Abstract
Objectives:
Such neuropsychiatric symptoms as autism spectrum disorders, attention-deficit/hyperactivity disorder (ADHD), intellectual disability, aggression, and epilepsy are very common in patients with tuberous sclerosis complex (TSC). Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is a recent and effective treatment for TSC patients with giant cell astrocytomas and renal angiomyolipoma, and it has been shown to have a potential to reduce tumor volume. However, there is a paucity of studies on the effects of everolimus on neuropsychiatric symptoms. The aim of the present study is to describe the effects of everolimus on emotional and behavioral symptoms and refractory epilepsy in a group of patients with TSC.
Methods:
Four boys and two girls (median age 16.5; range 7.5–23 years) were included in the study. Information on the clinical and treatment characteristics of the patients was gathered from the medical records.
Results:
Median everolimus dose was 10 mg/day (range 5–20 mg) and median time for follow-up was 17.5 (range 7–26) months. The drug was well tolerated with mild adverse effects, including stomatitis (three cases), increase in triglycerides and cholesterol (two cases), and constipation (one case). The adverse effects encountered during the course of treatment did not make it necessary to discontinue the drug or decrease its dose. All cases experienced very good to moderate response for controlling epileptic seizures. Besides, improvements in social contact, language, repetitive behavior, inattention, hyperactivity, and depression were observed in some patients.
Conclusions:
Everolimus was well tolerated without severe adverse effects. It was helpful in controlling seizures and additional improvements were noted in autistic, ADHD, and depressive symptoms.
Introduction
T
TSC is caused by the mutation of the TSC1 (encoding for TSC1, or hamartin) or TSC2 (encoding for TSC2, or tuberin) genes. Hamartin and tuberin bind together to form a biochemical complex that inhibits the mammalian target of rapamycin (mTOR) that controls translation, proliferation, and cell growth (Curatolo et al. 2010). This explains why patients with TSC have a predisposition to nonmalignant tumor formation in multiple organs. mTOR inhibitors (sirolimus and everolimus) act by specifically inhibiting the mTOR pathway by reducing the phosphorylation of downstream mTOR effectors. Everolimus is a recent and effective treatment for TSC patients with giant cell astrocytomas and renal angiomyolipoma and it has been shown to have a potential to reduce tumor volume (Bissler et al. 2013; Franz et al. 2013). Given that mTOR pathway is also involved in regulating such functions as protein synthesis and synaptic plasticity, researchers hypothesize that mTOR inhibitors may also be used to treat epilepsy and other neuropsychiatric manifestations of TSC (Wong 2013). Positive outcomes in the reversal of learning and social deficits have been observed in TSC mouse models with sirolimus (Ehninger et al. 2008; Sato et al. 2012; Tsai et al. 2012). Beneficial effects of everolimus have been reported in patients with TSC and refractory seizures (Krueger et al. 2013; Wiegand et al. 2013; Wheless 2015; French et al. 2016). It has been found out that everolimus also helped improve adaptive social behaviors, conduct problems, and insecurity/anxiety (Krueger et al. 2013). Davies et al. (2011) have observed increased immediate recall memory and executive function scores with sirolimus therapy in some patients with TSC.
In this article, we report the effects of everolimus therapy in a group of patients with TSC, refractory epilepsy, and emotional and behavioral disorders.
Methods
This study was carried out on six patients with TSC (four males and two females) in the Child Neurology and Child and Adolescent Psychiatry Departments, Istanbul Faculty of Medicine, Istanbul University between the years of 2014 and 2016. The patients, whose clinical and treatment characteristics were gathered from the medical records kept by the aforesaid departments, were treated on everolimus for different periods of time (at least 3 months).
All the patients underwent dermatological, cardiological, neurological, ophthalmological, and psychiatric examinations. The diagnoses were made by child neurology and psychiatry specialists. TSC was diagnosed according to revised clinical diagnostic criteria (Roach et al. 1998). The medical records of the patients were reviewed for seizure characteristics (e.g., type, age of onset, and response to the medication). Epilepsy was defined medically refractory when the patient reported at least eight seizures in 30 days despite adequate use of at least two approved antiepileptic drugs before everolimus (Krueger et al. 2013). Psychiatric diagnoses were made according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association 1994). Autistic symptoms were assessed with clinician-rated Childhood Autism Rating Scale (CARS; Schopler et al. 1980; Sucuoglu et al. 1996) and parent-rated Autism Behavior Checklist (AuBC; Krug et al. 1980; Irmak et al. 2007). Besides, parents reported about the behavioral problems and rated the Aberrant Behavioral Checklist (ABC; Aman et al. 1985; Sucuoglu 2003). Certified psychologists, experienced in cases with developmental disorders, determined the mental levels of the patients by making use of standardized intelligence tests (Wechsler 1974; Thorndike et al. 1986) and clinical examinations.
The medical records of the patients were reviewed for psychiatric diagnoses, clinical changes, and treatment-emergent adverse events. Routine laboratory investigations, such as blood counts, alanine and aspartate aminotransferase, glucose, cholesterol profile, as well as triglycerides, were performed at baseline and repeated every 2 months. Following completion of the above tasks, a single morning dose of 5 mg/m2 oral everolimus was started. A trough serum everolimus concentration was obtained at week 8, and the dose was adjusted to maintain concentrations between 5 and 15 ng/mL. All the cases used concomitant antiepileptic drugs; however, the agents or the doses were not changed during everolimus treatment. Patients demonstrating a ≥90% reduction in seizure frequency were considered as very good responders. A reduction between 60% and 90% was accepted as a good response, between 30% and 60% as a moderate response, and 30 or lower as a mild response.
Results
Median age of the patients was 16.5 (range 7.5–23) years. Median everolimus dose was 10 mg/day (range 5–20 mg). Median duration of follow-up was 17.5 (range 7–26) months.
Seizure disorder was the initial feature of TSC before 1 year of age in four children. All of the patients presented with more than two seizure types and had epilepsy refractory to treatment. Seizure characteristics before and after everolimus treatment are reported in Table 1.
GTCS, generalized tonic clonic seizure; IS, infantile spasm.
Four of the patients were diagnosed with ASD and three with ADHD. Except one, the degree of the ID of all the other patients ranged from moderate to severe. Three of them (Case 1, 2, and 3) received individual special education of 2 hours a week on behavioral intervention or modification; two (Case 4 and 6) went to schools for children with disabilities and received special education for 2 hours a week, and one (Case 5) graduated from mainstream secondary school and had a paid job. Psychiatric diagnoses and treatment characteristics of the cases are given in Table 2.
ABC, Aberrant Behavioral Checklist; ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorders; AuBC, Autism Behavior Checklist; CARS, Childhood Autism Rating Scale; ID, intellectual disability.
Case 1
Case 1 was a 7.5-year-old-male who had his first epileptic seizures at 7 months and was diagnosed with TSC at the age of 3. He had no verbal communication or eye contact. He did not share his interest by pointing or gesturing nor did he have any peer relations. He had repetitive behaviors, such as clapping hands, flapping arms, running aimlessly in the same path, and tearing paper. He mouthed objects and compulsively tidied the objects around. He had severe ID. His major behavioral problems were aggressiveness, severe temper tantrums, self-mutilation, hyperactivity, and autistic symptoms. He received everolimus for 14 months. Despite a good improvement in seizure control, no differences in aggressive, hyperactive, and autistic symptoms were noted.
Case 2
Case 2 was an 18-year-old female who had infantile spasms when she was 4 months old, and she was diagnosed with TSC when she was 6 months old. She infrequently attended to social cues and had severe problems with peer interaction. She did not have eye contact, nor did she engage in symbolic play. She communicated with two-word sentences and performed pronoun reversal. She repeated words or phrases over and over again and echoed others' statements. She had self-stimulatory behavior such as hand flapping. Her self-help skills were limited. Her parents reported that her main problems were frequent epileptic seizures, disregard of other people, and noncompliance with rules and inattentiveness. She was on everolimus for 12 months. The parents described a very good improvement in epileptic seizures, as well as increase in social interactions and reciprocal communication.
Case 3
Case 3 was a 16.5-year-old male. His generalized tonic seizures started at 13 months. His first words came at 3.5 years and two-word sentences at 5.5 years. Although he could produce three to four word sentences, he usually communicated with single words. He lacked social smile and his eye contact was inappropriate (looked through people). He had limited and inappropriate social contact with others. He had no friends and his imitation was poor. His stereotypic behaviors included whirling around, rocking himself, lining things, and hand flapping. He smelled objects and covered his ears with his hands. He gave strong reactions to minor changes. In addition, he had problems with hyperactivity, inattention, and aggression toward self and objects. He received everolimus for 19 months. His mother described a moderate improvement in frequency and duration of the epileptic seizures. Additional improvements, which became prominent by the 2nd–3rd months of treatment, were noted in carrying out instructions, speech, attention, and concentration. His ABC score at baseline and 12 months were 138 and 122, respectively. The decrease in the ABC score was primarily related to that in the social withdrawal/lethargy score (from 54 to 39). The mother reported an increase in temper tantrums and aggressive behavior with everolimus, which responded to clozapine 400 mg/day in the last 6 months.
Case 4
Case 4 was a 14-year-old male. His first seizures started at 4.5 months. His first words came at 3 years and two-word sentences at 7 years. At the time of assessment, he used one or two-word phrases, had echolalia and perseverations. He had limited eye contact and restricted peer relations; besides, he showed inappropriate effect. He had hypersensitivity to noise and suffered from highly selective eating. He had many stereotypical behaviors, including hand clapping, flapping, jumping, walking on his toes, opening and closing doors, and watching the same cartoons and movies more than 30 times. He was diagnosed with ASD and moderate ID. He was on everolimus treatment for 7 months and had moderate improvement with epileptic seizures. Besides, his mother reported that the medication had beneficial effects on speech (i.e., decrease in echolalia, more proper use of grammar, and verbal responsiveness), attention, learning, taking instructions, and hyperactive and aggressive behavior and that it helped to decrease stereotypies. He started reading after the treatment. His total ABC score at baseline and after 1 year were 63 and 37, respectively. Improvements in hyperactive, social withdrawal/lethargy, repetitive behavior, and self-mutilation subscales were noted.
Case 5
Case 5 was a 23-year-old male. He graduated from secondary school after 8 years of formal education and was working in a company at the time of treatment. He had epileptic seizures since he was 7. Despite his delay in talking (phrasal speech started at 3 years), he did not have any prominent autistic features. He had an average IQ. He had emotional and behavioral problems, such as depressed mood, shyness, and aggressive outbursts. His Beck Depression Inventory score was 18, pointing to mild depression. He was described as having problems with concentrating, remembering things, and multitasking. His self-esteem and stress level of the family were within normal limits. He had very frequent seizures that interfered with his working outside, and the last one ended in status epilepticus that resolved in 60 minutes. He remained seizure free for 2 years with everolimus. He reported that he himself felt much better. He did not ruminate on his illness, could stay focused on the task at hand, and make plans for the future. He described himself as being calmer and relaxed. That was an account which was agreed upon by the other members of the family. His Beck score dropped to 9 points.
Case 6
Case 6 was a 16-year-old female whose first epileptic seizures were noticed at 3 months. She sat without support at 1.5 years and walked at 3 years. Her single words came at 3, and she spoke with short phrases at 5 years. She used simple language and had problems with some of the self-care skills. Although she was reported to have problems with eye contact in the first 5 years, no such problem was detected during examinations. She responded to smile, answered questions, took instructions, and shared her interest and enjoyment with others. She wanted to interact with peers, but could only get on with younger ones. She neither had echolalia nor prominent stereotypical behavior or restricted interest. Her scores were 28 and 42 in CARS and AuBC, respectively. She was observed to have fewer seizures and positive effects on language, attention, and hyperactivity with everolimus. Of note, her ABC score, which was 52 points before she was started on everolimus, dropped to 32 at the 3rd month of the treatment and finally to 18 at the 12th month. The decrease in hyperactivity, social withdrawal, and repetitive behavior was remarkable. There was a significant decline also in inattention and hyperactive/impulsive symptoms with DSM-IV based ADHD rating scale at 3 and 12 months.
Discussion
Neurocognitive features of TSC, which show a wide variability, have generally been attributed to damage resulted from tubers and/or seizures. This model is supported by some studies showing correlations between IQ, tuber number, seizure type, seizure control, and age of seizure onset (e.g., O'Callaghan et al. 2004). However, de Vries and Howe (2007) suggested that neurocognitive manifestations of TSC result directly from cell signaling abnormalities associated with TSC1 and TSC2 and added that mTOR inhibitors might therefore improve or reverse some of these deficits. The beneficial effects of mTOR inhibitor everolimus on some of the physical manifestations of TSC have been well researched and already approved; however, the effects of everolimus on behavior have not been systematically studied (Gipson et al. 2013). From this point of view, this case series may be considered as one of the first attempts to describe the effects of everolimus on such behavior problems as hyperactivity, aggressiveness, and attention deficit, as well as some symptoms associated with ASD.
Four of the cases were diagnosed with ASD and displayed severe autistic behavior. Following everolimus treatment, the parents of three of them described a marked increase in social interactions, in speech and verbal response (Case 2, 3, and 4). Decrease in stereotypical behavior was also noted in Case 4. Case 6 did not meet formal criteria for ASD; nevertheless, improvements in speech, social withdrawal, and repetitive behavior were observed. In a preclinical study, Sato et al. (2012) found that impaired social behavior was reversed in TSC mutant mice as a result of mTOR inhibitor treatment. There is a recent report on a patient with autism associated with tuberous sclerosis who, following everolimus treatment, achieved remarkable improvements in social withdrawal/lethargy, inappropriate speech, stereotypic behavior, and irritability (Ishii et al. 2015). In an open label study, parents have reported improvement in adaptive social behaviors with everolimus (Krueger et al. 2013). Following everolimus treatment, autistic symptoms of some of our cases decreased considerably, a finding which is in accordance with the literature and provides confirmation that everolimus may be a promising drug for the treatment of patients with TSC and ASD.
Improvement in inattention and concentration was observed in half of our cases (Case 3, 4, and 6). This finding of ours supports those of other authors who have carried out animal and human studies and achieved improvements in cognitive deficits with mTOR inhibitors (Ehninger et al. 2008; Davies et al. 2011). Half of our cases displayed aggressive behavior, temper tantrums, and rare self-mutilative behavior before treatment. Medical examinations did not reveal any acid reflux, constipation, allergies, eczema, tonsillitis, menstrual cramps, ear infections, dental caries, urinary tract infections, or injuries in these children. Differing effects of everolimus on aggression and irritability were noted in Cases 3 and 4. These problems increased in Case 3, but decreased in Case 4. There are some studies in which decreased irritability and conduct problems have been reported (Krueger et al. 2013; Ishii et al. 2015); however, prospective studies are needed to clarify in what ways and to what degree everolimus affects aggressive and irritable behavior.
Everolimus helped all of the patients to control their epileptic seizures, and the response generally appeared after 2–5 weeks. In an open study, Krueger et al. (2013) reported that seizure frequency was reduced by 50% in 12 of 20 TSC patients with refractory epilepsy. Median seizure reduction rate in 17 of these patients was 73%. Wiegand et al. (2013) observed seizure reduction in four of six patients with intractable epilepsy and TSC. In our study, reduction in seizure frequency was not less than 50% in any of the cases, and the median rate was 77.5%. The relationship between improvement in seizure control and psychiatric symptoms is unclear. Our patients' rate of improvement in epileptic seizures ranged from very good to moderately good. Some of them also showed behavioral improvement, but this does not authorize us to make a generalization. This is why future studies are needed to investigate whether decrease in autistic and ADHD symptoms is caused by simultaneous improvement in seizure control, or it is related to some independent effects of the treatment.
In our study, none of the families reported severe side effects with everolimus. Three cases had stomatitis composed of one to three simultaneous aphthous ulcers, which regressed in a few weeks. Increased levels of triglyceride and cholesterol in two cases were returned to normal by diet modifications. Apart from the above, one patient suffered from constipation. The adverse effects encountered during the course of treatment did not make it necessary to discontinue the drug or decrease its dose. Increase in temper tantrums and aggressive behavior was described in Case 3. He had previously used several antipsychotics in high doses for similar behavior problems and scored high for hyperactivity and self-mutilation in ABC, even before starting everolimus. The mother stated clearly that aggressive behavior in her son increased after administration of the drug; however, she did not discontinue with it as it had prominent positive effects on epileptic seizures, speech, attention, and concentration. Occurring six to seven times per day and affecting the lives of the family members negatively, severe temper tantrums improved substantially with clozapine treatment. The finding that everolimus was well tolerated with limited treatment-emergent side effects is in accordance with the literature (Krueger et al. 2013; Wiegand et al. 2013).
The present report has several limitations: ASD diagnosis could not be determined by “gold standard” measures (i.e., Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule), because these instruments are not validated for the Turkish population. Instead, we used CARS and the DSM-IV criteria. The effects of medication on the neuropsychiatric symptoms were not measured with objective tools, but were mostly based on parental reports. The other important limitations of this study were as follows: use of retrospective, uncontrolled, and unblinded data and a small sample size. Double-blind and placebo-controlled studies are required to support the present findings.
Conclusions
In this study, we described the effects of everolimus on six cases with TSC and epilepsy, as well as emotional and behavioral disorders. Everolimus was well tolerated without severe adverse effects and helped to decrease the severity and frequency of seizures. Besides, improvements in autistic symptoms (e.g., social contact, language, and repetitive behavior), inattention, concentration, depression, and aggressive behavior were observed in some patients. These effects may be related to mTOR inhibitors in that they might be targeting the underlying pathophysiology of TSC, or some secondary gains like controlling the seizures. Further clinical trials with larger samples are warranted to confirm and better characterize our findings.
Clinical Significance
Everolimus was well tolerated without severe adverse effects. It was beneficial for the control of seizures in patients with TSC. Some of the patients also showed improvements in autistic symptoms (e.g., social contact, language, and repetitive behavior), inattention, hyperactivity, and depression.
Footnotes
Acknowledgment
The authors thank Cüneyt Bademcioğlu who kindly assisted in the proofreading and language editing of the article.
Disclosures
Z.Y. is an unpaid researcher who took part in the Phase 3 trial of everolimus in the treatment of refractory seizures associated with TSC. All other authors have no competing financial interests.