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Stressor-related disorders in tuberous sclerosis

Susana Boronat, MD

Department of Neurology, Massachusetts General Hospital, Boston, MA, USA, Department of Pediatric Neurology, Vall d’Hebron Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain

Agnies M. Van Eeghen, MD

Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

Julianna E. Shinnick

Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

Peter Newberry, MD

Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

Elizabeth A. Thiele, MD, PhD

Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

BACKGROUND: Patients with tuberous sclerosis complex (TSC) have high rates of psychiatric comorbidity, including mood and anxiety disorders. The aim of this study is to identify patients with stressor-related disorders such as posttraumatic stress disorder (PTSD) or adjustment disorder (AD) and to describe their clinical picture in the setting of TSC.

METHODS: Retrospective review of medical charts of TSC patients referred for a stressor-related disorder to a TSC psychiatric clinic.

RESULTS: We identified 7 females and 2 males (3 PTSD, 6 AD), including 4 children. Two patients with severe intellectual disability presented with aggression and the remaining patients presented with avoidance. The mean duration of symptoms at the time of the study was 21 months (range: 7 to 48 months) and 7 of the 9 patients still were having trauma-related symptoms. All the patients who received an initial diagnosis of AD had their diagnosis changed to another category because their symptoms lasted >6 months. In most cases, selective serotonin reuptake inhibitors improved the symptoms.

CONCLUSIONS: Stressor-related disorders in TSC frequently linger beyond 6 months and may appear with triggering events that typically are not viewed as trauma in a normal population.

KEYWORDS: adjustment disorder, anxiety, seizures, posttraumatic stress disorder, trauma, tuberous sclerosis



Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations in TSC1 or TSC2. It is characterized by benign tumors affecting multiple organ systems. Most of the patients have brain involvement, with variable presentations of epilepsy, cognitive deficits, autistic features, depression, and anxiety.1-3

Posttraumatic stress disorder (PTSD) is a psychiatric disorder characterized by abnormal fear extinction in response to a traumatic event involving actual or threatened death or serious injury of self or others. It lasts >1 month and is characterized by several symptoms, including re-experiencing, avoidance, negative alterations in cognition and mood, and hyperarousal.4 DSM-IV-TR, classifies PTSD under the chapter of trauma and stressor-related disorders. It is positioned next to other categories such as acute stress disorder—when similar symptomatology lasts for <4 weeks—and adjustment disorder (AD), which provides a residual diagnosis for individuals who have exhibited marked distress and functional impairment following exposure to stressful, but not traumatic, events. Stressor-related disorders in TSC are understudied and may be underestimated. The aim of this study is to describe the clinical characteristics of these disorders in the TSC population.


We identified all TSC patients referred to the TSC psychiatric clinic of the Massachusetts General Hospital between January 2009 and December 2012 with the clinical suspicion of stressor related-disorder. Patients diagnosed with PTSD, acute stress disorder, and AD, according to the DSM-IV-TR criteria4 were reviewed. All patients were evaluated by the same psychiatrist (P.N.). Patients with a preexisting diagnosis of PTSD that were seen in the psychiatric clinic during this period were excluded because the aim of the study was to obtain detailed information on the triggering event, the acute clinical picture, and evolution. We collected the following information: age at the time of the event, sex, result of genetic analysis, psychiatric history and treatment, comorbid epilepsy and medication, cognitive phenotype, triggering event, presentation, evolution and duration of the symptoms, and response to treatment.


Seven females and 2 males (mean age 22, range: 8 to 49) were identified. Three patients were adolescents (age 13 to 15) and 1 patient was age 8. (See TABLE 1 for clinical characteristics.) Three of these patients were diagnosed with PTSD, and 6 with AD. (See TABLE 2 for symptoms according to DSM-IV-TR criteria.) In all of the patients initially diagnosed with AD, this diagnosis was revised to other categories, mainly generalized anxiety disorder (GAD), because symptoms persisted >6 months. In the 2 patients with severe intellectual disability, the main presenting symptoms were irritability and aggression, while avoidance was the main symptom in patients with normal cognitive function. The triggering event or stressor was recalled easily in all the cases but it was not intense enough to be considered traumatic in 6 of the cases, because it did not involve actual or threatened death or serious injury of self or others.4 In the PTSD group, the stressor was physical aggression in 2 cases and a seizure in the other. As the duration of symptoms was >6 months in all the patients initially diagnosed as AD, their diagnosis was changed to GAD or specific phobia. The mean duration of the symptoms was 21 months (range: 7 to 48 months) but 7 of the 9 patients still were having symptoms related to the trauma at the time the study ended. Citalopram or other selective serotonin reuptake inhibitors (SSRIs) ameliorated the symptoms in most cases. All the patients also received non-pharmacological supportive therapy, which consisted of elements of cognitive-behavioral therapy (CBT) and caregivers guidance and education. Two patients received formal CBT, which ameliorated the symptoms in both cases.


Characteristics of TSC patients affected by stressor-related disorders

Patient (sex) Age at event (years) TSC mutation Psychiatric history History of epilepsya (treatment) Cognitive status Triggering event Presenting main symptoms Durationb Treatmentc and response
1 (Female) 15 TSC2 No Refractory (oxcarbazepine, gabapentin, levetiracetam) Normal IQ Seizure with conserved consciousness and sensation of imminent death in a boat (intense acute response) Avoidance of boat, panic attack when exposed 10 months Citalopram (15 mg); good response; supportive therapy
2 (Female) 8 TSC1 No No Normal IQ and behavior Streptococcus upper respiratory infection at the beginning of school year, paternal unemployment Avoidance of school; somatic complaints (throat and abdominal pain), generalized anxiety 1 year (resolved) Citalopram (15 mg) and CBT; good response
3 (Female) 13 TSC2 GAD, specific phobia Refractory (levetiracetam, oxcarbazepine) Borderline IQ (77) Emotional lability Impression that coach made sexual gesture and remark Avoidance of men (generalized to all men, even father) 2 years (resolved) Citalopram (15 mg); good response; supportive therapy
4 (Female) 14 TSC2 No In remission without treatment Normal IQ and behavior Viral illness, starting high school, lower performance in initial exams Avoidance of school; generalized anxiety 7 months Sertraline (100 mg), and starting on-line school; good response; supportive therapy
5 (Female) 25 TSC2 MDD at age 17, GAD No Normal IQ and behavior Dysfunctional family life (recurrent triggering events, every time they meet) Depressed mood; worsening of generalized anxiety; hyperarousal 9 months Sertraline (100 mg); good response; supportive therapy
6 (Female) 49 ND MDD (since husband’s death when she was age 45), GAD In remission without treatment Normal IQ and behavior Sexual assault while waiting in the emergency room Re-experience: fear when exposed to man resembling the assailant or hospital settings; depressed mood, hyperarousal, avoidance 4 years Quetiapine improved sleep initially; limited response to citalopram, mirtazapine, aripiprazole, and clonazepam; CBT
7 (Male) 32 ND ASD features, depressed mood previous year In remission without treatment Borderline Incident at work: impression that a law enforcement officer had been staring at him in an accusatory way Paranoia about others at work giving him accusatory glances and about getting arrested, avoidance of work place 2 years Citalopram (30 mg); good response; supportive therapy
8 (Female) 22 ND Severe ID, ASD In remission with treatment (carbamazepine, valproic acid) Severe intellectual disability Violent assault (hit with a belt by other student in school’s bathroom) PTSD, irritability, aggression, vomiting 3 years and 7 months (better after 22 months) No response to risperidone; improvement after school change and getting a pet; supportive therapy
9 (Male) 20 TSC2 Severe ID, ASD Refractory (levetiracetam, topirimate, lamotrigine) Severe ID Hospitalization for resection of a pancreatic neuroendocrine tumor Irritability, aggression, destructive behavior 15 months No response to aripiprazole, duloxetine, asenapine, and guanfacine; mirtazapine helped with sleep and appetite; good response to olanzapine (7.5 mg); supportive therapy
aAs defined by the International League Against Epilepsy,32 epilepsy was:
- refractory: after failure of adequate trials of 2 tolerated, appropriately chosen and used AEDs.
- in remission without treatment: no seizures for ≥5 years and not receiving AEDs at the time of ascertainment
- in remission with treatment: no seizures for ≥5 years and receiving AEDs at the time of ascertainment
bIf symptoms related to the triggering event have disappeared completely is indicated as resolved. In the rest of cases all or some symptoms persist.
cDosage used for maximum effect with minimal secondary effects.

ASD: autism spectrum disorder; AEDs: antiepileptic drugs; CBT: cognitive-behavioral therapy; GAD: generalized anxiety disorder; ID: intellectual disability; IQ: intellectual quotient; MDD: major depressive disorder; ND: not determined; PTSD: posttraumatic stress disorder.


DSM-IV-TR diagnostic criteria for PTSD or AD in identified patients

Patient Traumatic eventa Symptoms Duration >1 month Significant impairment in functioning Diagnosis
Re-experienceb Avoidancec Cognition and mood changesd Increased arousale
1 Yes Yes Yes Yes Yes Yes Yes PTSD
2 No No Yes Yes No Yes Yes Initial AD, diagnostic change to GAD
3 No No Yes Yes No Yes Yes Initial AD, diagnostic change to specific phobia
4 No No Yes Yes No Yes Yes Initial AD, diagnostic change to GAD
5 No No Yes Yes Yes Yes Yes Initial AD, diagnostic change to GAD
6 Yes Yes Yes Yes Yes Yes Yes PTSD
7 No No Yes Yes Yes Yes Yes Initial AD, diagnostic change to GAD
8 Yes Impossible recall Yes Yes Yes Yes Yes PTSD
9 No Impossible recall Yes Yes Yes Yes Yes Initial AD, diagnostic change to anxiety disorder NOS
Predominant symptoms in each patient are in bold type.
DSM-IV-TR PTSD clinical criteria:4

aTraumatic event: involving actual or threatened death or serious injury of self or others and the person’s response involved intense fear, helplessness or horror. Otherwise, considered stressful but not traumatic.
bRe-experiencing: in the form of intrusion symptoms such as spontaneous or cued distressing memories, flashbacks, or nightmares about the trauma.
cAvoidance of the reminders of the experience.
dNegative alterations in cognitions and mood, such as dissociative amnesia, pervasive negative emotional state, diminished interest in significant activities, or socially withdrawn behavior.
eHyperarousal: feeling easily startled, tense, having angry outbursts, or having difficulty sleeping or with concentration.

AD: adjustment disorder; GAD: generalized anxiety disorder; NOS: not otherwise specified; PTSD: posttraumatic stress disorder.


Our study describes the main clinical characteristics of PTSD and other stressor-related disorders in a TSC cohort. Although anxiety disorders are frequent in TSC patients,2,3 the frequency or clinical features of stressor-related disorders previously have not been reported, suggesting that stressor-related disorders may be underdiagnosed in patients with TSC.

The pathophysiology of PTSD is related to dysfunction of the neural circuitry of the fear response, in which learned fear due to a traumatic event becomes generalized to safe situations.5,6 Trauma is necessary but not sufficient to trigger PTSD. Some trauma victims develop PTSD (5% to 30%)7,8 while others seem resilient when experiencing the same trauma. A variety of factors may contribute to this, including genetic background, abnormal fear brain-circuitry, and stressful early life experiences.9

Anxiety disorders have a prevalence rate of 28% to 56% of TSC patients.2,3 Factors contributing to anxiety and stressor-related disorders in TSC patients may include a dysfunctional circuitry of fear response, due to anatomical disruption of neuronal tracts or to functional synaptic disturbance of the main implicated areas (such as amygdala, hippocampus and prefrontal cortex).6,10 The psychological burden of having a chronic and severe disease itself also may be a contributing factor. Our patients were predominantly women (7:2). In the general population, women experience anxiety disorders more frequently than men.11 In a study of psychiatric comorbidity among 43 TSC patients, ADs were diagnosed in 21% of the cases.2 Most of the large epidemiological surveys of mental health in the general population lack prevalence data for ADs, in part because there is no clinical interview used in large epidemiological surveys sufficiently robust in diagnosing these disorders.12

DSM-IV-TR PTSD clinical criteria usually are applied to normal adults experiencing a traumatic event. In other cases, such as children or cognitively impaired people, diagnosing this disorder is challenging. In children, PTSD may be expressed by disorganized or agitated behavior, which is also predominant in individuals with intellectual disability (ID). DSM-513 contains specific PTSD criteria for children age <6, because they may present with disorganized or agitated behavior and express intrusive memories as repetitive play. Nonetheless, a similar initiative has not been undertaken in DSM-5 for individuals with ID. Severe intellectual disability was present in 2 of our patients (patients 8 and 9) and their symptoms consisted primarily of irritability and aggression. Patient 8 suffered a clear traumatic event but, because of her intellectual disability, obtaining clinical details such as symptoms of re-experiencing needed for a PTSD diagnosis was not possible, so we made the diagnosis based on what we could infer from her behavior.

Individuals with ID are more likely to experience traumatic events and early life stressors such as hospital admissions, to have more invasive health procedures, and to experience high levels of parental stress. They also may have a different interpretation of distressing experiences such as being exposed to multiple caregivers and changes of house or school. Practitioners often attribute behavioral disturbances to ID itself, a phenomenon known as “diagnostic overshadowing,”14 which may preclude the detection of stressor-related disturbances.

The Diagnostic Manual-Intellectual Disability,15 developed in association with the American Psychiatric Association, provides some help in identifying the psychiatric symptoms that often are expressed differently in persons with ID. In the case of stressor-related disorders, they present mainly with affective disorders and aggressive or destructive behaviors.14 The predominant symptom in our cases with normal or borderline cognitive function was avoidance, and in the cases with intellectual disability, it was irritability and aggressiveness. This agrees with previous studies suggesting that the severity of PTSD is associated negatively with the level of intelligence.16 Interestingly, patients 2 and 8 presented somatic symptoms that could not be attributed to other processes; in patient 2, it was throat and abdominal pain, in patient 8, vomiting. It is important to recognize this as a possible part of the clinical picture to avoid added unnecessary work-up of physical symptoms.

The intensity of the immediate response (ie, extreme withdrawal, panic-like response) to the traumatic event is associated with an increased risk of developing PTSD.17 Patient 1 experienced a very intense initial response to the traumatic event, which consisted of a seizure with preserved consciousness that made her feel completely helpless. Data about seizures as the potential trigger of PTSD in epilepsy are scarce but a recent study suggests that PTSD may be frequent in this setting, with 51% of patients meeting the diagnostic criteria for full PTSD and 30% for partial PTSD.18 These results suggest that in patients with epilepsy, it is important to consider seizures as a potential triggering event of PTSD, mainly if it causes an intense panic response in the patient.

The observation that all our patients with an initial diagnosis of AD experienced persistent symptoms beyond 6 months raises some doubts about the clinical utility of this diagnostic category in the TSC population. In fact, the clinical value of the current DSM-IV-TR diagnosis of AD also is controversial in the general population because it is not characterized by sufficiently specific clinical, psychometric, or prognostic features, and mainly overlaps other mood and anxiety disorders.19 Also, the DSM-IV-TR classifies ADs into subtypes according to the predominant symptoms: depressed mood, anxiety, disturbance of conduct or unspecified. A new subtype with PTSD-like symptoms has been included in DSM-5.13 Our experience agrees with some authors who propose AD as a stress-response syndrome similar to PTSD, sharing a common pathophysiology.20

SSRIs are first-line pharmacologic interventions for PTSD and their use is supported by several randomized controlled trials.21 In our cases, citalopram and sertraline were useful in ameliorating some of the symptoms, but only 2 of the patients had a complete remission, both were treated with citalopram. Mirtazapine is a noradrenergic and serotonergic antidepressant that may be useful as a second-line treatment.22 We prescribed mirtazapine to 2 of our patients and 1 of them showed amelioration of sleep and appetite disturbances. Antiadrenergic medications, such as prazosin or guanfacine, are used occasionally for lowering the sympathetic tone and the associated hyperarousal, impulsivity, and intrusive symptoms, such as nightmares.23,24 We prescribed guanfacine for 1 patient but it was not effective. The antipsychotic quetiapine was useful in controlling nightmares in 1 of our patients but other prominent PTSD symptoms persisted. A meta-analysis of studies in adults25 suggests that antipsychotics may be particularly effective in reducing intrusive symptoms. Mood stabilizers such as lamotrigine, valproic acid, topiramate, carbamazepine, and levetiracetam also can be useful and overall, most studies have demonstrated modest improvement.24

Trauma-focused cognitive-behavioral therapy (CBT) and trauma-focused cognitive therapy (without exposure) are first-line treatments and have been used successfully to treat PTSD in the general population26 and also seem useful in patients with ID.14 Two of our patients received CBT, which was very useful in 1 case and partially effective in the other.

Interestingly, benzodiazepines, which are often used to treat anxiety, are not useful to prevent or treat PTSD,24 and may even harm these patients. Some studies27 suggest that early administration of benzodiazepines, which may enhance access to emotional memories, might interfere with normal spontaneous recovery. Also, benzodiazepines abolish the expected activation of the hypothalamic-pituitary-adrenal axis in stress.28 This consideration also is important for TSC patients with epilepsy because some of them use benzodiazepines as antiepileptic drugs. Only one of our patients was receiving benzodiazepines at the time of the event.

Recent PTSD research that focuses on the preventive role of glucocorticoids,29 estrogens,30 and omega-3 fatty acids,31 administered in the first hours after the traumatic event suggests these agents can prevent appearance of symptoms.

Our study presents some limitations inherent to its retrospective nature, such as lack of details about acute behavioral response at the trauma event, presence or not of specific symptoms related to PTSD, and detailed response to treatments. Nonetheless, it is the first study to date depicting the specific clinical characteristics of stressor-related disorders in TSC patients. More reports are needed to better understand these disorders in TSC and allow an earlier diagnosis and treatment.


TSC patients may have underlying vulnerability to anxiety and stressor-related disorders, even in the setting of a triggering event considered not traumatic for most of the general population. In TSC patients, these disorders usually have a chronic course (>6 months) and are quite resistant to standard treatments. Raising awareness about stressor-related disorders in TSC patients will allow an earlier diagnosis and treatment. Additional studies are needed regarding treatment of these disorders in TSC population and the possible role of prophylactic medications.

DISCLOSURES: The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

ACKNOWLEDGEMENTS: The authors thank all the patients with TSC and their family members for participating in this study and to Herscot Center for Tuberous Sclerosis Complex, NIH/NINDS P01 NS024279 and Carlos III Institute in Spain for funding this study.


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CORRESPONDENCE: Elizabeth A. Thiele, MD, PhD Pediatric Epilepsy Program Massachusetts General Hospital 175 Cambridge Street, Suite 340 Boston, MA 02114 USA E-MAIL: