By: M. Dawbin
While bipolar disorder (BD) and epilepsy seem like separate conditions, they share similar symptoms, physical abnormalities, and treatments. In 2017, a Baylor University student found that specific variants of the ANK3 gene played a role in both disorders (Lopez et al., 2017). This common genetic material may be responsible for the alarmingly high comorbidity of epilepsy and mood disorders, specifically bipolar disorder. What’s more, it appears the association is bidirectional – BD is more common amongst people with epilepsy (PWE) than the general population, and bipolar individuals experience higher rates of epilepsy than the general population (Salpekar, 2017).
Kindling Model of Progression
The typical clinical progression of one disorder parallels the other, as evidenced by the kindling model of progression, developed by Graham Goddard in 1969, and its later applications. Studying epilepsy, Goddard’s team found that repetitive, daily exposure to a certain level of brain stimulation eventually induced seizures in rodent test subjects. While this level of stimulation wasn’t enough to invoke a seizure at the beginning of the experiment, repeated exposure lowered the seizure threshold (Goddard, 1969). In the years since, Robert M. Post has spent two and a half decades applying this principle to mood disorders. His work concludes that both seizures and mood episodes may become more severe, and more easily triggered, with consistent repetition - like reinforcing a habit (Post, 2007). To mitigate the progression of either disorder, both in severity and frequency, seizures and mood-related symptoms should be treated as early and efficiently as possible.
Overlap of Symptoms
Though the diagnostic criteria for each disorder are strikingly dissimilar, people with one or the other may share some similar symptoms. Specifically, a study from 1985 compared 44 people with mood disorders (most of which had BD without a history of seizures) and 37 people diagnosed with complex partial seizures; common symptoms between the two groups were jumbled thoughts, increased sensitivity to sound and color, and olfactory hallucinations (Silberman, et al., 1985). It’s unclear whether these symptoms are related to specific mood states in affective disorders. Likewise, the study didn’t determine whether these symptoms were present in the preictal (before seizure) period, ictal (during seizure) period, postictal (after seizure) period, or interictal period (times of remission between seizures). Since epilepsy and BD both tend to appear in marked episodes, these similar symptoms may be caused by similar pathological mechanisms. More research on this subject could be useful to further understand the link between mood states and seizures.
Though it’s not a primary feature of the disorder – that is to say, not a clinical sign of BD – some patients with BD demonstrate EEG abnormalities, with some even displaying epileptiform waves. The aforementioned study, completed by Silberman et al. (1985), reported “diffuse, non-specific changes” on some of the EEGs performed on those in the affective illness group. In a 1988 study, “bitemporal paroxysmal epileptiform waves” were found in the 3 participants with the most frequent mood switching, suggesting that a rapid cycling course of illness is more likely to cause seizure activity (Levy et al., 1988). Unfortunately, due to the small sample size and limitations in the design, the results of Levy’s study were largely inconclusive and may not be replicable. More recently, in 1997, JG Small and her colleagues performed EEGs on 202 patients hospitalized for mania. 5% of these patients had epileptiform waves and 12% had “other sharp activity”. This is consistent with the result of a recent study of BD II patients in Norway – the authors found that 14% had epileptiform waves or other sharp activity (Drange, et al. 2020). Royal Air Force candidates are screened for seizure activity to ensure the safety of the pilots. If their data can serve as a control group, the expected occurrence in the general population would be 0.5% (Gregory et al., 1993).
Comorbidity
Well-established since the time of Hippocrates, the association between epilepsy and depressed states is hardly a new phenomenon. A recent conceptual development, however, is the possibility that one disorder may increase the individual’s risk for the other (Josephson et al., 2017; Salpekar, 2017). In some people with both disorders, mood/affective symptoms appear first. In others, seizure activity appears first. Regardless of whether or not the etiology of one disorder can influence the development of the other, researchers have demonstrated that the relationship between the two disorders is bidirectional, as previously discussed.
A study by Forty et al. in 2014 compared the risk of certain ‘physical’ illnesses in a bipolar group, a unipolar depressive group, and a control group. The occurrence rate of epilepsy among people with depression was 3.8 times higher than in the control group. The rate of epilepsy among people with BD was 6.19 times higher than expected – a staggering difference. It is possible that the over Another interesting finding from the study revealed that a history of rapid cycling presentation in bipolar (experiencing four or more mood episodes a year) was significantly correlated with multiple medical illnesses.
Forty et al.’s final findings highlighted that electroconvulsive therapy (generally reserved for severe or treatment-resistant cases of mood disorder due to potentially debilitating side effects) was correlated with a higher burden of medical illness (2014). Unfortunately, as with many treatments for BD, it’s unclear whether these risks are increased due to the etiological harms of the disorder itself, or if they may be an unintended consequence of the treatment. Further research will be needed to clarify this lack of information. Additionally, inconsistent methods and varying screening tools employed by studies in this area create results that are, at times, conflicting and unreliable. Regardless, controlled studies consistently demonstrate an increased rate of depression among PWE (Weatherburn et al., 2016; Kanner, 2003).
A relevant concern is that depressive symptoms and disorders among epilepsy patients may be underrecognized and undertreated. In a 2003 article, Andres M. Kanner specified that 70% of patients involved in their study had a presentation “akin to dysthymic disorder”. However, the symptoms were interrupted with brief periods of remission – barring them from a formally diagnosed depressive disorder. A harrowing 60 of the 97 patients had exhibited depression symptoms for over a year. Further, only 33% were treated within 6 months of symptom onset – a figure that did not change depending on the severity of the depression (Kanner, 2003).
Shared Precipitating Factors
Emmanuelle Bostock et al.’s detailed 2015 literature review examined factors that might contribute to both manic episodes and partial seizures. Of the factors included, the authors found that increased stress, menstruation, and experiencing a loss of sleep could trigger mood episodes and seizures. Stress, in particular, is a common contributing factor to psychiatric illness. Even positive stressors and eustress were found to cause mania – including at times of goal attainment. Similarly, the authors of the article quoted a study where PWE recorded a seizure diary that included their level of stress for the day. A one-point increase on the scale was correlated with seizure occurrence (Haut et al., 2007 as cited in Bostock et al., 2015). In regards to sleep, a decreased need for sleep is a key symptom of mania, but sleep deprivation also can trigger it. A study of depressed patients with BD found that 7 out of 67 patients switched to (hypo)mania after 40 hours of sleep deprivation (Wehr, 1982 as cited by Bostock et al, 2015). In other studies, sleep reduction was found to be a predictor of mania (Leibenluft et al., 1996 as cited by Bostock et al., 2015). Similarly, sleep reduction is a commonly reported seizure trigger, and seizures diminish the individual’s quality of sleep. Bostock et al. noted that these similarities between the disorders may be due to shared pathological mechanisms between BD and epilepsy.
Similar Pathophysiology
Serotonin/Norepinephrine Transmission
Genetically Epilepsy-Prone Rats (GEPRs), which exhibit both seizure and mood disorders in a manner analogous to humans, are often utilized to study BD And epilepsy. A deficit in serotonin and norepinephrine transmission, often found in GEPRs, is theorized to play a role in the expression of these disorders both in humans and rats (Jobe, 2003). Low serotonin concentration has a long-established history in the literature as a potential cause of depression. Based on this information, data selective serotonin reuptake inhibitors (SSRIs) were developed; increasing serotonin concentration by reducing the reuptake of serotonin, which leaves serotonin molecules underutilized. SSRIs continue to be a first-line treatment of depression (Brown et al., 1982). In an experiment, Quintin et al. examined the effects of acute tryptophan depletion. As a precursor to serotonin, tryptophan is vital for serotonin synthesis. While the control group was largely unaffected, a group of non-bipolar participants (having first-degree bipolar relatives) experienced diminished cognitive performance, suggesting that low serotonin concentrations may be a factor in the development of mood disorders and their subsequent cognitive effects (Quintin et al., 2001). Norepinephrine levels also play a role in both disorders. 𝜶-methyl-𝒑-tyrosine, a substance that inhibits norepinephrine synthesis, increases seizures in rats. In humans, the substance also contributes to depressive episodes in people with BD who were formerly in remission (Jobe, 2003). As a whole, this information suggests that serotonin and norepinephrine transmission may play a role in the pathophysiology of BD and epilepsy.
Gamma-aminobutyric Acid/Glutamate Transmission
Research suggests that gamma-aminobutyric acid (GABA) and glutamate imbalance may also play a role in BD and epilepsy. Data suggests that deficient GABA transmission and excessive amounts of glutamate contribute to epilepsy (Jobe, 2003). In an experiment, reduced GABA transmission caused audiogenic (resulting from auditory stimulation) seizures in animals that were otherwise normal (Faingold, 2002). Insufficient GABA transmission was present across multiple brain regions in a study of individuals with major depressive disorder (Kanner, 2011). While medications that increase GABA seem to have little to no antidepressant effects, glutamatergic drugs appear to be more effective (Kanner, 2011).
Common Regions/Structures
BD and epilepsy share similar structural abnormalities. Imaging studies involving patients with BD have shown reduced white matter in the thalamic region (Barysheva et al., 2013). A review of structural abnormalities among epilepsy patients discussed significant structural compromise in the thalamus – a change present in every type of epilepsy (Whelan et al., 2018). The mesial temporal lobe is often involved in temporal lobe epilepsy, frequently including hippocampal atrophy (Kanner, 2009). Hippocampal atrophy has also been demonstrated in patients with depression, and the length of depression may be correlated with the reduction in hippocampal volume (Bell-McGinty et al., 2002; Posener et al., 2003).
Relevant Treatments
Based on the similarities in pathophysiology, it’s unsurprising that some anticonvulsants can be potent mood stabilizers: carbamazepine, lamotrigine, and valproate have been found to increase monoamine transmission, which contributes to their mood-stabilizing effects (Yan et al., 1992). Antidepressants carry a risk of inducing mania or rapid cycling, but when used in combination with a mood stabilizer or antipsychotic, antidepressants may alleviate depressive symptoms in people with BD. Comparatively, there is some degree of risk that antidepressants can cause seizures. However, these risks appear minimal, and recent reviews of the literature suggest antidepressant medications are generally safe and well-tolerated among people with adequately treated epilepsy. Seizures are more associated with serum level toxicity (Rosenstein et al., 1993; Kanner, 2016). An additional form of treatment available for BD and major depression is electroconvulsive therapy (ECT). The practice involves therapeutically inducing a generalized seizure through electrical stimulation. In an article, the authors found that the seizure threshold was lower in manic patients than in depressed patients. While this procedure tends to be effective – the review found that it resulted in significant improvement of manic episodes in 80% of patients – it can have devastating side effects including severe memory loss (Mukherjee et al., 1994).
In sum, there is a significant degree of overlap between BD and epilepsy, particularly in their afflicted populations, pathologies, and triggers. Based on similarities in pathology, future studies – especially ones including children and early signs – about BD and epilepsy could inform how to treat and even prevent the shared symptoms (Salpekar, 2017). Further research would mean an increased understanding of the course and development of each disorder, helping clinicians improve the quality of life of their patients.
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