasal angle, large ears, sparse and lateral eyebrows, plagiocephaly and facial asymmetry. The occurrence of hemi-vertebrae, block vertebrae, fused vertebrae and missing ribs is com-mon and can lead to marked scoliosis in up to one-third 360E. Prinzivalli et al.seizures characterized by reduced muscle tone and very brief losses of consciousness that always followed bouts of crying.For these reasons several EEG were performed (at 7 months, 21 months, 2 years and 3 years of age) which showed among other things a slight anomaly of regula-tion of electrogenesis and mild abnormalities in the right hemisphere.Weight gain was very limited. In the course of develop-ment she presented a malfunctioning alvus with frequent, abundant, unformed mucous stools. The patient had dys-morphic features consisting of small forehead, sparse and dry hair, bushy eyebrows, flat nasal bridge, small teeth, fleshy nose, larger-than-normal right ear and a hammer toe. She also had a hypochromic patch on her face and trunk extending to the anterior abdominal wall, two small flat haemangiomas on her back, strabismus (heterotropia) and a pronounced lordosis. Various eye examinations de-tected severe myopic chorioretinal scarring with retinal chorioretinosis at the posterior pole of both eyes. An in-strumental brain examination (MRI) performed in 1992 detected a malformation consisting in agenesis of the splenium of the CC associated with dysmorphism in the back of medial ventricular cells. The last EEG recorded a moderate slowing-down of the base rhythm and graphoe-lements with transient spikes apparently originating from left frontal derivations.At the beginning of 2012, she was admitted to the U.O.D. Universitaria di Psichiatria, Ospedale “A. Fiorini” of Ter-racina for evaluation because she displayed symptoma-tology characterized by a compulsive behaviour aimed at arranging objects in a symmetrical fashion. The invol-untary interruption of this behaviour led to anxiety and irritability, and in extreme cases led to violent reactions. Moreover, since the patient suffered from a syndrome of subjects. These patients may also display an increased incidence of vascular malformations and pigmented le-sions 5.Gastrointestinal disorders such as gastro-oesophageal re-flux, diarrhoea and difficulty in feeding are perceived by parents to be the second most difficult problems to man-age after seizures 6.Survival is another characteristic that deserves further at-tention. Life expectancy was originally thought to be rath-er limited. Today instead, based on recent data from the USA, around 60% of the patients are expected to survive until the age of 27 years, with some cases reaching the age of 40 years. Survival is therefore highly variable and is probably related to the severity of disease.For these reasons, additional diagnostic criteria have been proposed (Table I) 5 7. The interest of the present case lies in the fact that it may confirm a hypothesis, already suggested by several studies, that the CC may play an im-portant role in various psychiatric disorders.Case descriptionPatient: 36 years of age (born 16 Jan 1976). Although birth was premature (at the 8th month), she was nonethe-less born after a full-term pregnancy. The delivery was long, the amniotic fluid was stained and the umbilical cord was wrapped twice around the newborn’s neck. No other maternal diseases were reported during pregnancy.At 3 months she had an epileptic fit characterized by muscular hypotonia and upwards rotation of the eyeballs. The same symptomatology recurred a short time later. The delay of psychomotor development became soon evident, as she managed to sit at 12 months and started walking at 21 months. Language development was also delayed. During this period, she suffered from several TAble I.Features. Criteri diagnostici.Classic triad Key features Supporting features Agenesis of the corpus callosum Cortical malformations (especially polymicrogyria) Vertebral and rib anomalies Pathognomonic chorioretinal lacunae Periventricular and subcortical retinal heterotopia Microphthalmia Infantile spasms Frequent brain cysts affecting the third ventricle and/or choroid plexus “Split-brain” EEG Optic disc/nerve coloboma or hypopla-sia Gross asymmetry of the cerebral hemisphere Vascular malformations or tumours The presence of the classical triad is diagnostic of Aicardi Syndrome. The simultaneous presence of two features of the triad and, in addition, of at least two main or support features is strongly suggestive of this syndrome.Based on Sutton 5.361Compulsive behaviour in a patient with Aicardi syndromeIt can thus be inferred that Aicardi syndrome is not lim-ited to the classic triad, but represents a much more com-plex neurodevelopmental disorder characterized by sev-eral neurological and constitutional symptoms.Psychiatric relevance of the caseOne of the features observed in the Acardi syndrome is agenesis of the CC. This wide, flat bundle, which is the largest white matter structure in the brain of all placen-tal mammals, connects the left and right cerebral hemi-spheres and contains numerous intra-, and interhemi-spheric axonal projections.Callosal fibres connect cerebral areas that are homotopi-cally positioned. Fibres from the inferior frontal lobes and the anterior and inferior parietal lobes cross in the genu, and those from the remaining part of the frontal area and from the parietal lobe cross in the body of the CC. Fibres from the temporal and occipital lobes cross in the sple-nium (Table II) 8. Corpus callosum agenesis (CCA), either total or partial, occurs in approximately 14% of central nervous system anomalies. Its typical clinical symptoms are macrocephaly, facial dysmorphy combined with dif-ferent levels of mental retardation, epileptic seizures, vi-sion and other nerve impairments. Moreover, CCA is as-sociated with Dandy-Walker, Aicardi, Toriello-Carey and Andermann syndromes 9.An alteration in the morphology, hypoconnectivity or hy-perconnectivity of the CC is therefore a common marker of various neuropsychiatric pathologies such as schizo-phrenia, bipolar affective disorder, attention deficit/hy-peractivity disorder (ADHD) and obsessive-compulsive disorder (OCD) 10-15. This relationship is confirmed by the altered morphology, hypoconnectivity, or hyperconnectiv-ity that all display. For example, Bersani and colleagues have found that schizophrenics have a reduced width of the splenium (which is involved in the transfer of visual information), while Walterfang et al. reported that patients with bipolar disorder have smaller anterior and posterior callosal regions and thinning of the CC  11-13. However, the precise function or dysfunction of this structure in the that involved mental retardation and language delay, it was impossible to investigate any obsession beyond the behaviour itself. A correct interpretation of clinical symp-toms was difficult due to the difficulties encountered in exploring the thought content. Moreover, the family’s re-quest for treatment was mainly focused on finding a treat-ment for the dysphoric characteristics, especially in terms of psychomotor restlessness and insomnia. Therefore, the treatment selected included a mood-stabilizer (valp-roic acid: maximum dose, 750 mg/day; plasma levels of valproate: 61 µg/mL) and a sleep inducer (delorazepam: maximum dose, 1.5 mg/day). These drugs complemented the previous neurotherapy that consisted of carbamaz-epine (600 mg/day), orfenadine (150 mg/day), biperiden (4 mg/day) and pericyazine (7.5 mg/day). This therapy re-sulted in a partial remission of dysphoric symptoms and sleep disturbance. Although the compulsive symptoms have not shown any clinical improvement, the additional pharmacotherapy did allow to the possibility to shed light on this psychopathological dimension as being predomi-nant in the patient’s mind.Syndrome-case comparisonOur patient presents symptoms and features that meet criteria for Aicardi syndrome (Table I) 8. The agenesis of the splenium of the CC and the severe myopic chorioreti-nitis are suggestive of Aicardi syndrome 1 2 7. The onset of symptoms at the age of three months is consistent with literature descriptions, according to which most of the seizures occur in the first three months of life 7. Likewise, the clinical history shows quite clearly that there is devel-opmental delay in psychomotor abilities 4.Gastrointestinal disorders, which are among the causa-tive factors of deficits in body weight gain in patients with Aicardi syndrome 6, began to appear early, at around 18th months. Furthermore, the patient displays dysmorphic features common in this syndrome such as ear asymmetry as well as vascular malformations and pigmented lesions (flat angiomas of the spine and a hypochromic patch ex-tending to the abdominal wall) 5.TAble II.Anatomical organization of callosal subregions. Organizzazione anatomica del corpo calloso.Rostrum Fronto-basal cortexGenu Prefrontal cortex and the anterior cingulate areaTruncus (midbody) Precentral cortex (premotor area, supplementary motor area), the adjacent portion of the insula and the overlying cingulate gyrusIsthmus Pre-and post central gyri and primary auditory areaSplenium Posterior parietal cortex, occipital cortex, medial temporal cortexBased on Raybaud 8.362E. Prinzivalli et al.3 Van den Veyver IB. Microphthalmia with linear skin defects (MLS), Aicardi, and Goltz syndromes: are they related X-linked dominant male-lethal disorders? Cytogenet Genome Res 2002;99:289-96.4 Prats Vinas JM, Martinez Gonzalez MJ, Garcia Ribes A, et al. Callosal agenesis, chorioretinal lacunae, absence of infantile spasms, and normal development: Aicardi syndrome with-out epilepsy? Dev Med Child Neurol 2005;47:419-20.5 Sutton VR, Hopkins BJ, Eble TN, et al. Facial and physical features of Aicardi syndrome: infants to teenagers. Am J Med Genet 2005;138A:254-8.6 Glasmacher MA, Sutton VR, Hopkins B, et al. Phenotype and management of Aicardi syndrome: new findings from a survey of 69 children. J Child Neurol 2007;22:176-84.7 Sutton VR, Van den Veyver IB. Aicardi Syndrome. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™. Se-attle, WA: University of Washington 1993.8 Raybaud C. The corpus callosum, the other great forebrain commissures, and the septum pellucidum: anatomy, develop-ment, and malformation. Neuroradiology 2010;52:447-77.9 Sepic´-Grahovac D, Ruzic´ Barsic´ A, Ruzic´ K, et al. Neuro-logical and psychiatric aspects of corpus callosum genesis. Psychiatria Danubina 2010;22:282-5.10 Swayze VW, Andreasen NC, Erhardt JC, et al. Developmen-tal abnormalities in the corpus callosum in schizophrenia. Arch Neurol 1990;47:805-8.11 Bersani G, Quartini A, Iannitelli A, et al. Corpus callo-sum abnormalities and potential age effect in men with schizophrenia: an MRI comparative study. Psychiatry Res 2010;183:119-25.12 Walterfang M, Malhi GS, Wood A, et al. Corpus callosum size and shape in established bipolar affective disorder. Aust N Z J Psychiatry 2009;43:838-45.13 Walterfang M, Wood AG, Barton S, et al. Corpus callosum size and shape alterations in individuals with bipolar disor-der and their first- degree relatives. Prog Neuropsychophar-macol Biol Psychiatry 2009;33:1050-7.14 Hutchinson AD, Mathias JL, Banich MT. Corpus callosum morphology in children and adolescents with attention deficit hyperactivity disorder: a meta-analytic review. Neu-ropsychology 2008;22:341-9.15 Saito Y, Nobuhara K, Okugawa G, et al. Corpus callosum in patients with obsessive-compulsive disorder: diffusion-tensor imaging study. Radiology 2008;246:536-42.16 Stewart SE, Platko J, Fagerness J, et al. A genetic family-based association study of OLIG2 in obsessive-compulsive disorder. Arch Gen Psychiatry 2007;64:209-14.17 Pujol J, Vendrell P, JunqueÏ C, et al. When does human brain development end? Evidence of corpus callosum growth up to adult- hood. Ann Neurol 1993;34:71-5.above disorders remains uncertain. The behavioural ab-normalities of several patients analyzed can indeed be at-tributed, other than to its action, to a secondary effect of dysfunctional cortical regions.Additionally, the CC has been shown to be involved in attentional processes and has therefore been indicated as a possible cause of ADHD, even though this syndrome does not show similar behavioural changes in split-brain patients. The areas connected by the splenium involve the parietal cortex, which supports functions such as sus-tained and divided attention. A review by Hutchinson, Mathias and Banich (2008) noted that children and ado-lescents with ADHD have a smaller splenium compared to control subjects 14.Finally, the CC might have also a role in OCD. In fact, several diffusion tensor imaging (DTI) studies have pre-viously reported callosal abnormalities in patients with OCD 15. Additionally, a recent examination of axial and radial diffusivity in patients with OCD has shown that the reduced white matter integrity in the CC may be caused by a myelin abnormality. This finding is consistent with preliminary data according to which the polymorphism of a gene that is a major regulator of the development of myelin-producing cells is associated with OCD 16. In some brain regions such as the CC, myelination contin-ues during adolescence and early adulthood, a period during which OCD may easily onset 17.Neurodevelopmental irregularities leading to abnormal myelination might therefore play a role in the pathophysi-ology of OCD. However, this hypothesis needs support with longitudinal and postmortem studies.The literature reports no specific psychiatric symptoma-tology in patients affected by Aicardi Syndrome. Judg-ing from our observation, the patient described is the first case in which a subject affected by this syndrome displays compulsive behaviour aimed symmetrically ar-ranging objects. In the future, in order to better assess its psychopathological aspects, it would be interesting to find out whether a similar framework is present in other patients with this syndrome. The occurrence of this symp-tomatology could be a further element supporting the hy-potheses about a possible role of the CC in OCD.References1 Aicardi J, Levebre J, Lerique-Koechlin A. A new syndrome: spasms in flexion, callosal agenesis, ocular abnormalities. Electroencephalogr Clin Neurophysiol 1965;19:609-10.2 Aicardi J. Aicardi syndrome. Brain Dev 2005;27:164-71.

Condotte compulsive in paziente con sindrome di Aicardi. agenesia del corpo calloso

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Condotte compulsive in paziente con sindrome di Aicardi. agenesia del corpo calloso

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