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PSYCHIATRIC MANIFESTATIONS IN CHILDREN WITH TUBEROUS SCLEROSIS

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Autor: Carmen Buloiu
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ABSTRACT:

Tuberous sclerosis (TS) is an autosomal dominant multi system genetic disorder characterized by the presence of multiple tumoroushamartomatous lesions in different organs. The cerebral lesions are represented by cerebral and cerebellar cortical tubers,subependymal nodules, cerebral white matter radial signs. The psychiatric features associated to tuberous sclerosis are mentaldelay, behaviour abnormalities including autistic spectrum disorders and diff erent cognitive impairment, sleep disorders. The risk factors for cognitive behaviour abnormalities in tuberous sclerosis are the number and localization of cortical tubers, history ofinfantile spasms (mainly with early onset), persistent seizures and abnormal genetic program.

This article reviews the literature data on the psychiatric manifestations in tuberous sclerosis and the possible risk factors implied as well as their influence in the occurrence and outcome of these features.

 

 

INTRODUCTION

The tuberous sclerosis (TS) is an autosomal dominant geneticalaly transmitted disease, characterized by skin abnormalities and the emergence of hamartoma tumour lesions in different  organs, especially the brain, heart, liver, kidney and eye. The aetiology of psychiatric manifestations associated with TS is in constant debate. The number and location of cortical tubers, and the presence of early infantile spasms or of temporal epileptiform electroencephalographic abnormalities are potential risk factors for developing mental retardation, autism and autism spectrum disorders.

 

MENTAL RETARDATION AND TUBEROUS SCLEROSIS

The association of mental retardation with tuberous sclerosis (TS) has been identified since the first cases described by Bourneville in 1880. For a long time, mental retardation was considered one of the characteristic signs of this disease and a diagnostic criterion of Voght’s classical diagnostic triad developed in 1908. Subsequent studies on population have concluded that mental retardation is not present in all patients with TS, some of them having even normal intellect; retardation is not a consequence of the disease but an associated aspect in TS (1.2, 3). The prevalence of mental retardation in TS  is between 30 and 80%. The degree of the disorder is variable, although some authors (4) claim that patients with TS that combines with mental retardation are severely affected. Mental delay is a common  aspect in the TS,  about 50% of patients  have a serious  disease (3). Joinson and colleagues’ study  published in 2003, which analyses the incidence of mental retardation in a group of 109 patients with TS, highlights its presence in about 44% of patients, 30.5% having severe impairment with IQ under 21, while 14% had IQ between 21 and 70, and 55.5% had normal IQ (5).

Studies in recent years have attempted to  clarify the  factors  involved  in the  intellectual  impairment of patients with TS, why some patients  are severely affected while others have normal intellect. Etiopathogenesis of mental retardation in TS is controversial. It seems to be dependent on the presence of early infantile spasms, on the number and location of cortical tubers in the brain revealed by brain MRI neuroimaging (1.5).

The role of infantile spasms in determining mental retardation is supported  by cases of TS with normal development until  the occurrence of spasms. It is rare the situation  where an individual  with TS without  infantile  spasms has a severely affected level of  intellectual   development.  On  the   other hand, acknowledging the involvement of infantile  spasms in determining intellectual  impairment  would mean that their intellectual impairment should improve or even normalize  with treatment. The action of infantile spasms is likely to overlap with the causal mechanisms of brain pathology in TS (1). In the study by Joinson and  colleagues,  all patients  with TS  and mental retardation  had  also  a  history of early-onset  crises under  the  age of 12 months  and often  the seizures were part of infantile  spasms (5). On the other hand, acknowledging the involvement of infantile spasms in determining intellectual impairment would mean that their  intellectual impairment  with  treatment should improve or even normalize. Infantile  spasms action is likely to overlap with the causal mechanisms of brain pathology  in TS  (1). In  the  study  by  Joinson  and colleagues all patients with TS  who had had mental retardation  and  history  of early-onset  crises  under the age of 12 months and often seizures were part of infantile  spasms (5). Prolonged duration of infantile spasms, prolonged duration since the initiation  of the treatment until  achieving remission  of these spasms, as well as the poor control of the crises that arose after the infantile  spasms are elements strongly correlated with the occurrence of mental retardation in patients with TS (6).

As for the cortical tubers, there is a significant  as- sociation between their number and the level of intel- ligence quotient (IQ) (1.7). The relationship between the large number of cortical  tubers and the degree of cognitive impairment  in TS was demonstrated using modern neuroimaging techniques. The higher the number of cortical tubers is, the higher the degree of intellectual impairment. The average number of corti- cal tuber is higher in patients who also have a history of infantile spasms, compared with those without in- fantile spasms. Patients with over 10 cortical tubers are severely affected while those with less than five tubers may have varied cognitive impairment  (8). Goodman and colleagues, too, say that there is a positive  linear relationship between the total number of tubers and the degree of intellectual impairment, the presence of more than 7 cortical tubers representing a high risk of intellectual impairment (9). O’Callaghan in his study also found  an  average of 10 tubers in patients with severe intellectual impairment. On the other hand, there is a report  of a patient with 27 cortical tubers whose IQ was 130, so we must be cautious about formulating a prognosis on the level  of intellectual development based on the number of cortical  tubers revealed by means of neuroimaging (1). Although the number of cortical tuber is correlated with intellectual impairment, normal cognitive function is compatible with extensive brain damage and present epileptic seizures (10).

The  degree of mental  retardation in TS is influenced not only by the number of cortical  tubers, but also by their location in certain specific brain areas (4). The separate analysis of the number of cortical tubers according to their location and the IQ shows a close correlation  between the number in each specific brain lobe and  the degree of intellectual  impairment.The frontal lobe seems to play a central role in determin- ing the neural bases of intelligence (11). Based on this finding,it is assumed that the frontal cortical locations of the tubers are more frequently associated with severe retardation;  so that we can say that the degree of intel- lectual impairment in TS is in close correlation with the extent of cortical tubers at frontal level (12).  More recent studies claim  that the number of tubers in the occipital lobe and then in the frontal lobe represent a significant predicting element of the IQ score (1).

At the same time, however, cortical and sub-corti- cal abnormalities  are also responsible for the occur- rence  of epileptic  seizures  and of epilepsy, which in turn may have adverse effects on intellectual  develop- ment resulting in severe brain dysfunction,  especially in cases with  f requent  and  severe seizures  (4).Thus, children with TS who develop epilepsy before the age of five years and especially those with early infantile spasms, will have  a  more  severe degree of impaired intellectual development (13).

Separate analysis of the influence of infantile spasms and of cortical tubers shows a strong correlation with  the degree of disorder of the intelligence level. Analysis of the two associated variables (number of cortical  tubers and epilepsy) is strongly correlated with the degree of intelligence of individuals  with TS (1).The presence of bilateral cortical tubers and early onset seizures are significantly correlated with cognitive impairment in TS  (14). Recent  data argue that cognitive development in TS is influenced more by the young age at the onset of seizures than by the number of cortical tubers (15).

The nature of genetic mutations causing TS also affects the degree of intellectual  impairment in patients with TS (16, 17). Patients with TS presenting TSC  2 gene mutation  have a more severe disease compared with those with impaired TSC 1 gene, possibly by the existence of an associated second somatic mutation in the TSC2 gene with or by the dominantly negative effect of TSC  2 mutation. The damage of TSC2 gene results in a larger brain damage which in turn will cause a more severe intellectual impairment. There are also patients with TSC1  gene mutation with severe intellectual impairment, thus the question arises whether other factors might cause this.

In most cases mental retardation in tuberous scle- rosis occurs early and progressively.

Patients with TS and normal intelligence quotient (IQ) may have specific cognitive deficits such as delay in language acquisition,  visual  and spatial disorders, dyscalculia, dyspraxia and memory difficulties  (4, 10, 18). Patients with TS, normal IQ  and language disorders have a particular  impairment of the receptive language (5).

In conclusion, the factors incriminated in the oc-currence of mental retardation in patients with TS are represented by: a history  of early-onset  crises, especially the aspect of infantile  spasms, number and location of the cortical tubers detected at neuroimaging tests, and the types of genetic mutation (1, 5, 9, 17).

 

BEHAVIOURAL DISORDERS AND TUBEROUS SCLEROSIS

Behavioural disorders are common in the TS and are represented by autistic  spectrum disorders, hyper-kinetic  syndrome or only attention deficit, aggression and sleep disorders (19.20). Patients with TS and severe mental retardation may associate repetitive abnormal head movements, rocking and even self-harm.

The emergence of behavioural disturbances in ST is mainly related to the presence of epilepsy. Some authors argue that the presence of seizures and, respectively, of epilepsy is the  main  determinant  element of these disorders  (18.19) while  other authors have shown that there is no significant correlation between epilepsy and behavioural disorders in patients with TS so that epilepsy would not constitute the only isolated factor incriminated in their appearance (21).

The most common behavioural disorder in patients with TS is the attention  deficit hyper-kinetic syndrome. It is now  present  in around 20%  of patients (21, 22, and 23) and may be worsened by epileptic seizures.

Autism or autistic spectrum disorders are  the second important psychiatric manifestation found in patients with TS (24).

The prevalence of autism and pervasive developmental disorders in the general population is 2 per 1,000 inhabitants, while the TS prevalence rate is 1: 6000 (25). There is a male  predominance in autism disorder (4:1), yet unexplained (12).TS seems to be the etiological  cause in about 1% of autism cases in general (26). But the actual percentage may be higher since not all patients with autism were carefully evaluated for signs characteristic of tuberous sclerosis. More recent epidemiological studies have shown that TS may be responsible for 3-4% of autism cases in general (12, 25). The frequency of autism in TS varies between 17 and 61% in different epidemiological studies. Curatolo and colleagues identify autism in 26%  of all patients with TS,  all of them having mental retardation accompanied by an IQ below 40 (19). Hunt  and Shepherd found in their study of 1993 an incidence of 24% while Smalley reported an incidence of 54% (26, 23). More recent studies report an incidence of autism in TS of 16% – 25% (25, 27). Variations in the incidence of autism in TS in various studies may be explained by the smaller number of patients and the use of more stringent or more lenient criteria for diagnosis. Using DSM III R and ICD 10 criteria, Calderon found an incidence of autism in TS of 26%, while Gilberg reported an incidence of 50%, and Bolton an incidence of 61% (28, 20, 29). Autism seems to affect both sexes equally, differently from what is generally observed in autism which is mainly affecting mainly males (12). Autistic behaviour in patients with TS was first described in 1932 by Critchley and Earl, 11 years before Kanner’s classic reporting on early infantile autism (30). Only in the 1980s it became evident that patients with TS frequently show autistic aspects (31, 26, and 12).

Despite  progress made in recent years, the neurobiological bases of associating autism with TS  are still insufficiently known. Factors incriminated in the occurrence of this abnormal behaviour in TS are: the number and location of cortical and sub-cortical tubers, generalized damage in brain development, mental retardation, the effect of crises and/or of electroencephalographic abnormalities and an abnormal genetic programme (25, 32).

Neuroimaging studies in patients with autism in general showed no significant brain alterations except for increased brain volume in some cases, corresponding to a large head perimeter but with no signs of macrocephaly. Starting from this finding, it has been assumed that  the  location of the cortical  tubers in specific areas of brain in TS could have a causative role in autism. In general the number of cortical tubers in TS is higher in the frontal lobe, and then in the parietal, the temporal ones, in the cerebellum and the occipital lobe. Autism associated with TS could represent an early dysfunction at the level of associative areas due to the location of the cortical tubers, with the temporal and the frontal lobes as areas involved in autism and in other pervasive developmental disorders (29, 33, 32, 19). Curatolo and colleagues have observed that patients with TS who developed a precocious form  of autism, under the age of 2, had cortical tubers localized predominantly at the pari- etotemporal level, while patients with autism who developed TS later, between the age of 3 and 5 years old had  lesions mainly on the frontal  and occipital lobes (19). The PET Research (Positron Emission Tomography) showed decreased glucose metabolism in bilateral temporal gyri in patients with autism and TS (34). Bolton and Griffiths, too, revealed a close association between the location of the cortical tubers in the temporal lobes and autism in TS (29). Analysing 18 patients with TS they detected autism in 9 cases, with 8 of the 9 patients having temporal tubers while the other nine patients had neither autism nor any tubers in the temporal lobes. But Bolton’s study is limited to the use of only the cerebral CT scan in the imaging  investigation of certain patients which makes it possible to underestimate the cortical tubers in patients who have not been investigated by cerebral MRI (29). Seri examined the presence of autism in 14 patients with TS who had been investigated only by brain NMR examination; he found cortical tubers in the temporal lobe in only 7 patients with autism, and only in these cases he also found impaired auditory evoked potentials (35).

The presence of cortical tubers at the temporal level is a necessary but insufficient condition for the development of autistic spectrum disorders in TS. There are patients with TS and temporal tubers without autism, so that one cannot appreciate what individuals  with TS and temporal cortical tubers may develop autism (36). Cortical tubers from the cerebellar level seem to have a role in autism in TS, too (37). But not all studies take this aspect into consideration. Discrepancies in studies on the relationship  between the location of brain and cerebellum tubers and autism are probably due to the use of only brain CT examination in initial studies which may result in letting the cortical tubers unobserved both the cerebral and especially the cerebellar ones, since CT examination is limited in determining the posterior fossa lesions.

Some authors claim that there is a more significant correlation between the number of cortical tubers and autism compared to their location (19). When analysing only the influence of the number of cerebral cortical tubers one ignores the fact that between the cerebellum and the cortical and sub-cortical structures there are extensive reciprocal connections, and the damage to the cerebellum in TS may also have a role in triggering autism (37).

Epilepsy affect  up to 92% of patients with TS (38). Several epidemiological  studies  suggest an increased incidence  of autism in patients with TS and epilepsy, epilepsy being considered  a risk factor for autism in children with TS (33, 38, 39). About 6.5% of patients with autism in general have epilepsy before the diagnosis of autism (40), and 15-20% of autistic children without a history of clinical seizures have epileptiform electroencephalographic (EEG) anoma- lies (41). Prolonged  EEG video  studies in children with autism and cognitive decline revealed epileptiform electroencephalographic abnormalities  in 46% of cases while magnetoencephalography (MEG) has identified epileptic  abnormalities in 82% of autistic patients with regression (41, 42). EEG studies show that the risk for the development of autistic spectrum disorders in children with TS increases when there is obviously  a temporal epileptogenic  focus (31). PET studies (Positron Emission Tomography)  performed on children with infantile  spasms reveal the fact that hypometabolism of the  bilateral  temporal  lobe is a predictive factor for an evolution to autism (43).

Patients with TS have more cortical tubers which may act as epileptic foci causing multiple seizures, often multi-focal and difficult to control ones. The greater the number of cortical tubers, the earlier the onset of epilepsy appears to be. Usually, epilepsy starts in infancy with crises having an aspect of infantile spasms, the presence of infantile  spasms being frequently associated with the occurrence of a disorder in the autistic spectrum. Most patients with TS and autism have a history of infantile spasms and mental retardation so that  the question arises of whether  seizures  are  the cause of the manifestation of autism or they are different ways of expression for the same brain dysfunc- tion, through genetic determinism; thus the common underlying pathology is a mutual cause responsible for the occurrence both of epilepsy and of autism and mental retardation (44). There is a high rate of infantile spasms in patients with TS and autism (20, 26). There is also an increased incidence of autism in patients with TS  and epilepsy, and especially with  infantile spasms (33). About 58% of patients with infantile spasms and TS from the series of Hunt  and Denis have associated autism (21). But there are a large number of patients with TS and autism without infantile  spasms, as well as patients with TS and spasms without autism and patients with TS and spasms without autism, so that nobody can claim with certainty the existence of a direct causal link between autism and infantile  spasms in TS (39). Although infantile spasms are a risk factor, there must be other aspects of TS than spasms alone to predispose to the development of autism (31, 45). The mechanisms determining  infantile  spasms to contribute to the development of these behaviour disorders are not sufficiently known yet (25). Infantile  spasms are considered to be a particular form of expression characteristic of the infant. They are caused by the suffering of a still immature brain  that is in its full process of development. Although  they are not a sufficient  cause for the occurrence of autism spectrum disorders, their presence in these patients suggests that the mechanisms which determine their emergence are largely the same as for the emergence of autistic disorders. It is unclear whether epileptiform electroencephalographic abnormalities and seizures have an effect on the cognitive function and on the occurrence of autistic behaviour or are the result of the same underlying pathology causing the emergence of autism (39, 44, 45). The presence of temporal epileptic foci in children with TS and autism brings into question the possibility that the increased risk for this dysfunction should originate in the precocious and non-specific disruption of the functional development of neural systems that support the representation of social behaviour in the temporal lobes (36). If epileptic seizures or epileptiform discharges contribute or are the cause of autism, it is assumed that the treatment with antiepileptic drugs or surgery in these situations could improve the development. The high rate of response of the infantile spasms to treatment with Vigabatrin (80-100%) (46), could provide an opportunity to determine whether the control of infantile spasms may influence the cognitive function and the evolution of behaviour and prevent the occurrence of autistic behaviour in ST (12). Some authors argue that early control of infantile  spasms can cause cognitive behavioural improvement in ST (13).There are few data to support the use of antiepileptic medications in patients without clinical seizures in order to improve behaviour. But there are no clinical trials that should address this issue and no justification  for surgery in patients with autism or autistic regression with EEG abnormalities in the absence of untreatable epilepsy (44).

Regarding the assumption of genetic determinism, it seems that TSC2 gene leads to a higher expression of tuberin at the level of the brain regions involved in autistic disorders, the candidate gene for autism being potentially located on the 16p13 chromosome (48). The large deletions in the 16p13.3 region detected in patients with TS  who associated also both polycystic kidney disease and autism might potentially affect an- other gene responsible for the development of autism (12). Patients with TS and TSC2 gene damage would thus be more prone to the development of autistic spectrum disorders, since autism reflects a direct effect of the abnormal genetic program (32). Sequencing the terminal two megabases on the short arm of chromosome 16 containing  the TSC2 locus revealed the existence of the linkage for the bipolar affective disorder and epilepsy as well as for autism in the same  area. An autism susceptibility locus has been identified in the 16p13.3 region (49). However, further studies are needed to determine if there is any association between one of the two loci, TSC and autism (12).

Recent data suggest that any of these factors could not correlate alone with the development of autism in children with TS (32). Disruption of brain functions includes the combination of multiple factors such as location of cortical tubers, seizures and early infantile spasms in particular, acting on a developing brain, brain development disorders in the areas involved in the occurrence of autistic spectrum disorders and the possible linkage between TS  genes and the gene responsible for the occurrence of autism (27).

Sleep disorders are another common manifestation in children with TS, but their prevalence is poorly known. The aspect of these disorders is different, which may be  either nocturnal ambulatory automatisms, or early awakenings or daytime sleepiness (49). Studies on large samples of patients with TS are needed where polysomnographic recordings should record the total sleep duration, the number of awakenings and transitional stages, the duration of the REM sleep and of the deep sleep. In the study conducted in 1995 by Bruni and colleagues (50) on a small sample of only 10 patients with TS, they found a reduction of the total sleep time and of the deep sleep period, with increased number  of awakenings and transitional stages, increased number of awakenings after falling asleep and decreased duration of REM sleep. TS may be associated with f requent awakenings but they may be related to hypnic epileptic seizures in patients with inadequately controlled epilepsy (Hunt 1994). In these cases, in order to establish the cause video-EEG is required for longer periods, sometimes even at home. Nocturnal  seizures are usually frontal and may join complex motor movements which must be distinguished from true sleep disorders in order to receive appropriate medicine treatment. The most frequent sleep disorder found in children with ST is the increase the period of falling asleep.

 

CONCLUSIONS

The concept of intellectual  and cognitive impairment in TS was substantially revised in recent years. The idea according to which all patients with TS inevitably present mental retardation has proved to be misleading. Mental retardation occurs less f requently than initially  thought affecting approximately 40% of patients (2, 5). Intellectual impairment seems to be correlated with the type of genetic mutation, the extension of brain abnormalities, age of the onset of seizures and their types (1, 5, 16, 17). In order to appreciate the participation of each factor, independently, to the degree of intellectual impairment it is necessary to perform prospective longitudinal studies on large samples of representative patients (36).

Patients with TS are at risk of developing an autiTSic spectrum disorder especially when there are cortical tubers in the temporal lobe, in association with temporal epileptiform discharges, with early onset seizures, under the age of three years in particular with aspect of infantile spasms and persistent seizures under medicine treatment (36). All these factors constitute together useful clinic indicators for assessing prognosis. Each factor taken in isolation does not represent a sufficient cause, even if a necessary one, which might determine an autistic behaviour. Some patients with TS  develop autistic behaviour following a specific location of the cortical tubers; others may experience specific epileptic phenomena, while still others may probably suffer from a deletion in an adjacent but independent gene which is critical for the genesis of autism (12). Clearly the underlying pathology of TS is prone to multiple intertwined morbidities, including mental retardation, epilepsy, behavioural dis- orders, with higher incidence of autism or of autistic spectrum disorders. Early diagnosis of autism associated with TS could allow early treatment and bet- ter development potential. Improving  the treatment of epilepsy in patients with TS, including the good answer of spasms to Vigabatrin as well as the success of epilepsy surgery may allow an independent analysis of the effects of localization of lesions, of mental retardation or of genotype on behaviour (12) and the elimination or reduction  of epilepsy as a variable  in distinguishing  possible factors which determine the occurrence of autism in TS.

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Correspondence to:
Carmen Burloiu “Al. Obregia” Hospital, Pediatric Neurology Clinic, Bucharest

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