Abstract
People with traumatic brain injury (TBI) can develop a variety of behavioural changes and psychiatric problems as a consequence of the TBI but the relationship with post-traumatic stress disorder (PTSD) has received increasing attention only recently.
The aim of this chapter is to discuss current literature on the relationship between PTSD and epilepsy in terms of neurobiology and clinical correlates and the potential relationship with TBI. As shown for other psychiatric disorders, people with PTSD seem to have a 3 to 6 times increased risk of developing epilepsy and this can be explained by a number of shared neurobiological mechanisms in addition to the role of brain damage when PTSD is associated with TBI. However, psychogenic-non-epileptic seizures (PNES) seem to be even more closely associated with PTSD, carrying sometimes substantial challenges in terms of differential diagnosis.
Data on treatment of PTSD are also reviewed, discussing specific issues of people with epilepsy, namely interactions and seizure risk.
Introduction
The intersection between post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) has become increasingly important during the last few years, especially in the context of military medicine.1, 2
In 2013, the American Psychiatric Association revised the diagnostic criteria for PTSD in the fifth edition of its Diagnostic and Statistical Manual of Mental Disorders (DSM-5).3 In DSM-5, PTSD is not classified among anxiety disorders anymore because it is now included in a new category named ‘Trauma- and Stressor-Related Disorders’. One of the novel aspects of the new classification is that all conditions included in this group require exposure to a traumatic or stressful event as a diagnostic criterion.
Traumatic and stressful events are not infrequent but epidemiological studies show that only a minority of people exposed to a traumatic stressor develop PTSD. Data from the National Comorbidity Survey have shown that around 1 in 8 woman and fewer than 1 in 10 men develop PTSD after a trauma.4, 5 It seems established that the severity of the trauma, in physical and psychological terms, is one of the main determinants for the development of PTSD. For example, 55% of rape victims develop PTSD against only 7.5% of accident victims.6 In this context, the relationship between PTSD and TBI is particularly fascinating. In the past, PTSD was considered rare in TBI because the loss of consciousness at the time of the trauma was thought to prevent the encoding of potentially traumatic memories which are necessary for the development of PTSD.7 On the contrary, cumulating evidence has subsequently challenged this concept showing that PTSD can follow any TBI from mild to severe8 and patients can suffer episodes of more or less prolonged retrograde and anterograde amnesia, sometimes with no recollection of the traumatic experience itself. 6 But what is the relationship between PTSD, TBI and post-traumatic epilepsy (PTE)? The aim of this chapter is to discuss the relationships between PTSD and epilepsy in terms of epidemiology, neurobiological mechanisms and phenomenology. A pragmatic approach to the treatment of PTSD in epilepsy is also presented.
Neurobiology
The neurobiology of PTSD is complex and only partially overlaps with that of anxiety disorder. In fact, as compared to anxiety disorders, PTSD is characterized by a number of immune, endocrine, inflammatory and epigenetic changes which seem to be related to the exposure to a stressor9 and some of them can be potentially relevant in the comorbidity between PTSD and epilepsy.
A core feature of PTSD is the dysfunction of the hypothalamic–pituitary–adrenal axis driven by sustained high levels of corticotropin-releasing hormone (CRH).10 High CRH levels are responsible for adrenocorticotrophin desensitization to CRH stimulation that ultimately leads to abnormal cortisol responses to stress and chronic hypocortisolism.10 Although the chronic hypocortisolism may sound like a paradox, it is, on the contrary, a basic principle of PTSD as these patients present with abnormal stress reactivity due to a decreased availability of stress hormones.
High CRH levels are a potential key factor explaining the link between PTSD and epilepsy (Table 11.1). In fact, high CRH levels are associated with progressive neuronal and volume loss in the hippocampi11 as well as hippocampal downregulation of GABA-A receptors12 and upregulation of NMDA receptors in the prefrontal cortex.10. All these changes are widely described in people with temporal lobe epilepsy and may contribute to the bidirectional relationship suggested by epidemiological studies in the subsequent section.
Table 11.1 Neurobiological mechanisms implicated in PTSD that may be of relevance in epilepsy
A: Neurochemical level Increased CRH levels Decreased serotonin levels Decreased GABA activity Increased NMDA activity |
B: Neuroanatomical level Reduced hippocampal volumes Increased amygdala firing Reduced prefrontal cortex volumes Reduced anterior cingulate volumes |
Another core feature of PTSD is the abnormal regulation of a number of neurotransmitters especially catecholamines and serotonin.10 The chronically high dopamine and noradrenalin levels are responsible for hyperarousal symptoms, increased blood pressure and heart rates but also increased encoding of fear memories.13 This seems also to be associated with a progressive downregulation of 5HT1A receptors and a progressive reduction of serotonin levels.14 The low serotonin levels would ultimately be responsible for the intrusive memories, the impulsivity and the hypervigilance described in patients with PTSD. However, low serotonin levels have been also described in animal models of epilepsy such as genetically epilepsy-prone rats, the pilocarpine status epilepticus model in Wistar rats and rhesus monkeys,15 further supporting the link between PTSD and epilepsy.
Epidemiology
Data from the World Mental Health survey showed lifetime prevalence rates for PTSD in Europe ranging from 2% of Italy and Spain to 8.8% of Northern Ireland while data from the US Department of Veterans Affairs, National Centre for PTSD, reported lifetime prevalence rates among adult Americans of about 6.8%.16
Data about the prevalence of PTSD in epilepsy are limited. A US study in 174 patients using the Mini-International Neuropsychiatric Interview (MINI) reported a diagnosis of current (active) PTSD in 5.7% of patients17 but a meta-analysis of 27 studies of anxiety disorders involving more than 3,000 people with epilepsy showed a pooled prevalence of 0.09% (95%CI 0.05–1.8).18 The conflicting results probably reflect variations in individual subpopulations of patients with epilepsy. For example, data from a multicentre study of US Veterans showed prevalence rates for PTSD in PTE in the region of 13%.19 It is, therefore, evident that the prevalence of PTSD is also influenced by the specific aetiology of the epilepsy, being higher in people with PTE as compared to other aetiologies (e.g. vascular, cortical dysplasia or hippocampal sclerosis) or other epilepsy syndromes (e.g. focal vs. generalized). However, data on the prevalence of PTSD in relationship to the specific epilepsy syndrome are still lacking.
A number of studies have shown a bidirectional relationship between epilepsy and depression, meaning that not only epilepsy is burdened by an increased prevalence of depression but also depression is associated with an increased risk of developing epilepsy.20 The same relationship has been established also for a number of other psychiatric disorders, from autism and attention deficit hyperactivity disorder to schizophrenia and other thought disorders. Data on the relationship between PTSD and epilepsy are almost non-existent with a single study available. A US study in veterans older than 65 shows that a previous history of anxiety disorders (at the time of this study PTSD was listed among anxiety disorders) is significantly more common in those who developed epilepsy as compared to controls.21 A cohort Danish study involving more than 200,000 subjects showed that people on selective serotonin reuptake inhibitors (SSRIs) at the time of the TBI are 5.6 times more likely to develop epilepsy than those who were not on SSRIs.22 Given that previous studies have shown that SSRIs per se are not associated with an increased risk of seizures,23 it is possible to speculate that to be on SSRI is likely to represent an indicator of a mood or anxiety disorder severe enough to require pharmacological treatment. A large cross-sectional study from Taiwan, using data from the Health Insurance Database and including more than 6,000 individuals, showed that people with PTSD have a 3–6 times increased risk of developing epilepsy after adjusting for demographic, medical and psychiatric comorbidities.24 All these data taken together seem to suggest that the relationship between PTSD and epilepsy is possibly similar to that shown for other psychiatric conditions.
Clinical Implications
In people with epilepsy, psychiatric comorbidities have been historically associated with poor quality of life, but there are now data suggesting their role as a prognostic factor. In fact, psychiatric comorbidities are associated with a high risk of side effects from antiepileptic drugs, especially cognitive complaints and psychiatric side effects.25 Psychiatric disorders are also associated with a 4-time increased risk of drug resistance in focal26 and generalized epilepsies.27 Psychiatric comorbidities are also associated with premature mortality,28 and this may be due to a variety of reasons, including increased risk of substance or alcohol abuse, increased risk of injuries and increased suicide rates.
Data from a population-based study of over 57,000 people in Sweden showed that females with epilepsy and psychiatric disorders have a 5-fold increased risk of sudden unexpected death in epilepsy (SUDEP) compared to those without such comorbidities.29
Data on the specific role of PTSD in epilepsy are not available and further studies are needed in order to clarify whether PTSD is associated with a poor prognosis in people with PTE.
As already discussed in Chapter 10, PTSD and TBI are also strictly interlinked with psychogenic non-epileptic seizures (PNES). A retrospective study from the Veterans Affairs Medical Centre reported a 57% prevalence of PNES after TBI against a 35% of PTE.30 Patients with PNES after TBI showed a strong correlation with a diagnosis of PTSD.19 However, there are no specific data about the co-occurrence of PTE and PNES. A recent meta-analysis on the prevalence of PNES in people with epilepsy showed a pooled prevalence of 12%, while the prevalence of epilepsy in people with PNES was reported as high as 22%.31 Given the strong association between TBI and PNES it is possible to speculate that the comorbidity between PTE and PNES could be substantial. However, it is important to point out that PNES seem to be more common in mild TBI while PTE is probably more common in moderate to severe TBI. Therefore, it may not be necessarily true that patients with PTE present higher PNES comorbidity rates than other epilepsy syndromes. The presence of PTSD may represent a valuable clinical indicator to investigate further the relationship among these clinical entities.
Management of PTSD in Epilepsy
There are no data on the treatment of PTSD in the context of epilepsy and this reflects the paucity of data about the management of anxiety disorders in epilepsy.32 In such a case, it seems reasonable to adapt current guidelines of treatment used outside epilepsy to the specific needs of people with epilepsy including interactions and seizure risk.
Psychological Interventions
It is now established that trauma-focused cognitive behavioural therapy (CBT) and eye movement desensitization and reprocessing (EMDR) are both effective in PTSD and superior to stress management.33
Studies comparing psychological and pharmacological interventions are limited. However, a number of small studies have shown the advantages of a combined treatment.34
Pharmacological Treatments
Regarding the acute treatment, data from randomized placebo-controlled trials (RCTs) suggest that most antidepressants, including SSRIs, are effective in PTSD.35 However, a meta-analysis of 37 RCTs using structured scales showed evidence only for paroxetine, sertraline and venlafaxine.36 Apart from antidepressants, there seems to be some evidence for the antipsychotics risperidone and olanzapine and the anticonvulsant topiramate.35 Medications which failed RCTs include citalopram, alprazolam, tiagabine and valproate.35
Prospective studies investigating the long-term treatment of PTSD are limited and most of the longitudinal data come from retrospective studies. Available data suggest that around 50% of patients with PTSD experiences a chronic course of the disease but the proportion of patients responding to treatment also increases over time.36, 37 The number of studies focusing on relapse prevention is scant with only a few RCTs available supporting evidence for fluoxetine38 and sertraline.39
Drug Interactions and Seizure Risk
When treating PTSD in people with epilepsy, clinicians need to pay attention to interactions with antiepileptic drugs and the potential effect of psychotropic medications on the seizure threshold (Table 11.2).
| First line | First choice: Sertraline Second: Venlafaxine or paroxetine |
| Augmentation strategies | First choice: Topiramate Second: Risperidone Third: Olanzapine |
Related posts:
Chapter 5 – Post-traumatic Epilepsy in Children
Chapter 6 – Sport-related Concussive Convulsions
Chapter 7 – Accidents and Injuries during Seizures
Chapter 12 – Antiepileptogenic Therapies for Post-traumatic Epilepsy: Is There Any Evidence?
Chapter 13 – Effects of Antiepileptic Drugs on Cognition
Chapter 14 – Post-traumatic Epilepsy in Low Income Countries
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