Epilepsy rarely travels alone. People with epilepsy carry a substantially higher burden of other health conditions compared to the general population, spanning psychiatric disorders, cardiovascular disease, bone loss, hormonal disruption, cognitive decline, and more. Many of these associations run in both directions: epilepsy raises the risk of the other condition, and the other condition raises the risk of epilepsy. Chronic brain inflammation appears to be one thread connecting many of these seemingly unrelated problems, though medication side effects and shared genetics also play major roles.
Depression, Anxiety, and the Two-Way Street
Depression is one of the most common conditions seen alongside epilepsy, and it is also one of the most underdiagnosed. The relationship is not simply that living with seizures makes people depressed, though that contributes. Research shows a genuine bidirectional link: people with epilepsy are more likely to develop depression, and people with depression are more likely to develop epilepsy later on. Shared disruptions in brain chemistry, particularly in serotonin and norepinephrine signaling, along with overlapping changes in frontotemporal brain networks and inflammatory processes, help explain why the two conditions feed into each other.1Europe PMC / Journal of Natural Science, Biology and Medicine. Epilepsy and Depression: A Bidirectional Relationship
Anxiety disorders follow a similar pattern. In studies of quality of life among people with drug-resistant epilepsy, depression and anxiety rank among the strongest predictors of poor well-being, outweighing even seizure frequency itself.2PubMed Central. Characteristics associated with quality of life among people with drug-resistant epilepsy That finding highlights something clinicians increasingly emphasize: controlling seizures is necessary but not sufficient. If depression and anxiety go untreated, quality of life stays low even when seizure counts drop.
Psychosis and Seizures
A less common but striking psychiatric comorbidity is postictal psychosis, where a person develops psychotic symptoms (hallucinations, delusions, paranoia) in the hours or days after a cluster of seizures. In some cases these episodes can persist for months. Case reports of patients with temporal lobe epilepsy have documented prolonged psychotic episodes lasting 12 weeks or more, during which the patients’ usual epileptic brain-wave abnormalities temporarily disappeared on EEG. The psychosis only resolved when those epileptic discharges returned, suggesting a kind of seesaw between seizure activity and psychotic symptoms.3Epilepsy & Behavior. Prolonged postictal psychosis and forced normalization: A report of two cases This phenomenon, sometimes called forced normalization, remains poorly understood but illustrates how deeply epilepsy is entangled with broader brain function.
Autism, ADHD, and Childhood Epilepsy
In children, the most frequent comorbidities are neurodevelopmental: autism spectrum disorder and attention deficit hyperactivity disorder. The overlap is extensive. All three conditions involve disrupted synaptic development, altered neurotransmitter signaling, and changes in how different brain regions connect to one another during early life.4PubMed. Epilepsy associated with autism and attention deficit hyperactivity disorder: is there a genetic link? Genetic studies have found that many of the same spontaneous mutations and chromosomal copy-number variations show up at elevated rates across autism, intellectual disability, and epilepsy, reinforcing the idea that these conditions share developmental roots rather than simply co-occurring by chance.5PubMed Central. Dissecting the genetic basis of comorbid epilepsy phenotypes in neurodevelopmental disorders
A large data-linkage study of over 3,200 children and adolescents with autism found that those who also had early childhood epilepsy faced roughly double the risk of being diagnosed with ADHD later, even after accounting for other factors.6PubMed Central. The association between early childhood onset epilepsy and attention-deficit hyperactivity disorder (ADHD) in 3237 children and adolescents with Autism Spectrum Disorder (ASD) That finding matters practically: pediatricians managing epilepsy in a child with autism should keep an eye out for emerging ADHD symptoms, because early intervention makes a difference.
Cognitive Decline and Dementia
The relationship between epilepsy and dementia, particularly Alzheimer’s disease, is another bidirectional one. A systematic review and meta-analysis of cohort studies concluded that late-onset epilepsy is a risk factor for dementia, and conversely, dementia and Alzheimer’s disease are risk indicators for developing late-onset epilepsy.7PubMed. Bidirectional relationship between late-onset epilepsy (LOE) and dementia: A systematic review and meta-analysis of cohort studies A UK Biobank study put some numbers on this: people with epilepsy had about 2.5 times the risk of developing Alzheimer’s compared to controls, while the reverse association was even more dramatic, with Alzheimer’s patients carrying roughly 15 times the risk of developing epilepsy. The risk was especially pronounced when epilepsy began in a person’s 60s or 70s and in individuals carrying the APOE ε4 gene variant, which is already a known Alzheimer’s risk factor.8PubMed. The bidirectional association of epilepsy with Alzheimer’s disease and other neurodegenerative dementias
This has practical implications for clinicians. When someone develops new-onset seizures in their 60s with no obvious cause like stroke or tumor, cognitive screening for early dementia may be warranted. And when someone with Alzheimer’s has episodes that look like confusion but seem unusually abrupt, subclinical seizures should be on the radar.
Sleep Disorders
Sleep apnea is more common in people with epilepsy than in the general population, and the relationship is not merely an inconvenience. Sleep apnea can worsen seizure frequency and severity.9Sleep Medicine and Research. Sleep and Epilepsy Detailed case studies have documented a precise temporal link: seizures are frequently preceded by an obstructive apnea event. In one well-documented patient, seizures decreased under CPAP therapy and reappeared immediately when CPAP was withdrawn. The epileptic discharges on EEG were tightly tied to micro-arousals during or just after airway obstruction, suggesting that the sleep-to-wake transition triggered by apnea is itself a seizure trigger.10Seizure. Direct relation between obstructive sleep apneas and epileptic events
The clinical takeaway is straightforward: treating sleep apnea in someone with epilepsy may improve seizure control. Yet sleep evaluations are not routinely part of epilepsy management in many settings, which represents a missed opportunity.
Stroke and Heart Disease
Stroke is the most common identifiable cause of epilepsy in older adults. Both ischemic (clot-based) and hemorrhagic (bleeding) strokes can trigger seizures in the acute aftermath or lead to chronic epilepsy that develops weeks to months later.11PubMed Central. Poststroke Seizure and Epilepsy: A Review of Incidence, Risk Factors, Diagnosis, Pathophysiology, and Pharmacological Therapies But the relationship goes both ways here as well. A systematic review of population-based studies found that people with epilepsy face a higher risk of both stroke and heart attack, with shared vascular risk factors like high blood pressure, diabetes, and high cholesterol partially explaining the overlap.12PubMed. Increased risk of stroke and myocardial infarction in patients with epilepsy: A systematic review of population-based cohort studies
Additionally, some seizure medications interact with cardiovascular drugs, complicating treatment. And sudden unexpected death in epilepsy (SUDEP), the most feared outcome, appears to involve seizure activity propagating through the autonomic nervous system and suppressing breathing, rather than directly triggering a fatal heart rhythm, though the cardiovascular system is still affected indirectly.13PubMed Central. Sudden unexpected death in epilepsy: respiratory vs. cardiac contributions
Bone Loss and Fracture Risk
One of the most underappreciated complications of epilepsy is what it does to bones. People with epilepsy have significantly higher rates of osteoporosis and fractures, and much of this comes from the medications themselves rather than the seizures. Older anti-seizure drugs like phenytoin, carbamazepine, and phenobarbital are enzyme inducers that speed up vitamin D metabolism and disrupt sex hormone levels, both of which weaken bone over time. Valproic acid and topiramate damage bone through different pathways, with direct effects on bone biology.14PubMed Central. Antiseizure Medications and Bone Health Observational studies suggest that anti-seizure medication use increases fracture risk somewhere between roughly 1.2 and 6 times compared to the general population, depending on the drug, the dose, and the duration of treatment.15PubMed Central. A Review of the Effect of Anticonvulsant Medications on Bone Mineral Density and Fracture Risk16PubMed. Impaired bone health as a co-morbidity of epilepsy
Given that many people take these medications for years or decades, routine bone density screening and vitamin D supplementation should be part of epilepsy care, especially for women after menopause and for anyone on enzyme-inducing drugs. This is one area where the comorbidity is largely iatrogenic — caused by the treatment rather than the disease — and therefore preventable with proper monitoring.
Hormonal and Reproductive Effects
Women with epilepsy develop polycystic ovary syndrome (PCOS) at higher-than-expected rates. PCOS affects roughly 8% to 13% of the general female population, but prevalence in women with epilepsy has been reported as high as 26%.17PubMed Central. Research Progress on the Effect of Epilepsy and Antiseizure Medications on PCOS Through HPO Axis Both the epilepsy itself and the medications contribute. Seizure activity can disrupt the hormonal signaling axis between the brain and the ovaries. On the medication side, valproic acid is a particular culprit: in a study of 102 Chinese women with epilepsy, those on valproate had a PCOS rate of about 34%, along with elevated testosterone and altered hormone ratios.18Seizure. Polycystic ovary syndrome in patients with epilepsy: A study in 102 Chinese women This is a significant consideration when choosing anti-seizure medications for women of reproductive age.
Migraine
Migraine and epilepsy share an unusual degree of overlap in their biology. Both involve waves of abnormal electrical activity in the brain, both can produce visual auras, and both respond to some of the same medications (valproate and topiramate are prescribed for both conditions). Research has identified shared genetic mutations in ion channel genes — specifically CACNA1A, ATP1A2, and SCN1A — that predispose people to both migraine and epilepsy.19PubMed. Migraine and epilepsy: a focus on overlapping clinical, pathophysiological, molecular, and therapeutic aspects People with epilepsy are more likely to have migraines than the general population, and distinguishing a migraine aura from a seizure aura can be clinically challenging, particularly when they co-occur.
Autoimmune Connections
An increasingly recognized frontier in epilepsy research is the role of the immune system. Autoimmune epilepsy is a real and treatable condition, most commonly involving antibodies that target proteins on the surface of neurons, such as NMDA receptors and LGI1. These antibodies can cause recurrent seizures that resist standard anti-seizure drugs but respond to immunotherapy (steroids, plasma exchange, or other immune-suppressing treatments).20PubMed. Autoimmune epilepsy Systemic autoimmune diseases like lupus (SLE) are also associated with seizures, likely through a combination of vascular damage and antibodies that cross-react with brain tissue.21Brain. The association between systemic autoimmune disorders and epilepsy and its clinical implications
In a study screening epilepsy patients for antibodies against neuronal surface antigens, about 6% tested positive, and these positive results were concentrated among patients with drug-resistant epilepsy and those with known autoimmune disease.22PubMed Central. Occult Autoimmune Background for Epilepsy—The Preliminary Study on Antibodies Against Neuronal Surface Antigens The implication is that some people currently labeled as having “unexplained” drug-resistant epilepsy may actually have an autoimmune condition that could respond to a fundamentally different treatment approach.
Inflammation as a Shared Thread
A pattern running through many of these comorbidities is neuroinflammation. When the brain is injured — whether by prolonged seizure activity, trauma, or infection — immune cells in the brain (microglia and astrocytes) become activated and release inflammatory signaling molecules. This inflammatory cascade can increase neuronal excitability and promote further seizures while simultaneously damaging mood-regulating circuits and impairing memory formation.23PubMed. Behavioral comorbidities of epilepsy and neuroinflammation: Evidence from experimental and clinical studies Experimental and clinical data show that epilepsy, depression, autism-like behavior, and cognitive impairment are all associated with elevated brain inflammatory markers, and that targeting inflammatory pathways in animal models can reduce the severity of seizures and behavioral symptoms alike.24PubMed. Neurobehavioral comorbidities of epilepsy: Role of inflammation Early-life inflammation may even “prime” the brain, making it more vulnerable to both seizures and psychiatric symptoms later.25PubMed. Role of inflammation in epilepsy and neurobehavioral comorbidities: Implication for therapy
Obesity, Diabetes, and the Gut
People with epilepsy are less likely to exercise regularly, and certain anti-seizure medications — valproate is again the main offender — promote weight gain and elevated insulin levels. These factors create a pipeline toward obesity and type 2 diabetes. A scoping review linking the two conditions found that epilepsy is associated with obesity, obesity is associated with diabetes, and the medications bridge the gap further. Topiramate, by contrast, tends to cause weight loss, which is one reason some clinicians factor metabolic risk into their drug selection.26PubMed Central / Elsevier. Drivers for the comorbidity of type 2 diabetes mellitus and epilepsy: A scoping review
Emerging research also points to the gut microbiome as a mediator. People with epilepsy show differences in their gut bacteria compared to healthy controls, and gut-derived metabolites called short-chain fatty acids appear to influence both intestinal barrier integrity and brain inflammation.27PubMed. Therapeutic potential of gut microbiota modulation in epilepsy: A focus on short-chain fatty acids The ketogenic diet, which has been used for seizure control since the 1920s, dramatically reshapes the gut microbiome, and researchers are investigating whether some of its anti-seizure benefit comes through that route rather than solely from altered brain metabolism.28PubMed Central. Microbiota-Gut-Brain Axis and Epilepsy: A Review on Mechanisms and Potential Therapeutics
When Medications Become Part of the Problem
Anti-seizure medications are essential, but they come with their own comorbidity burden. Psychiatric and behavioral side effects are common with certain drugs. Levetiracetam, one of the most widely prescribed anti-seizure medications, carries the highest rate of psychiatric and behavioral side effects at about 22%, driven largely by irritability and aggression. Perampanel, felbamate, and stiripentol also cluster at the high end of behavioral risk.29PubMed. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy30PubMed. Psychiatric and behavioural side effects of antiseizure medications in epilepsy Meanwhile, carbamazepine, lamotrigine, and oxcarbazepine sit at the lower end and may even have mood-stabilizing properties.
Drug interactions pose another layer of risk. Older enzyme-inducing anti-seizure drugs can reduce the effectiveness of oral contraceptives, antidepressants, blood thinners, and even chemotherapy agents.31PubMed Central. Antiepileptic drug interactions – principles and clinical implications In a study of 265 epilepsy patients taking other medications alongside their seizure drugs, about 30% had clinically significant drug interactions, with the most common involving contraceptives, antidepressants, and cholesterol-lowering statins. Using enzyme-inducing anti-seizure drugs nearly tripled the odds of having a major interaction.32PubMed. Co-medication and potential drug interactions among patients with epilepsy For people with epilepsy who are also being treated for depression, the interaction goes both ways: certain antidepressants like fluoxetine and paroxetine can raise anti-seizure drug levels, while enzyme-inducing seizure drugs can lower antidepressant levels enough to undermine their effect.33PubMed. An update on the pharmacokinetic and pharmacodynamic interactions between antidepressants and antiseizure medications
Diagnostic Overshadowing
One underappreciated problem in epilepsy care is diagnostic overshadowing, where the seriousness of epilepsy itself causes clinicians to attribute new symptoms to the seizure disorder or its treatment, missing separate treatable conditions. A case report of a child with Lennox-Gastaut syndrome, a severe form of epilepsy, illustrates this vividly: a metabolic condition causing vitamin B12 deficiency went undetected for years because the child’s symptoms were assumed to be part of the neurological picture.34PubMed. Diagnostic Overshadowing in Lennox-Gastaut Syndrome: Immerslund-Gräsbeck Syndrome Unmasked by Radiosurgical Stress This tendency is especially problematic in people with intellectual disabilities, where communication barriers make it harder to report new symptoms. The fix requires deliberate clinical vigilance: when someone with epilepsy develops new problems, the default assumption should not be that the seizures explain everything.
Social Determinants and Health Disparities
The comorbidity burden of epilepsy falls unevenly across populations. Lower socioeconomic status and minority status are associated with higher epilepsy risk, more emergency department visits (and fewer neurology visits), lower medication adherence, and reduced access to surgical treatment.35PubMed. Social determinants of health in epilepsy A recent study examining social determinants of health in epilepsy patients found that those with greater unmet social needs had more emergency room visits without a corresponding increase in specialty neurology care. After adjustment, patients with moderate and significant social needs had markedly lower odds of survival by the end of the study period. African American patients and those without commercial insurance had higher emergency department use and fewer neurology visits, underscoring persistent disparities in how epilepsy comorbidities get managed.36PubMed. The effects of social determinants of health on patients with epilepsy
Genetics, Copy-Number Variations, and Shared Risk
Large-scale genetic studies have helped explain why epilepsy co-occurs so frequently with other conditions. An exome sequencing study of nearly 21,000 individuals with epilepsy identified shared rare genetic variants between epilepsy and other neurodevelopmental disorders, confirming that the overlap is partly hard-wired into people’s DNA rather than arising solely from environmental triggers.37PubMed. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes Separately, in a study of over 1,000 patients with “epilepsy plus” — epilepsy accompanied by other neurological or developmental features — about 11% carried at least one chromosomal copy-number variation classified as disease-causing.38PubMed Central. Diagnostic implications of genetic copy number variation in epilepsy plus These genetic findings do not change day-to-day management for most patients, but they reinforce the biological reality that epilepsy is not an isolated electrical problem in the brain. It is part of a broader set of neurodevelopmental and inflammatory vulnerabilities that manifest differently in different people.
How Comorbidities Shape Quality of Life
The accumulation of comorbidities does not merely add to the burden of epilepsy — it multiplies it. Among post-9/11 veterans with epilepsy, those who had both post-traumatic epilepsy and drug-resistant seizures reported the lowest quality of life across every measure studied, and this remained true even after accounting for the number of comorbid conditions.39PubMed Central. Multimodal Quality of Life Assessment in Post-9/11 Veterans With Epilepsy: Impact of Drug Resistance, Traumatic Brain Injury, and Comorbidity In broader studies of drug-resistant epilepsy, the factors most strongly associated with poor quality of life — depression, anxiety, stigma, and medical comorbidities — are all potentially addressable, yet they often go unaddressed because clinical attention remains focused on seizure frequency alone.2PubMed Central. Characteristics associated with quality of life among people with drug-resistant epilepsy The evidence increasingly points toward a model of epilepsy care that treats the whole person — screening routinely for depression, monitoring bone density, checking for sleep apnea, reviewing drug interactions at every visit — rather than treating seizure control as the sole metric of success.