The comorbidities of epilepsy explained

KEYWORDS:

• Epilepsy
• comorbidities
• prognosis
• treatment

Epilepsy is a serious neurological disorder affecting over 70 million people worldwide with incidence rates of around 50 per 100,000 per year in high-income countries and above 100 per 100,000 per year in low-income countries [1]. Epilepsy poses a substantial burden for health systems, individuals and their families and it is still today a highly stigmatized condition [2].

It is now widely accepted that having epilepsy is not just having seizures and comorbidities are now included in the framework for classification of the epilepsies [3]. In fact, epilepsy rarely stands alone and more than 50% of people with epilepsy have one or several additional medical problems [4].

In 1970, Alvan Feinstein defined as ‘comorbidity’ any distinct additional clinical entity that existed during the clinical course of a patient’s index disease [5]. However, in the context of epilepsy, the term ‘comorbidity’ includes a heterogenous group of conditions whose pathophysiology can be quite different in terms of relationship with the epilepsy itself. For example, some diseases are simply the cause of the epilepsy; others are a consequence of the epilepsy or its treatment while other conditions have a complex relationship with epilepsy. Whether these problems are due to shared biological mechanisms, a consequence of having epilepsy, or simply due to the unfortunate occurrence of two conditions in the same individual, the management of these problems can be challenging [6]. Still, comorbidities profoundly affect not just the quality of life of patients with epilepsy but seems to be connected with the outcome of the epilepsy itself [7]. Finally, comorbidities have obvious economic consequences resulting in increased hospitalization length of stay, frequent health-care visits and, ultimately, higher health-related costs [8].

In order to develop successful therapeutic interventions and prevention strategies, it is important to have a clear understanding of the pathophysiology of comorbidities of epilepsy and the magnitude of the problem.

Ley Sander pointed out that comorbidities can be grouped into five major categories according to the underlying pathophysiological mechanisms [4]. These are summarized in Table 1.

Table 1. Types of comorbidities of epilepsy

Type	Mechanism	Examples	Management
Causative	One is the cause of the other	Stroke Traumatic brain injury CNS infections (e.g. neurocysticercosis, HIV) Multiple sclerosis Brain Tumors Heart diseases	Tailored treatment strategies; prevention of drug-drug interactions
Reciprocal	One is associated with increased risk of developing the other and vice versa (complex multifactorial reasons)	Mood and anxiety disorders Psychosis ADHD Autism Spectrum Disorder Irritable bowel syndrome Headaches Psychogenic non-epileptic seizures Diabetes Suicide	Screening for early diagnosis and management
Mutual	Shared risk factors or etiological mechanisms	Tuberous sclerosis Cerebral palsy Autoimmune encephalitis Intellectual disabilities Anti-GAD antibody associated type 1 diabetes Dementia Headaches Heart diseases	Precision medicine and disease modifying agents
Resultant	Caused by seizures and their treatments	Sexual dysfunction Obesity Osteoporosis Heart diseases Obstructive sleep apnea syndrome Type 2 diabetes	Screening and prevention strategies
Coincidental	By chance	Any condition	Tailored treatment strategies; prevention of drug-drug interactions

HIV = Human immunodeficiency virus; ADHD = attention deficit hyperactivity disorder; CNS = Central nervous system; GAD = glutamic acid decarboxylase

Causative comorbidities represent those conditions which are the cause of the epilepsy such as, for example, stroke, brain tumors, brain infections, or many other neurological problems leading to a structural damage. The management of these patients poses challenges related to interactions between antiseizure medications (ASMs) and drugs prescribed for the underlying condition as well as the epilepsy type and the outcome of the epilepsy itself which seems to differ in epilepsies due to a different etiology.

Reciprocal comorbidities include a number of conditions characterized by the so-called ‘bidirectional relationship’ meaning that not just the epilepsy is associated with an increased risk of developing these disorders but also these disorders are associated with an increased risk of developing epilepsy. This phenomenon has been historically described for many psychiatric comorbidities including mood and anxiety disorders, psychoses and schizophrenia, attention deficit hyperactivity disorder (ADHD) and autism [7] but more recently the same phenomenon has been described for medical conditions such as type 1 diabetes, irritable bowel syndrome, and autoimmune disorders [9]. Mechanisms linking reciprocal comorbidities are complex, multifactorial, and likely to be different from condition to condition. It is possible that a combination of shared biological mechanisms, genetic predisposition, and environmental factors as well as epilepsy treatment-related factors is present and operant at the same time.

Mutual comorbidities represent a sort of simplified and straightforward version of the former, in fact in this group of conditions it is possible to identify a specific etiological factor shared by the epilepsy and the other condition and clearly leading to both. The tuberous sclerosis complex (TSC) gene mutation is a classic example. TSC1 mutation is the cause for tuberous sclerosis which is a multiorgan disease that may present with cardiac rhabdomyomas, subependymal giant cell astrocytoma, renal angiomyolipoma, pulmonary lymphangioleiomyomatosis, thyroid nodules, bone fibrous dysplasia, and dental problems. However, at the same time, up to 90% of patients with TSC have epilepsy. Epilepsy and type 1 diabetes in people with anti-GAD antibodies is another classical example.

Resultant comorbidities represent a large group of conditions which are a consequence of seizures/seizure activity or the epilepsy treatments such as, for example, osteopenia and pathological fractures, sexual dysfunction, obesity. These conditions are not simply long-term treatment emergent adverse effects of ASMs because their pathophysiology is usually more complex than that and they ultimately represent self-defined diseases requiring medical treatments and impacting on patients’ health and health resources. Obesity is a clear example. Obesity is not simply due to weight gain induced by ASMs; some studies have pointed out that epileptic seizures per se are associated with increased ghrelin, leptin and adiponectin serum levels, ultimately leading to weight gain and obesity [10].

Coincidental comorbidities are those conditions whose occurrence does not seem to be linked to epilepsy in any way.

Although these categories seem quite straightforward, it has to be acknowledged that some comorbidities may be characterized by multiple mechanisms and may therefore belong to multiple groups. Heart diseases and headaches are classic examples. Some arrhythmias linked to K channel mutations leading also to epilepsy may be classified as mutual comorbidities but there are also cardiac conditions secondary to the seizures like Takotsubo syndrome or arrhythmias due to ASMs which can be classified as resultant comorbidities.

Further studies in this area are needed in order to clarify the nature of the relationship between epilepsy and other medical conditions as it happened for the interictal dysphoric disorder which showed to be not just specific of epilepsy but it was also described in migraine [11].

The spectrum of conditions linked to epilepsy is large and Figure 1 shows prevalence ratios in people with epilepsy as compared to the general population [7,12]. However, different comorbidities may impact in different ways on people with epilepsy. The burden of comorbidities is often measured in terms of impact on mortality. Many clinicians may be familiar with the Charlson Comorbidity Index (CCI) which has been used to predict mortality in hospitalized patients with a range of medical conditions [13]. More recently, a new comorbidity index specific for people with epilepsy was developed to predict mortality and this index proved to be more accurate than the CCI [14]. However, mortality should not be the only parameter to measure the impact of comorbidities. Comorbidities may impact treatment decisions, quality of life of patients and their families as well as the society. More research is needed in order to identify reliable measures to fully appreciate the impact of comorbidities.

Figure 1. Prevalence ratios with confidence intervals of some comorbidities in people with epilepsy (data from [7] and [11])

In terms of management, it is evident that the identification, treatment, and prevention of comorbidities should become an integral part of epilepsy care and epilepsy centers should lead on the development of guidelines of treatment, prevention policies, and structured referral pathways for the management of these conditions. Screening programs are important for early identification and prompt management. Classical general medicine observations like blood pressure and pulse as well as weight should go back to our epilepsy clinics as part of our routine practice.

Regarding the use of screening tools in everyday clinical practice, only a limited number has been validated in people with epilepsy. For example, the NDDIE, GAD7 have been validated in epilepsy for major depression and anxiety disorders; the SDQ and the Epworth Sleepiness Scale are also supported by lots of data in the people with epilepsy for ADHD and daytime sleepiness and obstructive sleep apnea syndrome but other screening instruments for specific comorbidities are still lacking. However, this does not mean that these tools should not be used until new research is available. For example, QFracture (www.qfracture.org) is a well-known web-based instrument externally validated in independent cohorts to assess the risk of pathological fractures and it is currently considered first line in the UK. This could be used to identify patients requiring further tests in order to prevent osteoporosis and pathological fractures.

These are just some examples of how epilepsy clinics should start integrating multiple assessments to have a proper holistic approach to epilepsy care.

Epilepsy care is changing rapidly, and the study of comorbidities is of crucial importance to our understanding of epilepsy. Not only do they pose questions about associations and causality, biology of diseases and the effects of medications but they also affect our ability to provide the best care to our patients. Continuous research in this area will allow a better understanding of the epilepsies and their management.

Declaration of interests

The author reports personal fees from UCB, Eisai, Bial, Elsevier, outside the submitted work in the last three years; in addition, he also has intellectual property rights with Springer and Elsevier.

Additional information

Funding

This work did not receive any specific funding.