Non-adherence and epileptic emergency—reasons and solutions

The patient is an 18-year-old woman who presented in February 2022 for the first time with three consecutive unclear episodes of nausea, visual hallucinations, subsequent loss of consciousness, postictal vomiting, fatigue as well as an insidious start of cognitive decline with impaired memory and concentration. Electroencephalography (EEG) at a private neurological practice was slightly abnormal, but cerebral magnetic resonance imaging (MRI) was completely normal. The symptoms abated over a few weeks without therapy. She had no preexisting diagnosis or treatment for epilepsy and no family history of epilepsy. A second bout of these episodes occurred in May 2022, which led to hospitalization. While repeated cerebral MRI revealed no pathological changes and the cerebrospinal fluid (CSF) was normal, the EEG showed multifocal epileptic discharges over the parieto-occipital and frontal regions as well as short runs of focal-to-bilateral epileptic discharges. A comprehensive panel of antineuronal autoantibodies associated with autoimmune encephalitis in both the serum and the CSF was negative. Thus, the patient fulfilled the criteria for possible (“seronegative”) autoimmune encephalitis according to the Graus et al. criteria [11], given the subacute onset of working memory decline, altered mental status, the seizures with most likely parieto-occipital onset, and the swift bilateral spread according to the EEG and semiology (visual hallucinations, nausea, and loss of consciousness) along with the exclusion of another etiology. The patient was treated with intravenous (i.v.) high-dose methylprednisolone (500 mg daily for 5 days) and i.v. immunoglobulins (0.4 g per kg body weight daily for 5 days). Antiseizure medications (levetiracetam, 750 mg twice daily, and increasing doses of lamotrigine, up to 2 × 100 mg/day) were started. She improved upon a tapering scheme of oral steroids within the next few months, although memory complaints and rare seizures persisted for about 6 months. Therefore, we performed long-term video-EEG monitoring over 73 h in October 2022, which showed normal background alpha rhythm with signs of drowsiness and bi-temporal-occipital focal slowing. After rapid spread to bilateral and anterior regions, polyspike-wave complexes were observed in the bi-frontal and left central regions; thus, the EEG was still very active and we increased the dosage of lamotrigine to 200 mg twice daily.

Surprisingly, serum levels of lamotrigine and levetiracetam were repeatedly sub-therapeutic for lamotrigine and below detectable range for levetiracetam since October 2022 (Table 1).

The neurologist suspected non-adherence to treatment or altered pharmacokinetics such as increased metabolism.

The concept of medication adherence has evolved thanks to the contributions from psychosocial models. Non-adherence to treatment is not “now or never” but a complex and multifaceted behavior [12]. Non-adherence occurs at different phases (when?) and with different patterns (how?). Medication adherence consists of three consecutive and intrinsically related phases that are initiation, implementation, (or execution) and persistence (Table 2; [13]). Thus, the consequences will be different if a patient is not starting a new medication, not implementing the treatment into daily routine, or not persisting with the prescribed drug. In addition, evaluation of adherence should be repeatedly performed because behavior may change with time.

Although there are myriad adherence patterns and each patient is unique, ten different types of errors have been described while using medications [14], which will be discussed in the following. The first error consists in obtaining a prescription but starting the intake later or never. In this case, it is called “primary non-adherence” [15] and represents the simplest form of non-initiation (i.e., zero use). Second, “medication holidays” means some gaps during the treatment that range from 1 day to several days. Third, the “toothbrush effect” depicts an intensive medication use immediately before or after the medical visit that returns to insignificant use some days after the visit. Taking the wrong medication (fourth) can have dramatic consequences but is generally easily recognized, while overdosing (fifth), underdosing (sixth), random dosing (seventh), and a wrong frequency (eighth) are more difficult to detect. The ninth error, stopping the treatment too early, is equivalent to non-persistence. Finally, patients may take several medications as they think best, which leads to an erratic form of polypharmacy. Patients can make any, from one to all, of the errors during their treatment, and several errors may simultaneously occur with different medications.

Because the overall goal of antiseizure pharmacotherapy is to maintain therapeutic coverage, that is, concentrations within therapeutic ranges, occasionally missing a dose or compensating missed doses by additional doses might result in a variation in concentration levels. The consequences range from loss of effect (resulting in seizures) to overdosing ASM with toxic and severe adverse effects [16]. Thus, determining the phase and the pattern of adherence is crucial in order to establish the adequate intervention needed (Fig. 1).

Approximately half of the newly treated epilepsy patients fail to successfully respond to the initial antiseizure medication [17]. Various terms such as “intractable,” “refractory,” or “drug resistant” have been used to describe the situation that seizures are not being controlled by two ASMs. Drug-resistant epilepsy in its proper sense was defined in 2010 as “the failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug (AED) schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” [18]. Independently of the term used, a prerequisite to any intervention is to elucidate the underlying reasons for sub-therapeutic concentrations or impaired response to an appropriate antiepileptic treatment with ASMs (i.e., at a correct dose and schedule). The reasons for treatment resistance are still poorly understood [19, 20], and research targets mechanisms related to the disease, to the ASM, and to genetics [21]. It is noteworthy that non-adherence is also mentioned in articles investigating pseudo-refractory epilepsy [22]. We suggest categorizing the reasons for failed seizure control into biological (unmodifiable) reasons and into therapeutic and behavioral (modifiable) reasons.

Among the therapeutic factors, special attention should be given to contra-indications due to drug–drug interactions. The interaction check should include the multiple ASMs themselves, also including plant products such as cannabidiol, which is a powerful inhibitor of cytochrome CYP 2C19 (increasing markedly the half-life of the active metabolite of clobazam, desmethylclobazam, and thus, inadvertently leading to increased drowsiness, as an example), and antiviral and immunomodulatory medications, including anti-COVID-19 agents [23]. The list of drug–drug interactions with ASMs is exhaustive [24] and all may influence the pharmacokinetics [23, 25‐27]. However, there are some interactions that are clinically relevant, namely, those mediated by induction or inhibition of drug-metabolizing enzymes [28] or by inhibition of gastrointestinal absorption through modulation of the expression of drug transporters [29]. As a rule of thumb, the interaction is greatest with substances that undergo extensive first-pass metabolism (e.g., itraconazole, indinavir, dihydropyridine calcium antagonists) or with a narrow therapeutic index (e.g., oral contraceptives, oral anticoagulants, immunosuppressants, chemotherapeutic agents [28]). A less clinically important interaction consists in the displacement from protein-binding sites (e.g., phenytoin with valproic acid [28]). Regarding the newest ASMs, particular caution should be taken because our understanding of the mechanisms responsible for their interactions is evolving slowly [27]. In addition, interaction checks should include food, herbal health products, and diet supplements. Only few case reports exist for interactions between Ginkgo biloba and valproic acid, carbamazepine, and lamotrigine [30]; the same is true for glucosamine supplements (at least 1500 mg) with valproic acid [30] and for noni juice fruit with phenytoin [31], for which the exact mechanism of interaction is still unknown [32]. However, because “absence of evidence is not evidence of absence” [33], caution is recommended with the co-administration of alternative medicines especially because patients may use them on a regular basis and over a long time [31].

Among the multitude of individual reasons that exist for not taking medication [9], only a few are modifiable.

Identifying the current modifiable factors of non-adherence is a prerequisite to developing tailored interventions that will encourage adherence to reliable long-term medication use (see Fig. 2). In addition, tailored interventions are likely to have the greatest impact or effect [34]. Among the modifiable causes for non-adherence, forgetfulness, or carelessness are indubitably non-intentional [35]. The distinction between non-intentional and intentional (i.e., a patient’s active decision not to adhere to the therapeutic recommendation) medication non-adherence has been extensively investigated [36]; however, the studies were seldom conducted in light of modifiable factors of non-adherence [37, 38]. Because individuals who take their medicines (and those who do not take their medicines) do it with a health-related intention, all modifiable causes should be categorized as intentional when the behavior differs from the recommendation.

Among the modifiable reasons, we distinguish three categories: the medication management; the beliefs/concerns regarding the disease and medications; and the price of the treatment.

Despite the fact that seizures are often triggered by a cascade of events (e.g., emotional stress, sleep deprivation, alcohol), the most common reason for an epileptic emergency in patients with known epilepsy is related to low levels of ASMs, and thus, unequivocally to non-adherence or to the addition of co-medication that interacts with the ASMs. In a study in the emergency room, missed medication was demonstrated in 38% of patients on the basis of low serum concentration/dose ratios from therapeutic drug monitoring [47], and in 71% of patients with self-reported failure to take the correct dose of their medication [48]. Unfortunately, non-adherence is rarely identified in the emergency setting because patients’ personal medication history is mostly unavailable.

With the emerging evidence of genetic determination of variant alleles in transporter genes or cytochrome families, new reasons for non-response to antiseizure pharmacotherapy are now accessible [49]. Today, the evolving field of pharmacogenetics (PGx) addresses the genetic variations that are important for the metabolism of one specific substance in humans. These PGx tests are used to predict how an individual may respond to a specific pharmacotherapy. The evidence regarding the effect of genetic variations on clinical response is sufficient for only a few ASMs and mainly concerns toxicity (Table 3). For example, adverse effects and toxicity (Stevens–Johnson syndrome) are to be expected with lamotrigine and carbamazepine in patients with the HLA‑B variant*15:02, which is more frequently prevalent in South-East Asia, while the HLA‑A variant 31:01 is more prevalent in countries of Northern Europe [50, 51]. High-level evidence for genetic variations leading to alterations in pharmacokinetic metabolism currently exists only for phenytoin. Therefore, most questions about optimizing antiseizure therapies cannot be answered by PGx analysis alone [52, 53]. The PGx information might contribute to answering specific questions in particular cases only.

The patient in our case is a young woman with possible autoimmune encephalitis and recovery of seizures and cognitive decline 1 year after onset of symptoms. She had no family history of epilepsy and was started on a dual ASM treatment with twice daily intake and the halving of one tablet, which are clear barriers to high adherence. The patient has obtained regular and sufficient refills from the pharmacy. She did not report side effects from the ASM, which may contribute to poor adherence. However, during a medical visit, it became evident that the patient had an aversion to swallowing the large levetiracetam tablets and skipped doses. A liquid formulation was prescribed and dispensed. At a visit in February 2023, serum concentrations were still below the therapeutic range, indicating potential non-adherence. PGx testing was considered to investigate potentially altered pharmacokinetic metabolism of lamotrigine and levetiracetam. However, after consulting with a clinical pharmacist, no PGx testing was performed because known genetic variations cannot currently explain sub-therapeutic concentrations of the two substances.