Governance of the clinical pathway and management of the patient suffering from epilepsy and drug-resistant epilepsy

Disease characteristics

Epilepsy (E) is a chronic neurological disease diagnosed according to the criteria by the International League against Epilepsy (ILAE) if one of the following conditions occurs: (1) At least two unprovoked (or reflex) seizures occurring >24 hours apart; (2) One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) Diagnosis of an E syndrome (1).

An epileptic seizure is a brief and transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity (1). Epileptic seizures can be classified as acute symptomatic seizures when they have a strict temporal association with a transient and acute brain insult, which can be of metabolic, toxic, structural, infectious or inflammatory origin (2), and as unprovoked seizures when an enduring cerebral predisposition to generate epileptic seizures can be identified (1). Therefore, both types of epileptic seizures can be defined considering the reversibility of the underlying responsible cause and the temporal relationship with the acute brain insult (1,2). For example, a cortical dysplasia or a brain tumour may permanently alter specific neuronal networks, predisposing a particular area of the brain to develop seizures; so, in these circumstances, it is right to talk about unprovoked seizures.

The classification of a remote epileptic seizure, which is symptomatic of E, can be made according to the onset of the abnormal neuronal activity, which can be generalized – if the abnormal electric discharge involves simultaneously both cerebral hemispheres from the beginning – or focal – if the discharge originates within a specific neuronal network limited to one hemisphere and may (or may not) rapidly engage the contralateral hemisphere (3). The clinical presentation of seizures can be characterized by impaired or unimpaired awareness/consciousness and presence or absence of more or less diffuse motor phenomena (3).

E is a medical condition in which epileptic seizures can be the main but not the only symptom (4). In fact, along with seizures, other signs or symptoms (neurological, psychiatric or involving other organs and apparatus) can be identified (4), as in the case of epileptic encephalopathies or developmental encephalopathies, which can be defined as electro-clinical syndromes with broad genetic spectrum in which E often combines with cognitive and behavioural alterations, electroencephalographic (EEG) abnormalities and other possible neurological or systemic manifestations (5).

The most recent classification of E elaborated by the ILAE has included the classificatory axes into the aetiologies of E, identifying six groups: structural, genetic, metabolic, infectious, immune and unknown (4). An aetiology does not rule out another one; in fact, a patient suffering from tuberous sclerosis carrying characteristic brain lesions and presenting with seizures has both structural and genetic aetiologies. The category ‘unknown aetiology’ indicates that we are not able to identify the exact cause of the disease, but this gap will hopefully be filled in the future through the improvement of the available diagnostic tools or the discovery of new ones (6). The neurodegenerative aetiology has not been nosologically defined as another possible aetiology of E yet. However, considering the increasing scientific evidence about the existence of a bidirectional relationship between E and neurocognitive disorders in the elderly (i.e. Alzheimer’s disease), the involvement of neurodegenerative processes into epileptogenesis should be further analysed and studied (7-9). There is an age-dependent variability of the aetiology of E (10). Once the diagnosis of seizure or E has been made, the second step for the clinician should be the identification of the underlying aetiology. Recognizing the responsible cause is fundamental because it allows diagnostic as well as prognostic accuracy, other than the identification of the best therapeutic approach possible for that specific patient.

Anti-seizure medicines (ASMs) are a milestone in the treatment of E. Nevertheless, even with a large number of therapeutic alternatives, about 30% of people with E continue to have uncontrolled seizures despite different and rational pharmacological associations, belonging to the pharmacoresistant portion of people with E (11). ILAE defined drug resistance as ‘failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom’ and considered this a testable, working hypothesis to be refined with time (12). It is known that after the failure of two appropriate and adequately chosen ASMs the possibility to have a clinically successful response with another ASM drastically decreases (13).

From a therapeutic point of view, a part of people with focal types of E could undergo surgical treatment. Aim of E surgery is to obtain complete seizure control in the absence of neurological complications, trying to eliminate the potential cognitive, psychological and socio-professional consequences caused by seizure persistence and/or chronic anti-seizure therapy (14). Before surgical treatment, the patient should be thoroughly studied and the evaluation should be directed to the identification of the so-called epileptogenic zone, the part of the brain from which the abnormal neuronal discharge originates, which should be possibly removed without consequences. Pre-surgical evaluation requires specific equipment and qualified medical staff. In the last decades, E surgery has become a more concrete therapeutic option, and a safer and less invasive surgical approach is now possible thanks to advances in structural and functional neuroimaging and video EEG monitoring, along with the simplification of invasive electrode implantation and the availability of new neurosurgical tools such as neuronavigation, intraoperative echography, endoscopic techniques and new resective surgical approaches (thermocoagulation, laser ablation, etc.) (15).

Currently, patients who may benefit from surgical treatment of E (as long as the resection of the epileptogenic zone is possible and without sequelae) should have the following prerequisites:

• Drug-resistant E;
• Patients with controlled seizures thanks to ASMs, but suffering from unbearable treatment-related adverse effects;
• Patients without drug-resistant E presenting with structural brain lesions, such as brain tumours, which should be further studied because of their high risk of determining pharmacoresistant E (15).

The ‘ideal’ candidate is a person with focal E, a clearly identifiable epileptogenic zone located outside eloquent cortical areas (15).

In case of drug-resistant patients who cannot undergo or refuse surgical treatment of E, there are other ‘palliative’ therapeutic options available, between them neuromodulation (vagus nerve stimulation, deep brain stimulation, etc.) (16).

Recent biotechnological progress and the rapid spread of information about the biological basis of some forms of E led to the so-called ‘precision medicine’, which is an innovative approach to discovering and developing therapies which can give better clinical outcomes to patients, by integrating clinical and molecular information to understand the biological basis of disease (17). In this field some goals have been achieved, even though there is a long way to go yet. For example, it has been elucidated that some epileptic and neurodevelopmental encephalopathies are caused by genetically determined deficits of some molecular transporters, as in GLUT-1 deficiency (18), or by altered enzymatic functions, as in pyridoxin-dependent encephalopathies (19). The earlier a specific substitutive therapy is started, the better could be the outcome for the patient.

Psychosocial impact

Many decades have passed since the famous epileptologist William Gordon Lennox (1884-1960) said that the person with E suffers more for its social consequences than for the disease itself and, in an editorial often cited in the British Medical Journal, the neurologist Rajendra Kale wrote, ‘The history of epilepsy can be summarised as 4.000 years of ignorance, superstition, and stigma followed by 100 years of knowledge, superstition, and stigma’ (20). Even though significant progress has been made in the last few years about the understanding of biological and molecular basis of E and despite the availability of multiple therapeutic options, people with E continue to be victims of discrimination and stigma (21). The origins of stigma are deep and resistant and, in our opinion, trying to understand why they exist could help in the management of E.

Intuitively, the impairment of awareness/consciousness happening during an epileptic seizure can increase the risk of traumas, fractures, accidents, burns and drowning for the patient, and this could happen everywhere, at home, at school, in the street or in the workplace (22). The risk of these E-related risks has a burden on patients and caregivers, especially parents of children with E, leading to a progressive inactivity (i.e. physical inactivity), dependence and social isolation (23). When seizures are characterized by impaired awareness/consciousness but do not provoke violent falls to the ground, there is surely a lower risk of physical injuries for the person, but even so the patient does not have control of him/herself in relation to the environment, compromising educational, professional and social activities, such as driving. Limitations on driving can influence employment, social interactions and personal independence, representing one of the biggest issues for patients with E (24). That being said, the global situation of a patient with E includes not only seizure recurrence but also higher risk of anxiety, depression, suicide, cognitive impairment and systemic diseases, such as obesity (25). This complex clinical scenario leads to psychological consequences (impairment of self-esteem) and psychosocial implications (lower possibility of having a partner, low-grade educational goals, unemployment or unqualified jobs, low income and stigma) (25).

On the other hand, motor phenomena that often accompany seizures scare witnesses of these events, especially those not familiar with the disease, worsening the burden of the stigma over people with E.

E is a burdensome disease because of seizure recurrence, chronic anti-seizure treatment and E-related somatic and psychological consequences (26). Compared with other neurological disorders, in men and women, E has both the highest rates of standardized disability-adjusted life years (DALYs) – the measure combining the time lost for premature death and the time lived in suboptimal conditions or in a condition of disability related to a specific disease – followed by migraine and Alzheimer’s disease. E accounts for >13 million DALYs (27).

Based on these considerations, in November 2020, the 73rd World Health Assembly (WHA) adopted a resolution to develop an intersectoral global action plan on E and other neurological diseases. The action plan aims to reduce and eliminate preventable deaths caused by E and other neurological disorders, to improve access to promotion, prevention, management and care services, decreasing stigma and discrimination and protecting the human rights of people with neurological disorders. This action plan promotes physical and mental health, prevention, early diagnosis, assistance, treatment and rehabilitation, along with social, economic and educational needs and necessity of inclusion for people with E or different neurological diseases and their family (28).

T0: the diagnosis

Epileptic seizures are brief and transient episodes characterized by recurrence of signs/symptoms often resembling other paroxysmal events, so that the differential diagnosis can be challenging. The risk of misdiagnosis is still very high if we consider that about 20% of patients presenting to centres specialized in E surgery have an erroneous diagnosis or suffer from seizure recurrence due to wrong therapeutic management (33). This initial diagnostic mistake is the starting point of a diagnostic and therapeutic odyssey with increasing healthcare costs for the national sanitary system (34), other than E-related psychological and psychosocial consequences (26). This scenario is quite common because the initial diagnosis of E is often made by a clinician without specific education in E.

T1: the diagnosis of pharmacoresistance

After the failure of the second appropriately chosen and adequately used ASM, according to ILAE guidelines, the patient is considered drug-resistant (12), even though this is a dynamic condition that can change over time even for the same person. As mentioned earlier, the chances of achieving seizure freedom drastically diminish with subsequent therapeutic approaches (13), so in this exact moment it is mandatory to revise the clinical history of the patient, taking into account the possibility of a surgical approach. E surgery, when possible, can give optimal outcomes with benefit for the patient and the healthcare system.

E surgery should be immediately considered in front of a patient with focal seizures, in the absence of cognitive or behavioural disabilities and with an epileptogenic zone located outside eloquent cortical regions (15).

In this way, the right to have the best therapeutic approach in the least time possible would be guaranteed to the patient, avoiding the psychological and social consequences of drug-resistant E (26).

Hypothesis of virtuous governance: to verify in the less time possible if the patient could be a candidate to surgical treatment of E.

T2a: the surgical management of drug-resistant E

Once the criteria for the inclusion of the patient in the pre-surgical evaluation are fulfilled, in the majority of cases, a video EEG is required. So, the presence of specific equipment and specialized medical and paramedical staff completely dedicated to the ‘long-term monitoring’ of EEG is essential for the structure where the patient has been sent.

In the case of positive outcomes after ‘long-term’ registration, the patient will be guided to hyper-specialized centres dedicated to E surgery.

The possibility of ‘long-term monitoring’ of EEG – and the subsequent E surgery as well – should be guaranteed to the patient, even though this is not an ubiquitous and homogeneous condition in Italy.

Hypothesis of virtuous governance: early access to E surgery increases the number of centres completely dedicated to increasing surgical treatment of E.

T2b: the medical management of drug-resistant E

This is the case of people with drug-resistant E who refuse or cannot/did not benefit from E surgery.

People with drug-resistant E and rare and complex epilepsies are burdened not only by seizure recurrence but also by different and multiple comorbidities, which require specific interventions and a multidisciplinary approach with the involvement of various medical figures as geneticists, psychologists, psychiatrists, gynaecologists and physiatrists. Moreover, chronic diseases and E in particular affect not only the single individual but also caregivers. Intellectual disability and behavioural alterations associated with E add an additional burden on caregivers’ shoulders in terms of costs, responsibility of care, centralization of the family’s attention and social isolation (36).

In our opinion, the most appropriate form of management in these cases is represented by the so-called ‘complex and coordinated ambulatorial programmes’, which are a group of medical services finalized to specific diagnostic and therapeutic goals, tailored to the patient and included in the regional list of ambulatorial specialties. These programmes take place in the morning, requiring about half a day, avoiding economic expenses to patient and caregivers and hospitalization, guaranteeing a better quality of life and a reduction of healthcare costs.

Also in these cases, only highly specialized centres with specific equipment and trained medical and paramedical personnel can adopt this kind of multidisciplinary programmes, where the cooperation between different specialists is a fundamental requirement.

The multidisciplinary approach in a selected setting dedicated to E and its comorbidities can improve the quality of care (i.e. with the access to new treatments in compassionate programmes or the simplification of complex and often useless polytherapies) and the quality of life for the patient and his/her family, reducing the number of hospitalizations or accesses to emergency settings.

In patients with drug-resistant E, ‘palliative’ and non-pharmacological approaches can be adopted, such as vagus nerve stimulation, which can reduce seizure frequency and intensity, improving the quality of life (16).

Hypothesis of virtuous governance: create highly specialized centres where trained and expert personnel could guarantee to the patient and his/her family a multidisciplinary approach, especially in case of rare and complex epilepsies.