Pediatric Radiology

, Volume 33, Issue 5, pp 334–345

MRI in children with mental retardation

Authors

    • Department of NeuroradiologyHôpital Roger Salengro
  • Béatrice Joyes
    • Department of NeuroradiologyHôpital Roger Salengro
  • Marie-Pierre Lemaître
  • Louis Vallée
  • Jean-Pierre Pruvo
    • Department of NeuroradiologyHôpital Roger Salengro
Original Article

DOI: 10.1007/s00247-003-0891-z

Cite this article as:
Soto-Ares, G., Joyes, B., Lemaître, M. et al. Ped Radiol (2003) 33: 334. doi:10.1007/s00247-003-0891-z

Abstract

Background

In mental retardation (MR) an aetiological diagnosis is not always obtained despite a detailed history, physical examination and metabolic or genetic investigations. In some of these patients, MRI is recommended and may identify subtle abnormal brain findings.

Objective

We reviewed the cerebral MRI of children with non-specific mental retardation in an attempt to establish a neuroanatomical picture of this disorder.

Materials and methods

Thirty children with non-specific MR were selected to undergo cerebral MRI. The examination included supratentorial axial slices, mid-sagittal images and posterior fossa coronal images. Brain malformations, midline and cerebellar abnormalities were studied.

Results

In 27 of 30 patients, the neuroimaging evaluation revealed a relatively high incidence of cerebral and posterior fossa abnormalities. The most frequent were: dysplasia of the corpus callosum (46%; hypoplasia, short corpus callosum and vertical splenium), partially opened septum pellucidum and/or cavum vergae (33%), ventriculomegaly (33%), cerebral cortical dysplasia (23%), subarachnoid space enlargement (16.6%), vermian hypoplasia (33%), cerebellar and/or vermian disorganised folia (20%), and subarachnoid spaces enlargement in the posterior fossa (20%). Other anomalies were: enlarged Virchow-Robin spaces (10%), white matter anomalies (10%) and cerebellar or vermian atrophy.

Conclusions

MRI has shown a high incidence of subtle cerebral abnormalities and unexpected minor forms of cerebellar cortical dysplasia. Even if most of these abnormalities are considered as subtle markers of brain dysgenesis, their role in the pathogenesis of mental retardation needs further investigation.

Keywords

MRIBrainCerebellumMalformationsCortical dysplasiaMental retardation

Introduction

Mental retardation (MR) is a human disability characterised by cognitive impairment existing concurrently with limitations in two or more adaptive skills. It is generally accepted that MR occurs in 2–3% of the population as an isolated finding or as a part of a syndrome or broader disorder [1, 2]. Even if a number of factors (single-gene disorders or chromosome abnormalities, congenital malformation, fetal infection, toxins, metabolic disorders, prematurity) can cause MR, the aetiology is not identified in 30–50% of cases [2, 3]. Clinical, laboratory and radiological evaluation of the aetiology is necessary to answer questions regarding management, prognosis and recurrence risks, and they are also necessary to devise prevention strategies [2].

There have been few neuroimaging studies on non-specific MR. The descriptions depend on patient selection criteria and on consideration of MR as an isolated finding or as a part of a syndrome. MRI has shown minimal abnormalities: mega cisterna magna, hypoplasia of the corpus callosum, wide cavum septum pellucidum, white matter alterations, heterotopia and cerebellar hypoplasia [2, 4, 5, 6]. Some are generally considered as incidental findings and/or normal anatomical variants. Even if MRI is usually not helpful for understanding either the cause of these brain abnormalities or their relationship with MR [7], a consensus conference on evaluation of MR recommended large uniform MRI studies. Neuroimaging should be considered in patients with abnormal head size or shape, craniofacial malformation, somatic anomalies, neurocutaneous findings, seizures or neurological signs [1, 2]. The objective of these studies is to confirm that abnormalities commonly found in retarded individuals are incriminated in the pathogenesis of this disorder.

Using currently available techniques, we could define subtle dysgenetic abnormalities of the cerebral hemispheres and cerebellar development. Our purpose was to study the type and frequency of brain abnormalities in children with non-specific MR in order to establish a neuroanatomical picture of this disorder. Because these subtle morphological changes could represent markers of brain dysgenesis [3], the recognition of minor brain abnormalities could probably be the first step in understanding the pathogenesis of MR.

Materials and methods

We reviewed the MRI findings of 30 patients with non-specific MR. Table 1 documents their general clinical background and presentation. They were selected from a cohort of 81 children (47 boys, 34 girls; M:F 1.4/1; mean age 5.2 years; range 1 month to 15.3 years) referred to the university-based paediatric neurologists of our institution for evaluation of developmental delay between November 1999 and June 2000. A group of paediatric neuropsychologists evaluated the children with impaired cognitive function as regards their intellectual skills using neuropsychological tests and developmental assessment. MR was severe in 36 (44.5%) patients (IQ<50) and moderate in 45 (55.5%; IQ 50–70). Further clinical, metabolic and genetic investigations were carried out, including infection and metabolic tests, otorhinolaryngological examination, karyotype, and tests for fragile X, Angelman, Prader-Willi and Di George syndromes. In patients with focal neurological deficits and/or facial deformities (77 patients; 35 with severe MR and 42 with moderate MR), neuroimaging was performed. Because access to MRI was difficult compared with CT, 35 of 77 patients had a CT scan and 42 of 77 had MRI.
Table 1.

Clinical background and IQ

Case

Sex/age (years, months)

Prenatal course

Clinical background (family)

Clinical background (personal)

MR

1

M/10

Unknown. Brazilian adopted child

Unknown

Absent

IQ 53 moderate

2

F/8

Fever at 5th month of pregnancy

Father has Glanzmann thrombopathy

None

IQ 41 severe

3

F/6,7

None

Cousin with MR

Cryptogenic epilepsy

IQ 63 moderate

4

M/0,11

None

Maternal alcohol

West syndrome

IQ 40 severe

5

F/7,5

None

None

None

IQ 45 severe

6

F/12,5

None

Maternal epilepsy

Partial complex epilepsy

IQ 57 moderate

7

F/1,2

Mother-fetal infection

Family history of MR

Axial hypotonia at 24 h of age

IQ 62 moderate

8

F/3,10

None

None

Febrile convulsions at 9 months

IQ 45 severe

9

M/6,1

Anti-hypertensive treatment

None

Surgery at 3 weeks for pyloric stenosis

IQ 65 moderate

10

M/6,5

Maternal hypertension

Uncle mentally retarded

Transient Respiratory distress and hypocalcaemia; oral infections and anaemia

IQ 45 severe

11

F/1,7

Maternal hypertension; born at 36 weeks' gestation

None

Surgery for oesophageal atresia

IQ 53 moderate

12

F/5,6

None

None

Growth delay

IQ 50 moderate

13

M/4,4

Twin pregnancy. Born at 34 weeks' gestation

None

CIV Febrile convulsions at 2 years

IQ 60 moderate

14

M/3

None

None

None

IQ 72 moderate

15

M/7,10

None

Parental consanguinity

Previous cyanosis

IQ 51 moderate

16

F/3,2

None

None

Partial convulsions

IQ 40 severe

17

M/12,5

None

MR in family members

Obesity

IQ 40 severe

18

M/5,2

Polyhydramnios; caesarean section

MR in mother's cousin

Partial convulsions; hypocalcaemia

IQ 40 severe

19

F/5,4

Antenatal haemorrhage at 6 months

Parental consanguinity; 2 brothers with developmental delay and dystonia died

Measles infection

IQ 52 moderate

20

M/2,2

Absent fetal movements in last week

Febrile convulsions in father

None

IQ 50 severe

21

M/1,3

Antenatal haemorrhage 14 months; caesarean section

None

None

IQ 66 moderate

22

F/2

Apgar scores 3/7/10

MR in family members

None

IQ 72 moderate

23

M/6,3

Maternal alcohol; born at home at 36 weeks

Alcohol

Hypocalcaemia; absent eye pursuit

IQ 40 severe

24

M/2,10

Ventriculomegaly

MR in uncle

Oedema of extremities

IQ 45 severe

25

M/7,2

Viral infections, lipothymia; Apgar score 3/10/10

None

Cyanosis and partial epilepsy

IQ 54 moderate

26

F/1,11

Polyhydramnios; caesarean section; Apgar score 8/10/10

Uncle retarded

Hypotonia; ecchymoses; febrile convulsion

IQ 54 moderate

27

F/4,1

Viral infection at 5 months; caesarean section

MR in both parental families

None

IQ 45 severe

28

M/12,8

Born at 33 weeks; Apgar score 3/4 during resuscitation

Uncle and cousins with MR

Hyperkinesia

IQ 59 moderate

29

F/15,11

None

None

Partial epilepsy since 6 years of age

IQ 51 moderate

30

M/4,11

None

Cousin with MR

None

IQ 53 moderate

Only patients with non-progressive MR were included if complete clinical and MRI evaluations were available and if the aetiological diagnosis before MRI remained unknown (n=29; 36%). Patients with unavailable or incomplete MRI studies were excluded (n=12/29 patients of unknown aetiology).

The cerebral MRI scans of 30 patients with cerebral malformations (n=13) and with mental retardation of unknown aetiology (n=17) were reviewed by two experienced neuroradiologists blinded to the aetiology of MR. They assessed cerebral and cerebellar malformations, and minor brain abnormalities. According to the descriptions of normal MRI brain anatomy reported by Barkovich [8], we have considered as minor abnormalities: enlargement of subarachnoid spaces with or without macrocephaly, minor abnormalities of the corpus callosum including short corpus callosum or vertical splenium [8, 9], cerebellar atrophy defined as enlarged cerebellar sulci (>1 mm), and enlargement of the posterior fossa subarachnoid spaces (mega cisterna magna and supravermian cistern) with or without enlargement of the fourth ventricle. Other abnormalities were: prominent and diffuse enlargement of the perivascular fluid spaces (Virchow-Robin spaces), ventricular enlargement considered according to standard linear measurements (Evan's ratio, Huckman's measurement, minimal lateral ventricular width and lateral ventricular span at the body) [10] and patchy or diffuse white-matter hyperintensities.

MRI examinations were performed in a 1.5-T magnet. Axial, sagittal and coronal images were acquired using turbo spin-echo (TSE) T2-weighted (TW-2) sequence (slice thickness 5, 3 and 4 mm, respectively). The acquisition parameters were TR/TE 5,000/120, NEX 2, FOV 20–25 cm, matrix 300×512. An inversion recovery sequence (TR/TI/TE 11,520/400/60, NEX 2, FOV 20–25 cm, matrix 198×512) was performed in one or two orthogonal planes according to the results of the previous sequences. The total scanning time was about 20 min per patient. Children under 1 year of age or 10 kg body weight were sedated using chloral hydrate 50–100 mg/kg; anaesthesia using a laryngeal mask was used for the other patients.

Results

In our group of 30 patients, clinical, metabolic and genetic investigations were positive in 2. One had duplication of chromosome 2 (case 7) and 1 patient had a disorder of amino acids and organic acids (case 16).

According to the MRI findings, three groups could be defined. They are summarised in Tables 2, 3, and 4, which compare their clinical presentations and MRI findings. Brain malformations were diagnosed in 13 patients (16%).
Table 2.

Group 1. Clinical and MRI findings

Case

Clinical

Posterior fossa MRI

Supratentorial MRI

1

Facial and extremity dysmorphism; motor disturbances; hypotonia

Amygdalar ectopia

Normal

2

Small mandibule; hypochromic spot at left shoulder; left monoparesis; strabismus

Normal

Corpus callosum Hypoplasia

3

Epilepsy

Normal

Corpus callosum hypoplasia and verticalised

4

Microcephaly; facial dysmorphism; West syndrome; tetrapyramidal signs; hypertonia

White-matter hyperintensities

Corpus callosum hypoplasia; ventricular enlargement; white-matter hyperintensities

5

Absent

Normal

Septum pellucidum cyst

6

Left pyramidal syndrome

Normal

Enlarged Virchow-Robin spaces

7

Ohtahara syndrome; spastic tetraparesis; axial hypotonia; swallowing difficulties

Enlarged posterior fossa subarachnoid spaces

Enlarged subarachnoid spaces and ventricles; septum pellucidum cyst; corpus callosum hypoplasia

8

Craniostenosis; facial dysmorphism; minor cerebellar syndrome

Normal

Enlarged subarachnoid spaces and ventricles; cavum vergae; corpus callosum hypoplasia

9

Retrognathia; minor skeletal abnormalities; motor disturbances; hypotonia

Normal

Moderate ventricular enlargement; cavum vergae

Table 3.

Group 2. Clinical and MRI findings

Case

Clinical

Posterior fossa MRI

Supratentorial MRI

10

Facial deformities; hypertelorism; thin upper lip without philtrum; large ears; bilateral clinodactyly

Cerebellar atrophy

Asymmetrical lateral ventricles

11

Tetrapyramidal syndrome

Superior vermis atrophy

Enlarged subarachnoid spaces; corpus callosum hypoplasia

12

Facial deformities; hypertelorism; epicanthus; triangular-shaped mouth; diadochokinesia

Superior vermis atrophy

Enlarged occipital horns of lateral ventricles

13

Left pyramidal syndrome

Fourth ventricle and posterior fossa subarachnoid spaces enlarged; vermian atrophy

Septum pellucidum cyst

14

Microcephaly; plagiocephaly; hypotonia; ataxia with cerebellar syndrome

Fourth ventricle and posterior fossa subarachnoid spaces enlarged with vermian atrophy

Posterior corpus callosum verticalized

15

Microcephaly; retrognathia; cerebellar syndrome

Inferior vermis hypoplasia; cerebellar atrophy

Septum pellucidum cyst; isolated focus of white-matter hyperintensity

16

Arched palate; prominent forehead; pyramidal syndrome; asymmetrical hypotonia

Inferior vermis hypoplasia; mega cisterna magna

Enlarged occipital horns of lateral ventricles; corpus callosum hypoplasia; enlarged Virchow-Robin spaces

17

Retrognathia; round face; obesity; abnormal dentition; clinodactyly; high arched palate

Vermis hypoplasia

Septum pellucidum cyst; corpus callosum hypoplasia

18

Microcephaly; nose and ear malformations; epicanthus; hypotonia; ataxia

Vermis hypoplasia

Septum pellucidum cyst; frontal white-matter hyperintensities

Table 4.

Group 3. Clinical and MRI findings

Case

Clinical

Posterior fossa MRI

Supratentorial MRI

19

Microcephaly; tetrapyramidal syndrome with dystonia and extrapyramidal syndrome

Superior vermis atrophy; abnormal white-matter arborization suggesting cortical dysplasia

Normal

20

Epicanthus; minor facial abnormalities; clinodactyly; strabismus; hypotonia; cerebellar signs; right-sided deficit

Enlarged vermis; subarachnoid spaces absent

Short corpus callosum

21

Talipes; epicanthus; bilateral enophthalmia; prominent forehead; thin lips; hypotonia

Cerebellar and vermian cortical dysplasia; medial vermian fissure and enlarged cortex; vermian hypoplasia

Corpus callosum hypoplasia; enlarged ventricles and frontal subarachnoid spaces; cavum vergae

22

High arched palate; prominent forehead; retrognathia; hypotonia; ataxia; pyramidal syndrome

Normal

Cavum vergae; parietal atrophy; ventricular asymmetry

23

Minor facial abnormalities: forehead, nose, ears; arched palate; hypotonia; tetrapyramidal syndrome

Cerebellar cortical dysplasia; right cerebellar cortex enlargement; left tentorial agenesis

Probable right hemimegalencephaly: right hemispheric enlargement with internal occipito-temporal cortical infoldings, heterotopia and enlarged Virchow-Robin spaces

24

Microcephaly; absent eye pursuit; deafness; abnormal movements; tetraparesis; axial hypotonia

Dandy-Walker variant; cerebellar cortical dysplasia

Ventricular enlargement; corpus callosum hypoplasia; pachygyria

25

Partial epilepsy; hypotonia; cerebellar syndrome

Cerebellar and vermian cortical dysplasia and heterotopia; vermian hypoplasia

Short corpus callosum; ventricular enlargement and right hemimegalencephaly

26

Multiple minor facial abnormalities; hair fragility; tetrapyramidal and cerebellar syndrome

Inferior vermis and pons hypoplasia; cerebellar cortical dysplasia: cortical thinning

Ventricular enlargement; corpus callosum hypoplasia; polymicrogyria, and white-matter hyperintensities

27

Strabismus; hypermetropia; retrognathia; plagiocephaly; clinodactyly; short palate; hypotonia; cerebellar signs

Normal

Pachygyria

In the first group, the posterior fossa was normal or demonstrated non-specific anomalies and was associated with minimal supratentorial abnormalities (n=9; cases 1–9). MRI abnormalities were: enlarged subarachnoid spaces, white matter hyperintensities and tonsillar ectopia. Supratentorial anomalies were: dysgenesis of the corpus callosum (n=4; hypoplasia or vertical orientation of the splenium), septum pellucidum or cavum vergae cysts (n=3), ventricular enlargement (n=2) and one case each of white matter hyperintensities and enlargement of subarachnoid and Virchow-Robin spaces.

A second group comprised patients with vermian or cerebellar hypoplasia or atrophy associated with subtle cerebral anomalies (n=9; cases 10–18). MRI abnormalities were: cerebellar or vermian atrophy (n=6; Fig. 1), vermian hypoplasia (n=3), enlarged fourth ventricle or subarachnoid spaces (n=2) and one case of mega cisterna magna. Supratentorial anomalies were: corpus callosum hypoplasia (n=2), vertically orientated splenium of the corpus callosum (n=1; Fig. 2), septum pellucidum cysts (n=3; Fig. 3), ventricle enlargement or asymmetry (n=3), white matter hyperintensities (n=2) and one case of Virchow-Robin enlargement.
Fig. 1.

a Case 15. Cerebellar atrophy. Coronal T2-weighted MRI shows diffuse enlargement of vermian and cerebellar fissures as compared with the supratentorial subarachnoid spaces. b Case 19. Cerebellar vermian atrophy. Coronal T2-weighted MRI shows superior vermian atrophy with enlarged transverse fissures

Fig. 2a, b.

Multiple minor posterior fossa and midline abnormalities. a Sagittal T2-weighted MRI shows enlargement of the posterior fossa cisterns and fourth ventricle associated with vermian hypoplasia and minor posterior corpus callosum hypoplasia. As described by Gabrielli et al. [9], the splenium is thin and vertically orientated. b A normal corpus callosum in another patient with normal MRI

Fig. 3.

Case 17. Absent closure of the septum pellucidum. Axial IR T1-weighted MRI shows separation of the two thin plates or 'laminae' of the interventricular septum

The third group included patients with vermian hypoplasia or cerebellar cortical dysplasia (CDD) associated with severe brain malformations (n=9; cases 19–27). In this group the posterior fossa anomalies were: CCD within the cerebellar hemispheres or vermis (n=6; Figs. 4, 5, 6), vermian anomalies including atrophy, hypoplasia or enlargement (n=5), and one case each of the following: pontine hypoplasia, unilateral tentorial agenesis, Dandy-Walker variant and cerebellar heterotopia. Supratentorial anomalies were: anomalies of the corpus callosum (short corpus callosum n=2, hypoplasia n=3, Fig. 7), enlarged ventricles (n=4), enlargement of subarachnoid spaces (n=1), cavum vergae (n=2), hemimegalencephaly (n=2), pachygyria (n=2; Fig. 8), polymicrogyria (n=1; Fig. 9), enlarged Virchow Robin spaces (n=1), white-matter hyperintensities (n=1) and ventricular asymmetry (n=1).
Fig. 4a–d.

Case 21. Cerebellar cortical dysplasia. a Coronal T2-weighted MRI shows bilateral hypoplasia of the white matter, thick cerebellar cortex and vertically orientated folia, compared with normal findings (b). c Axial view shows vertically orientated folia in the cerebellar hemispheres (white arrow) compared with normal findings (d). Subarachnoid spaces posterior to the amygdala are difficult to distinguish from bilateral clefts (black arrow head)

Fig. 5a, b.

Case 23. Cerebellar cortical dysplasia. a Coronal T2-weighted MRI (compared with normal findings in b) shows defective, large or vertical fissures with lack of normal arborisation of the white matter within the superior cerebellar hemispheres leading to disorganised foliation (cerebellar polymicrogyria)

Fig. 6.

Case 24. Vermian hypoplasia. Coronal IR T1-weighted MRI shows vermian hypoplasia and superior vermian dysgenesis; the transverse fissuration is absent and the cortex is thickened (white arrow). These abnormalities are associated with supratentorial ventricular enlargement

Fig. 7a, b.

Case 4. Corpus callosum hypoplasia. a Sagittal T2-weighted MRI shows a thin corpus callosum. Note enlargement of the posterior fossa cisterns and fourth ventricle, and medial vermian hypoplasia. b White-matter hyperintensities and moderate hypoplasia of the white matter are associated with corpus callosum hypoplasia in a 10-year, 5-month-old boy

Fig. 8.

Case 27. Pachygyria. Axial T2-weighted MRI shows shallow gyri and thickened cortex in frontal lobes

Fig. 9a, b.

Case 26. Cortical dysplasia. Coronal T2-weighted MRI show ventriculomegaly and diffuse cortical dysplasia associated with thin superior cerebellar cortex

Our results revealed that MRI was normal in 10% of cases, anomalies of the posterior fossa and supratentorial compartment were associated in 47% of cases, whereas they were isolated to the posterior fossa in 10% of cases and to the supratentorial compartment in 33% of cases. In the posterior fossa the most frequent anomalies were: vermian hypoplasia (33.3%), enlargement of subarachnoid spaces (20%), CCD (20%), enlargement of the fourth ventricle (16.6%), vermian atrophy (16.6%) and cerebellar atrophy (6.6%). The most frequent supratentorial anomalies were: hypoplasia of the corpus callosum (43.3%), ventricular enlargement (33.3%), cavum vergae or septum pellucidum cysts (33.3%), cortical dysplasias (23.3%) enlargement of subarachnoid spaces (16.6%), enlargement of Virchow-Robin spaces (10%) and white-matter abnormal signal (10%).

From the 17 patients previously diagnosed with MR of unknown aetiology (cases 1–7, 10–14, 19, 20, 28–30), only three had normal MRI findings (cases 28–30)

Discussion

In accordance with the established literature, our study showed a high frequency of brain malformations in mental retardation [2, 4, 5, 6]. We found two types of brain abnormalities in mentally retarded patients: severe malformations, especially cortical dysplasias, and minor cerebral or cerebellar abnormalities. In the latter, the abnormalities were of different types and often associated. The most frequent supratentorial findings were: corpus callosum hypoplasia (43.3%), ventriculomegaly (33.3%), enlargement of subarachnoid spaces (16.6%), cavum vergae or septum pellucidum cysts (33.3%) and cortical dysplasias (23.3%). Compared to previous reports on non-specific MR, we have found a higher incidence of posterior fossa abnormalities. These include: vermian hypoplasia (33.3%), vermian atrophy (16.6%), enlargement of posterior fossa subarachnoid spaces (20%), enlarged fourth ventricle (16.6%) and cerebellar hemispheric atrophy (6.6%). Furthermore, we found CCD in 20%, which to our knowledge has never been reported before in MR, and also a very high incidence (63.3%) of craniofacial dysmorphism and/or multiple somatic anomalies associated with MR.

Brain dysgenesis is one of the most common diagnostic categories in MR of unknown aetiology [5]. Shaefer et al. [11] predicted that many findings, representing markers of brain dysgenesis, will be better identified with progression in neuroimaging techniques. Our results confirm this statement; abnormal MRI findings were present in 90% of the patients. Some of these findings include abnormalities that are generally accepted to be present in normal individuals or may be the result of some other unknown underlying process. However, some have been reported in association with MR and are considered as markers of brain dysgenesis representing a risk for developmental delay—wide cavum septum pellucidum [12], corpus callosum hypoplasia [4] and mega cisterna magna [3, 13].

One of the most important findings in our study is that in patients with non-specific MR, subtle brain abnormalities are frequently multiple in the same patient and are located at different sites, including cerebral hemispheres (ventricles or cortex), the midline, the cerebellum or the vermis. Interpretation of these findings is difficult because their significance is currently unclear [12]. In order to investigate their pathogenic significance in retarded individuals, a Consensus Conference recommended large uniform studies in 'control' subjects to assess the incidence of these morphological findings in the 'normal population' [2]. A limitation of our study is the absence of a control group. The selection of a paediatric 'control group' is a difficult task. Patients having MRI for other clinical indications may not only be a poor representative cross-section of the general population, but may also introduce a bias because of their clinical symptoms. On the other hand, a group of so-called 'normal children' is difficult to define. Ethical considerations advocate against MRI screening of a normal population, since minor abnormalities of no specific significance or pathological findings without clinical symptoms can be found in these children. For all these reasons, we have compared our results to the anatomical and radiological descriptions of the normal brain in children [8, 9], neuropathological literature [14, 15] and radiological studies. These studies have reported tonsillar ectopia, ventriculomegaly, corpus callosum hypoplasia and white matter hyperintensities [16], delayed myelination, white matter hyperintensities, corpus callosum hypoplasia and migration malformations [17] and microcephaly, cerebellar hypoplasia, corpus callosum agenesis, and 'cerebral dysgenesis' [18]. In agreement with these reports, we have found minor and multiple anomalies in 90% of patients.

In the diagnosis of non-specific MR, the role of MRI has been clearly defined. Although the underlying cause of brain dysgenesis remains mostly unknown, its radiological diagnosis is often the first positive finding in the evaluation of mentally retarded patients, excludes other potentially more serious conditions and may avoid further aetiological testing. In other cases, MRI may identify specific features of a neurometabolic or degenerative disorder. Aetiological diagnosis not only modifies the medical management of the child, but is also needed to inform the family of prognosis, recurrence risks and genetic counselling [1]. Thus, MRI must be recommended if a diagnosis has not been achieved after a detailed history and physical examination, and in children with abnormal head size or shape, craniofacial malformations and/or multiple somatic anomalies, neurocutaneous findings, cerebral palsy or motor asymmetry, seizures, loss or plateau of developmental skills, and an intelligence quotient (IQ) below 50 [2]. According to the literature, the aetiology of severe MR can be identified in 60–70% of affected individuals and in 35–55% of patients with mild MR [12]. In a cohort of 60 patients, Majnemer and Shevell [5] made an aetiological diagnosis in 63.3% of children, and they explained their results by the improvement of diagnostic testing, especially neuroimaging and cytogenetic analysis. They suggested that biological factors underlie the majority of cases of MR. No single cause predominates; cerebral dysgenesis, chromosomal anomalies (Down's syndrome, fragile X), toxins (fetal alcohol syndrome), and hypoxic-ischaemic perinatal/postnatal encephalopathy account for two-thirds of aetiological diagnoses [19]. In cases of unknown aetiology, a chromosomal abnormality can be detected in as many as a quarter of patients [20]. For this reason, even in retarded patients with apparent well-being and a nearly normal phenotype, a Consensus Conference [2, 20] recommended 500-band level karyotyping to determine chromosome aberrations.

Another limitation of our study is that the selection of patients could be biased: the results of only 30 complete MRI examinations have been analysed from a cohort of 81 children with MR. In MR, we perform MRI for some indications according to recommendations of the Conference of Consensus in MR [2]. Despite this bias, our study suggests that in patients with non-specific MR, subtle brain abnormalities are frequent and may affect cerebral cortex or ventricles, the midline structures (corpus callosum and septum pellucidum) and the posterior fossa (cerebellar hemispheres or vermis). Although we were not able to define clinical phenotypes in non-specific MR, relying on our MRI findings, we defined three groups of patients. The first group includes patients with normal posterior fossa and minor supratentorial abnormalities. Clinical manifestations in this group were variable, including neurological deficits (44%), epilepsy (33%), motor disturbances (22%) and hypotonia (22%), associated with facial and skeletal abnormalities in 55% of cases. The second group includes patients with mild or moderate MR. Their clinical manifestations were also variable, but they included cerebellar signs (33.3%) and dysmorphism (77.7%). On MRI they had subtle cerebral anomalies associated with vermian or cerebellar hypoplasia or atrophy. Finally, we distinguished a third group of patients who presented frequently (77.7%) with hypotonia and congenital ataxia associated with severe MR, neurological deficit and dysmorphism. In these patients, MRI showed severe brain malformations and vermian hypoplasia or CCD. Although these morphological findings have previously been described in MR, to our knowledge CCD has not been previously reported in non-specific MR.

CCD has been reported in trisomy chromosomal abnormalities [21, 22], congenital muscular dystrophies and related syndromes [23], intrauterine infections [24, 25], gamma radiation [26], ethanol exposure [27] and in cases with widespread brain malformations [28]. Isolated cases of CCD are infrequent [28, 29, 30] and the pathogenesis has been considered a genetic disorder affecting the migration of cerebellar cells or a pathological event secondary to infection, hypoxia or toxins such as ethanol [24, 25, 27, 31]. MRI findings in CCD include defective, large or vertical abnormal fissures, irregular grey/white matter junction, lack of normal arborisation of the white matter and heterotopia within the cerebellar hemispheres, leading to disorganised foliation [28]. In histological studies, some cases of CCD have shown cerebellar polymicrogyria [23]. As for other subtle cerebral anomalies that have been found in non-specific MR, the functional significance of CCD is poorly understood. Moreover, its correlation with MR is difficult to confirm because it is frequently associated with other brain abnormalities. Nevertheless, neurobehavioral, neuroimaging and functional MRI studies suggest that cerebellar as well as frontal regions make distinctive contributions to cognitive performance and that cerebellar pathology leads to some general cognitive, memory and language deficits [3, 11, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42]. Such data inevitably lead us to wonder whether CCD may have a role in some particular cases as in the third group of our study in which non-specific MR was associated with congenital ataxia.

The recognition of subtle brain abnormalities or CCD could probably be the first step in understanding their role. Their study should be completed by further functional and metabolic investigations in order to evaluate whether they may affect brain function. Identifying areas of abnormal metabolism by metabolic imaging may help to increase our understanding of pathogenesis in conditions in which morphology seems to be normal with abnormal neurological function. Although this information could increase our knowledge about the underlying cause and effects of brain dysgenesis, its characterisation as a dysgenetic event involved in the pathogenesis of MR should be problematic. In this setting, molecular mechanisms of cerebral dysgenesis, neurotransmitters, genetic programs and other epigenetic stimuli factors that influence the development and differentiation of neuronal precursor cells and synaptic dysfunctions have been described recently [43, 44, 45, 46, 47, 48, 49, 50] and have revealed alterations of cortical connectivity and excitability, which are important in different clinical disorders. These alterations may be related to disorders of cortical organisation which could be responsible for developmental disabilities and/or MR. Further investigation of children with non-specific MR and subtle brain dysgenesis should be undertaken to improve our understanding of the role of brain dysmorphism in the clinical expression of MR.

In conclusion, aetiological diagnosis in MR could modify the medical management of the retarded child and is also needed to inform the family with regard to prognosis, recurrence risks and genetic counselling. Neuroimaging and cytogenetic analysis, together with the history and physical examination, are helpful in determining the aetiology of MR

Neuroimaging studies must be carried out whenever clinical evaluation reveals abnormal head size or shape, craniofacial malformations and/or multiple somatic anomalies, neurocutaneous findings, cerebral palsy or motor asymmetry, seizures, loss or plateau of developmental skills and an IQ below 50. Imaging results could reveal several subtle abnormalities within the cerebral hemispheres, the brain midline or the cerebellum. Some of these findings may be incidental and unrelated to MR. CCD may be included in the list of minor brain abnormalities found in non-specific MR. The increased use of metabolic imaging studies in these cases should enable researchers to identify subtle dysgenetic events of brain development that could help establish their role in the pathogenesis of MR.

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© Springer-Verlag 2003