Self-injurious behavior and tuberous sclerosis complex: Frequency and possible associations in a population of 257 patients

Self-injurious behavior (SIB) has been observed in people with tuberous sclerosis complex (TSC), although the frequency of SIB in TSC is largely unknown. SIB is associated with intellectual and developmental disabilities, but there is no single cause of SIB. We retrospectively examined the frequency of SIB in a population of 257 patients with TSC and determined possible associations with SIB. We found a 10% frequency of SIB in our TSC population. When compared with patients without psychiatric symptoms, we identified a significantly higher rate of electroencephalographic interictal spikes in the left frontal lobe and a significantly lower number of tubers in the left occipital, parietal, and posterior temporal lobes. We also found that frequency of TSC2 mutation, history of infantile spasms, history of seizures, mental retardation, and autism are significantly associated with SIB.     

Is there a link between traumatic experiences and self-injurious behaviors in eating-disordered patients?

To find out more about the relationship between the presence of self-injurious behavior (SIB) and a history of traumatic experiences, we studied this link in 70 patients with an eating disorder (ED). The sample showed a high frequency of SIB (38.6%), particularly in patients with bulimia nervosa. We also found high percentages of self-reported experiences of physical (32.3%) and sexual abuse (47.7%). The presence of SIB turned out to be associated with a history of physical and/or sexual abuse. Patients who had suffered interpersonal abuse before the age of 15 were more likely to develop self-destructive behaviors. In line with other investigations, we found that high levels of dissociation and self-criticism differentiated sexually abused ED patients with SIB from those without SIB. We discuss some clinical implications of our findings, with suggestions for treatment.     

Mutational analysis of paediatric patients with tuberous sclerosis complex in Korea: genotype and epilepsy

To date, only a few studies have reported that, in tuberous sclerosis, TSC2 mutations are more frequently associated with infantile spasms and cognitive impairment compared to TSC1 mutations. We analyzed the mutational spectrum of patients with tuberous sclerosis in Korea and attempted to explore the associations between genotype and seizure type/outcome. We performed mutational analyses on 70 unrelated patients with clinically confirmed tuberous sclerosis by using direct DNA sequencing and/or multiplex ligation‐dependent probe amplification. The patients’ medical records, including epilepsy type and outcome, were reviewed retrospectively. We identified pathogenic mutations in 55 patients (79%), 25 of which were novel. There were 12 TSC1 mutations and 43 TSC2 mutations. TSC1 mutations included 8 frameshift and 4 nonsense mutations. TSC2 mutations included 12 frameshift, 10 nonsense, 6 splicing, and 6 missense mutations, as well as 4 in‐frame deletions and 5 large deletions. Fifty‐eight patients had epilepsy (83%), including 19 patients with a history of infantile spasms. Compared to patients with TSC1 mutations, individuals with TSC2 mutations had a significantly higher frequency of epilepsy (p<0.05) and tended to have a higher frequency of infantile spasms (37% vs 17%; p<0.3). Most of the patients with TSC2 mutations who developed infantile spasms exhibited subsequent epilepsy (13/14; 93%). However, the presence/absence of infantile spasms did not influence seizure remission or cognitive outcome.     

Cyclical self-injurious behavior, contingent water mist treatment, and the possibility of rapid-cycling bipolar disorder

Cyclical self-injurious behavior (SIB) in the form of self-slapping was treated in a 45-year-old, profoundly retarded woman who had a life-long history of SIB. Her SIB alternated between high (mean=8.54 responses per min; SD=6.77 and low (mean=0.05 responses per min; SD=0.20) frequencies every 8 weeks on average. Instances of self-slapping produced water mist treatment paired with a verbal command, “No hitting”. Absence of selp-slapping and/or completion of a work task led to a variety of outcomes, including brief back rubs, sips of water, small edibles, and praise. Water mist treatment reduced the frequency of SIB within treatment days during high frequency periods, but produced no reduction across treatment days. Treatment onset was associated with a slight increase in the frequency of SIB during three of the five low frequency periods. However, water mist treatment suppressed SIB completely in sessions during low frequency periods and the suppression continued across treatment days. Water mist treatment produced no discernible changes in the length of the high and low frequency periods of SIB.     

Altered hypothalamic-pituitary-adrenocortical function in rhesus monkeys (Macaca mulatta) with self-injurious behavior

Individually housed rhesus monkeys sometimes spontaneously develop self-injurious behavior (SIB) in the form of self-directed biting that, on occasion, results in severe tissue damage and mutilation. We previously demonstrated lower levels of plasma cortisol in rhesus monkeys with a history of self-wounding (SW) when compared to non-wounders (NW). Furthermore, cortisol levels were negatively correlated with rates of self-directed biting. The present study was designed to further characterize the relationships between hypothalamic-pituitary-adrenocortical (HPA) activity, self-wounding, and self-directed biting. Basal 24-h urinary free cortisol excretion, the urinary free cortisol response to a low dose of dexamethasone, and the plasma cortisol response to ACTH were examined in 24 individually housed rhesus monkeys, based on wounding history, i.e. the presence/absence of a veterinary record of self-wounding, and current rates of self-directed biting, i.e. the median split of self-directed biting frequency (independent of wounding status). There were no reliable group differences on any of the physiological measures when analyzed by wounding history. However, the plasma cortisol response 30 min post-ACTH stimulation was significantly correlated with wounding recency, such that lower responsivity was associated with more recent wounding episodes. When the results were analyzed on the basis of biting frequency, high frequency biters (HFB) compared to low frequency biters (LFB) showed decreased HPA negative feedback sensitivity to dexamethasone and a trend towards an attenuated plasma cortisol response to ACTH stimulation. These findings suggest that SIB in socially reared monkeys is associated with complex changes in HPA axis function that are related to the expression of the pathology, i.e. self-directed biting, and to the recency of a wounding episode. It remains to be determined whether humans who exhibit SIB show similar alterations in HPA function.     

Infantile spasms in tuberous sclerosis complex: prognostic utility of EEG

Purpose:   To assess cognitive and epilepsy outcomes in tuberous sclerosis complex (TSC) patients with a history of infantile spasms (IS), in relation to spasm history, electroencephalography (EEG) characteristics, genetic mutation, and treatment history.
Methods:   The authors conducted a retrospective review of 45 children and adults with TSC and a history of IS. EEG reports from the time of spasms were evaluated for all patients, and EEG tracings were accessible and evaluated for 20 patients.
Results:   Clinical outcome was unfavorable for the majority of patients. However, 33% had experienced at least one year of seizure freedom at follow-up, and 24% of those tested had IQs above 70. Hypsarrhythmia severity scores varied widely, with some EEGs severely hypsarrhythmic and others essentially normal. Lower IQ was significantly associated with higher hypsarrhythmia severity scores on EEG report, the presence of background disorganization on EEG report, the absence of normal sleep patterns on EEG, and a lower degree of treatment success on vigabatrin. A relationship between poor cognitive outcome and poor epilepsy outcome was confirmed. The correlation between poor epilepsy outcome and a greater degree of background disorganization on EEG approached significance, as did the association between subsequent intractable epilepsy and an older age at IS cessation. A greater than expected ratio of TSC2 to TSC1 patients was observed across this IS population.
Discussion:   Early detection and successful treatment portend a more favorable outcome in TSC patients with IS. Although EEG findings in these patients vary, specific characteristics may serve as clinically useful prognostic markers.     

The psychopathologies of children and adolescents with tuberous sclerosis complex (TSC)

Tuberous Sclerosis Complex (TSC) is a multi-system genetic disorder associated with a wide range of physical features and very high rates of numerous neurocognitive manifestations. However, there is great variability of expression of these features and understanding of the mechanisms underlying this variability is still limited. Mental retardation (MR) and male gender are known to be associated with increased risks of psychopathologies in the general population, but no study has examined these subgroups in TSC as possible contributors to the variable expression observed. It has also remained unclear whether familial-sporadic differences may contribute to variable expression. In this postal survey, UK families reported the frequency and range of physical and behavioural abnormalities in 265 children and adolescents with TSC. Analysis revealed no gender or familial-sporadic differences. Children with MR were significantly more likely to have an autism spectrum disorder, attention deficit-related symptoms and speech and language difficulties. They were more likely to have a history of epilepsy, facial angiofibromata and shagreen patches and tended to have a greater number of physical features of the disorder. However, about one third of the children without MR had features suggestive of a developmental disorder. Anxiety symptoms, depressed mood and aggressive outbursts occurred at equally high rates in those with and without MR. These findings show that TSC can place any child or adolescent at significantly increased risk of a range of neurodevelopmental disabilities. These difficulties, often not recognised, require significant clinical and research attention.     

Behavior problems in children with tuberous sclerosis complex and parental stress

Behavioral problems are common in children with tuberous sclerosis complex (TSC) and can be challenging to manage at home. Standardized measures were used to assess behavior in 99 pediatric patients with TSC and to evaluate parenting stress in their parents. About 40% of the pediatric patients presented clinically significant behavioral problems, most frequently involving symptoms of autism spectrum disorder, inattention, and hyperactivity. Higher seizure frequency, mixed seizure disorder, and low intellectual functioning placed the patient at significant risk for behavior problems. Almost 50% of participating parents reported experiencing clinically significant parenting stress, which was associated with specific characteristics of the child, including the presence of current seizures, a history of psychiatric diagnosis, low intelligence, and behavioral problems. Clinicians should be aware that behavioral problems are prominent in children with TSC. Referrals for behavioral intervention and monitoring of parental stress should be included in the medical management of children with TSC.     

Salivary biomarkers of HPA axis and autonomic activity in adults with intellectual disability with and without stereotyped and self-injurious behavior disorders

Salivary levels of biomarkers for the hypothalamic–pituitary–adrenal axis (HPA; cortisol) and sympatho-adreno-medullary system (SAM; α-amylase) were measured in 51 adults (57% male) with neurodevelopmental disorders associated with intellectual disability (i.e., mental retardation) and chronic self-injurious behavior (SIB) and compared with matched controls without SIB. Cortisol levels differed significantly (p < 0.01) between the SIB and control group (SIB > control). Within-group analyses showed significant differences (p < 0.05) in levels of salivary α-amylase between individuals with SIB and those with SIB meeting criteria for stereotyped movement disorder (SMD; SIB + SMD > SIB). Salivary α-amylase was significantly correlated with frequency of stereotypy among the SIB group (r = 0.36, p < 0.05). These preliminary findings warrant further exploration into the role of the SAM system in the pathophysiology of SIB and related repetitive behaviors among individuals with neurodevelopmental disorders associated with intellectual disability.     

Alterations of gray matter volumes and connectivity in patients with tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an inherited genetic disorder caused by mutations in the TSC1 or TSC2 genes, encoding hamartin and tuberin. We aimed to evaluate structural volumes and connectivity of patients with TSC compared to those of healthy subjects. We consecutively enrolled 13 patients with a diagnosis of TSC and 15 age- and sex-matched healthy control subjects. Subjects underwent three-dimensional volumetric T1-weighted imaging, suitable for a quantitative analysis. Structural volumes were investigated using FreeSurfer image analysis software, and structural connectivity was calculated from a connectivity matrix, which was estimated from the correlation analysis of structural volumes using the Brain Analysis using Graph Theory software package. Differences in structural volumes and connectivity were analyzed between patients with TSC and healthy subjects. There were no differences of cortical volumes between the patients with TSC and healthy controls. However, we found decreased gray matter volumes in several subcortical regions in the patients with TSC compared to those in healthy controls, specifically in the putamen (0.3212 vs. 0.3841%, p = 0.001), even after multiple corrections. Regarding global structural connectivity, the small-worldness index was significantly decreased in patients with TSC compared to that in healthy controls (0.907 vs. 0.977, p = 0.049). This study revealed structural volumes and connectivity in patients with TSC that are significantly different from those in healthy controls. These alterations have implications for the pathogenesis of TSC.     

Naltrexone attenuates self-injurious behavior in mentally retarded subjects

The effect of naltrexone on the frequency of self-injurious behavior (SIB) was investigated in 6 male subjects with profound mental retardation. Following a double-blind placebo-controlled crossover design, naltrexone was administered in a dose of 50 mg once daily for 3 consecutive weeks. In 2 of 5 subjects, a significant decrease of SIB frequency could be demonstrated, and in 1, a tendency to a reduction was found. No effect on duration of restrain time was found in 3 subjects. These data suggest that disturbances of the endogenous opioid systems may be involved in the pathophysiology of SIB of certain patients.     

Lamotrigine therapy of epilepsy in tuberous sclerosis

PURPOSE: Lamotrigine (LTG), a newer antiepileptic drug (AED), has activity against both partial-onset and generalized seizures. Its reported benefits for behavior, and its effectiveness in Lennox-Gastaut syndrome and other forms of refractory epilepsy, make it a logical choice for treatment of epilepsy in tuberous sclerosis complex (TSC). We present our experience with LTG therapy of epilepsy in 57 patients with TSC. METHODS: Patients fulfilled the diagnostic criteria for clinically definite TSC. LTG was initiated and increased until improvement in seizure frequency was noted, intolerable side effects occurred, or maximal doses were reached. Seizure frequency and behavioral changes were recorded during LTG therapy and compared with those prior to the introduction of LTG. RESULTS: Twenty-four (42%) were seizure free, and 21 (37%) had a >50% reduction in seizure frequency. Eighteen (32%) had subjectively improved behavior and/or alertness with daily activities. Thirty-eight (67%) had no change in this regard, whereas one (2%) became worse. Responders were more likely to not have a history of infantile spasms, and to have experienced only partial seizures (p < 0.05). Otherwise no phenotypic correlations with response were apparent. CONCLUSIONS: Among patients with TSC and epilepsy, LTG was effective and well tolerated, including as initial monotherapy. Improved alertness and behavior were apparent in many patients. The incidence of side effects is similar to that reported for other pediatric populations with symptomatic partial epilepsy. The usefulness of LTG in TSC may relate to an underlying defect of glutamatergic neurotransmission in partial epilepsy.     

Malignant Tourette syndrome.

The aim of this work was to draw attention to potentially life-threatening symptoms associated with Tourette syndrome (TS) and to explore their relationship to TS comorbidities. Medical records of all patients with TS evaluated at our Movement Disorders Clinic between July 2003 and July 2006 were reviewed. Data on patients with malignant TS, defined as >or=2 emergency room (ER) visits or >or=1 hospitalizations for TS symptoms or its associated behavioral comorbidities, were entered into a dataset and analyzed. Five illustrative cases are described. Of 333 TS patients evaluated during the 3-year period, 17 (5.1%) met the criteria for malignant TS. Hospital admission or ER visits were for tic-related injuries, self-injurious behavior (SIB), uncontrollable violence and temper, and suicidal ideation/attempts. Compared with patients with nonmalignant TS, those with malignant TS were significantly more likely to have a personal history of obsessive compulsive behavior/disorder (OCB/OCD), complex phonic tics, coprolalia, copropraxia, SIB, mood disorder, suicidal ideation, and poor response to medications. Although TS is rarely a disabling disorder, about 5% of patients referred to a specialty clinic have life-threatening symptoms. Malignant TS is associated with greater severity of motor symptoms and the presence of >or=2 behavioral comorbidities. OCD/OCB in particular may play a central role in malignant TS; obsessive compulsive qualities were associated with life-threatening tics, SIB, and suicidal ideation. Malignant TS is more refractory to medical treatment than nonmalignant TS.     

Psychiatric comorbid conditions in a clinic population of 241 patients with tuberous sclerosis complex

Psychiatric symptoms were retrospectively assessed in a clinic population of 241 children and adults with tuberous sclerosis complex (TSC). Sixty-six (27%) patients had a history of mood disorder symptoms, 66 (27%) had a history of anxiety disorder symptoms, 73 (30%) had a history of attention-deficit hyperactivity disorder (ADHD) symptoms, and 68 (28%) had a history of aggressive/disruptive behavior disorder symptoms. Significant relationships were found between these symptoms and patient age, gender, genetic mutation, seizure history, surgical history, cognitive impairment, features of autism or pervasive developmental disorder, and neurological manifestations of TSC. In 43 patients seen by at least one of two affiliated psychiatrists, the most common formal diagnoses were anxiety disorders (28%), mood disorders (26%), adjustment disorders (21%), ADHD (21%), and mental disorders not otherwise specified due to general medical condition (42%). Citalopram demonstrated efficacy in treating anxiety and depression, and risperidone, in treating problematic behaviors.     

Self-injurious behaviour before and after deinstitutionalization

The deinstitutionalization movement is presently spreading in Europe. Studies evaluating the effects of deinstitutionalization on behaviour disturbances among people with intellectual disability (ID) have been inconclusive. The present paper focuses on people without self‐injurious behaviour (SIB) who developed SIB after deinstitutionalization. The present authors studied individual and environmental characteristics before and after deinstitutionalization to look for factors associated with the development of SIB which could also be possible intervention points for preventive action. All those individuals in an institution for people with ID who did not have SIB before deinstitutionalization were included in the present study. The individuals who developed SIB after deinstitutionalization (n = 15) formed the study group (group A) and those who did not (n = 53) comprised the control group (group B). The population was examined both before and after deinstitutionalization. As far as possible, the same methods were used at both occasions. The covariates were both individual (e.g. mental health, behaviour disturbances and behaviour deficits) and environmental (e.g. caretaker education, caretaker:patient ratio, housing and leisure activities). Psychiatric disorders were identified in 1987 and 1995 with the Psychopathology Instrument for Mentally Retarded Adults, which was filled in by the caretakers. In 1987, the people in group A who acquired SIB had lower developmental quotients, used wheelchairs more often and had trouble with moving around without help. They also had a greater frequency of epileptic seizures, and hearing and communication impairment. In 1995, there were only minor environmental differences between groups A and B. There were significantly more individuals involved in the rotation period and more unskilled caretakers working with the people in group A than group B. The present authors found no differences between the two groups on variables such as global mental health and behaviour disturbances, or in the use of neuroleptics before or after deinstitutionalization. Groups A and B did not show differences in behaviour disturbances or psychiatric disorders in 1987. In both 1987 and 1995, there were no differences between groups A and B on variables such as accommodation, caretaker:patient ratio, the number of caretakers involved in direct care, the caretakers' education, or the time spent in structured activities before and after deinstitutionalization. The individual characteristics indicating that a person may acquire SIB are behaviour deficits which are suggestive of central nervous system dysfunction or damage, even if the results are inconclusive. The development of SIB may also be facilitated by communication deficits or by reinforcement of a incidentally occurring SIB if the staff includes many unskilled caretakers in the rotation period.     

Irradiation exacerbates cortical cytopathology in the Eker rat model of tuberous sclerosis complex, but does not induce hyperexcitability

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multi-organ pathologies. Most TSC patients exhibit seizures, usually starting in early childhood. The neuropathological hallmarks of the disease - cortical tubers, containing cytopathological neuronal and glial cell types - appear to be the source of seizure initiation. However, the contribution of these aberrant cell populations to TSC-associated epilepsies is not fully understood. To gain further insight, investigators have attempted to generate animal models with TSC-like brain abnormalities. In the current study, we focused on the Eker rat, in which there is a spontaneous mutation of the TSC2 gene (TSC2+/-). We attempted to exacerbate TSC-like brain pathologies with a "second-hit" strategy - exposing young pups to ionizing irradiation of different intensities, and at different developmental timepoints (between E18 and P6). We found that the frequency of occurrence of dysmorphic neurons and giant astrocytes was strongly dependent on irradiation dose, and weakly dependent on timing of irradiation in Eker rats, but not in irradiated normal controls. The frequency of TSC-like pathology was progressive; there were many more abnormal cells at 3 months compared to 1 month post-irradiation. Measures of seizure propensity (flurothyl seizure latency) and brain excitability (paired-pulse and post-tetanic stimulation studies in vitro), however, showed no functional changes associated with the appearance of TSC-like cellular abnormalities in irradiated Eker rats.     

Epilepsy surgery in tuberous sclerosis: a systematic review

PURPOSE: Tuberous sclerosis complex (TSC) is often associated with intractable epilepsy. Although epilepsy surgery has gained interest in recent years uncertainties exist about which patients are good surgical candidates. A systematic review of the available literature has been undertaken to assess the overall outcome of epilepsy surgery and identify risk factors of seizure recurrence. METHODS: We searched MEDLINE, Embase, and bibliographies of reviews and book chapters to identify articles published in English since 1960. Twenty-five articles, describing postoperative seizure outcome and type of surgery in 177 TSC patients, were included in this study. Seizure outcome was analyzed both as seizure freedom and good outcome, including patients with >90% seizure reduction. RESULTS: Seizure freedom was achieved in 101 patients (57%). Seizure frequency was improved by > 90% in 32 patients (18%). Moderate or severe intellectual disability (IQ < 70) (RR 1.8; 95% CI 1.2-2.8) and the presence of tonic seizures (RR 1.7; 95 % CI 1.2-2.4) were related to seizure recurrence. CONCLUSIONS: A relation between multiple seizures types with early onset, multiple cortical tubers and multifocal epileptogenicity, and poor outcome is not supported by this systematic analysis. Although there is considerable variation among studies reviewed here, the literature suggests that resective surgery may offer benefit in a selected population of TSC patients with drug-resistant epilepsy.     

Self-injurious behavior and fragile X syndrome: findings from the national fragile X survey

We used National Fragile X Survey data in order to examine reported self-injurious behavior (SIB) to (a) generate lifetime and point prevalence estimates, (b) document detailed features of SIB (frequency, types, location, severity) in relation to gender, and (c) compare comorbid conditions between matched pairs (SIB vs. no SIB). Results indicate significant gender differences in frequency, topography, and location of SIB as well as sleep difficulties, comorbid conditions, pain sensitivity, and seizures. Matched pair comparisons (SIB vs. no SIB) revealed differences for males in sensory and attention problems, hyperactivity, aggression, autism, and anxiety and for females, in autism, attention, and anxiety. These results further clarify gender differences as well as comorbidity patterns between children with fragile X syndrome with and without SIB.     

Naltrexone decreases self-injurious behavior

The effect of naltrexone (0.5, 1.0, 1.5, and 2.0 mg/kg) on the frequency of self-injurious behavior (SIB) was investigated in three male adolescents. The frequency of total SIB was reduced significantly in all three subjects; dose-dependent decreases (at 0.5, 1.0, and 1.5 mg/kg) in SIB frequency were observed in the two mentally retarded subjects. These data suggest a role for opioid peptides in SIB.