When people with epilepsy are hospitalised for medical or surgical conditions, they may be unable to take their home antiepileptic drugs (AEDs). Such ‘nil by mouth’ people with epilepsy require alternative AED regimens to prevent breakthrough seizures. Here, we describe several strategies for maintaining seizure control in patients with epilepsy who have medical or surgical contraindications to their home oral regimens. These strategies include using non-pill oral formulations, using an intravenous formulation of the patient's home AED(s), using a benzodiazepine bridge and/or using alternative intravenous AED(s) when there are no intravenous formulations.
- ANTIEPILEPTIC DRUGS
- INPATIENT NEUROLOGY
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When people with epilepsy are hospitalised, their problems with altered consciousness, dysphagia, vomiting, impaired enteral absorption or their perioperative ‘nil by mouth’ status may prevent them from taking their home antiepileptic drugs (AEDs).1 Breakthrough seizures may delay necessary treatments and procedures or result in medical complications, such as aspiration pneumonia, and can even progress to status epilepticus. Here, we describe several strategies that may help to maintain seizure control in people with epilepsy who cannot take their usual oral antiepileptic medications during an elective or emergent hospitalisation. Unfortunately, there are no data comparing different strategies for managing AEDs in this setting, and no evidence-based guidelines.
The strategies we discuss are therefore presented as a framework within which physicians can develop individualised treatment plans for each patient, taking into account patient characteristics and medication availability. Formularies vary from country to country and between hospitals in the same country, so the neurologist must be familiar with each hospital's AEDs and their available formulations. When treating a patient with epilepsy who cannot take oral medications, it is best to contact the patient's primary epileptologist if possible, in order to determine which AEDs the patient has responded to and tolerated in the past, depending on the particular epilepsy syndrome.
People who cannot swallow pills
Some people cannot swallow whole pills because of inattention or oropharyngeal pathology, but have normal gastrointestinal absorption and can therefore tolerate other enteral formulations of AEDs. Some AEDs are available as a solution, suspension, elixir, sprinkle, chewable tablet, dispersible or disintegrating tablet, or capsule that can be opened (see table 1).2 Alternatively, the home tablet formulation may be crushed and administered after mixing with food or liquids (see table 1). Extended-release formulations of AEDs should never be crushed, but can be converted to immediate-release formulations, which can generally be crushed. When patients cannot consistently ingest an enteral formulation of an AED, we recommend using one of the strategies described below in order to avoid missed or incomplete doses.
Case reports and small case series have described successful rectal administration of several AEDs. Some benzodiazepines are available in rectal formulations, including diazepam (and clobazam in the UK). A diluted oral solution of valproate, an oral suspension of carbamazepine, and intravenous lorazepam have been administered rectally for maintenance AED therapy.3 Valproate and carbamazepine have also been administered as suppositories, but these are not commercially available.3
Patients who are nil by mouth
Patients who are nil by mouth before a surgical procedure or for bowel rest require conversion to an intravenous AED regimen. We propose three potential strategies in this scenario.
Strategy #1: oral-to-intravenous conversion of the same drug
When an intravenous formulation of the patient's home AED is available, this is the most straightforward solution. AEDs with currently available intravenous formulations are acetazolamide, clonazepam, lacosamide, levetiracetam, phenobarbital, phenytoin and valproate (table 1). All are dose-equivalent between oral and intravenous formulations, with the exception of extended-release oral formulations of valproate. Extended-release doses of valproate sodium are 8%–20% higher than standard doses of valproate. When converting from extended-release to intravenous formulation, physicians in the United States commonly reduce the dose accordingly.
Because of the long half-life of delayed-release valproate, people who take this medication two times per day should be prescribed the same total daily dose when receiving intravenous valproate, but it should be given in three or four divided doses (every 6–8 hours). Similarly, patients who take extended-release phenytoin capsules once daily should be prescribed the same total daily dose when receiving intravenous phenytoin, but it should be administered in three or four divided doses (every 6–8 hours).
There will be more intravenous AED options available in the near future. Intravenous brivaracetam was approved in both the European Union and the USA as an adjunctive therapy for partial-onset seizures in early 2016. Intravenous carbamazepine has completed phase III trials but has not yet been approved, although it is currently under review by the Food and Drug Administration in the USA.
Strategy #2: a benzodiazepine bridge
A benzodiazepine bridge allows clinicians to ensure seizure control without risking the potential adverse effects or potential need for slow up-titration of a new AED. Several commonly prescribed benzodiazepines are available in alternative enteral formulations, and three (lorazepam, diazepam and clonazepam) are available in intravenous formulations (see table 2).5 ,6 Midazolam is also available in an intravenous formulation, but it has a short duration of effect and requires intensive care unit management. It is also the only benzodiazepine that may reliably be given intramuscularly in the setting of status epilepticus, if intravenous access is unavailable. Diazepam is also available in a rectal formulation, but this too is typically reserved for acute seizures.
When using the strategy of a benzodiazepine bridge, we generally give 1 mg of intravenous lorazepam three times per day (see box 1). Patients who have previously been exposed to benzodiazepines may require higher doses. While benzodiazepine bridges avoid the potential toxicity of a new AED, they can result in breakthrough seizures (if underdosed) or respiratory depression (if overdosed). Benzodiazepine bridges should not be used in elderly people or in anyone prone to delirium, in patients who will be nil by mouth for more than 2 days or as monotherapy in patients who take more than one AED. In these cases, an intravenous AED should be used instead (see strategy #3).
Case example #1
A 57-year-old woman with epilepsy underwent a laparoscopic sleeve gastrectomy. She had been diagnosed with epilepsy 25 years earlier after presenting with a generalised tonic–clonic seizure. She started treatment with carbamazepine and had good seizure control. She briefly took phenytoin during her pregnancies. On admission, she was taking an extended-release carbamazepine, 400 mg two times per day, and had not had a seizure in 15 years. She reported that she rarely missed her evening dose and did not have breakthrough seizures when doing so.
She was kept nil by mouth the night before her gastrectomy, and the surgical team planned to allow her to resume clear liquids and oral medications the day after the surgery. During her hospitalisation, she was treated with 1 mg of intravenous lorazepam every 8 hours. She restarted her home carbamazepine dose within 36 hours. She remained seizure-free throughout.
Strategy # 3: replacement with one or more intravenous AEDs
In a person who is taking one or more AEDs that do not have intravenous formulations, it is necessary to substitute with at least one intravenous AED. If the patient is taking one AED or low doses of two AEDs, substitution with intravenous AED monotherapy can be considered (see box 2). We generally use intravenous levetiracetam since it is usually well tolerated (especially if only being used briefly as in this setting), and has very few pharmacokinetic drug–drug interactions.
Case example #2
An 85-year-old man with left-sided temporal lobe epilepsy presented with dark stools and was admitted to the medicine service for gastrointestinal bleeding. Before admission, his seizures were well controlled on lamotrigine 50 mg two times per day. He initially tolerated pills and so continued his home regimen. Three days later, he developed an ileus, and so a nasogastric tube, without suction, was placed. Lamotrigine was delivered through the tube at his usual dose for 1 day. The next day, however, on the consulting neurologist's recommendation, lamotrigine was stopped due to concern for poor absorption secondary to ileus and was replaced with intravenous levetiracetam 500 mg two times per day. His ileus resolved and he restarted his home regimen 2 days later, having remained seizure-free throughout.
Phenytoin and valproate may also be considered, but drug–drug interactions limit their use in hospitalised patients who are often taking multiple medications. For example, the serum concentration of valproate is lowered by carbapenem antibiotics, and both valproate and phenytoin increase the anticoagulant effect of warfarin. Phenytoin is metabolised in a dose-dependent manner in which the half-life increases with increasing serum concentration, and it is highly protein bound, causing free phenytoin levels to fluctuate with albumin levels, which are often low in hospitalised patients. Thus, when using phenytoin, it is appropriate to consider measuring both total and free levels.
The intravenous dose of the substituted AED(s) should be roughly proportional to the home dose of the oral AED(s) being replaced, although there is no direct conversion between AEDs. For example, someone taking a low dose of lamotrigine (eg, 50–100 mg two times per day) could be treated with a low dose of intravenous levetiracetam (eg, 500–750 mg two times per day), whereas someone taking a higher dose of lamotrigine (eg, 250 mg two times per day) could be treated with a higher dose of intravenous levetiracetam (eg, 1250–1500 mg two times per day).7
If a patient is taking high doses of two or more AEDs, or low doses of three or more AEDs, clinicians should consider substitution with two intravenous AEDs. We generally use levetiracetam and lacosamide, unless there is a contraindication to one of these medications, or the home regimen includes a different AED that is available intravenously (see box 3). Both medications have few drug–drug interactions and minimal adverse effects. However, lacosamide can cause prolongation of the PR interval, and therefore should not be used in patients with a PR interval >200 ms, and should be used cautiously in patients with cardiac disease.
Case example #3
A 52-year-old woman with epilepsy of unknown cause presented with abdominal pain and was admitted to the general surgery service with a diagnosis of cholecystitis. Before admission, her seizures were well controlled on phenobarbital 60 mg daily and carbamazepine 200 mg two times per day. She underwent a cholecystectomy, and had a nasogastric tube placed for gastric suction postoperatively, preventing the administration of enteral medications. Her phenobarbital was converted to the intravenous formulation. Carbamazepine was stopped and was replaced with intravenous levetiracetam 500 mg two times per day. Her postoperative course was complicated by hypoxaemia and she remained nil by mouth for 10 days. She remained seizure-free throughout and restarted her home regimen on discharge.
Valproate and phenytoin are potential alternatives if lacosamide is not available or is not tolerated, but both medications have extensive drug–drug interactions, as discussed above. A phenytoin and valproate combination therapy should be avoided as phenytoin induces valproate metabolism while valproate inhibits phenytoin metabolism; also, both AEDs are highly protein bound, with valproate displacing phenytoin from plasma protein-binding sites. As a result of these complex interactions, the levels of both medications are unpredictable and frequently fluctuate. When the home regimen includes an oral benzodiazepine such as clobazam (box 4), it may be replaced with an alternative benzodiazepine (see table 2).
Case example #4
A 26-year-old woman presented with a small bowel obstruction 7 months after undergoing a right-sided anterior temporal lobectomy for refractory epilepsy. She was admitted to the general surgery service. She could not tolerate oral medications due to vomiting. A nasogastric tube was placed for gastric suction, preventing the administration of enteral medications.
She had been diagnosed with epilepsy 5 years earlier after presenting with several episodes of altered consciousness. She had stopped taking several antiepileptic medications, including rufinamide, perampanel, topiramate, levetiracetam, zonisamide and oxcarbazepine, because of breakthrough seizures or adverse effects. Of note, she stopped taking levetiracetam because of low mood rather than breakthrough seizures. Following her epilepsy surgery, her seizures were initially well controlled on lacosamide 200 mg two times per day and lamotrigine 200 mg two times per day. She had two breakthrough seizures a few months later and clobazam 10 mg every evening was added to her regimen.
During her hospitalisation, her lacosamide dose was converted to the intravenous formulation. Lamotrigine was stopped and was replaced with intravenous levetiracetam 1000 mg two times per day. Clobazam was stopped and was replaced with intravenous lorazepam 0.5 mg three times per day. She had one breakthrough seizure (an episode of altered consciousness followed by confusion) on hospital day 2. She restarted her home regimen on hospital day 4 and remained seizure-free thereafter.
Hospitalised patients with epilepsy who cannot receive their home oral AED regimen present a challenge for the consulting neurologist. Using the strategies described above, these patients can be treated with alternative regimens in order to reduce the risk of breakthrough seizures during admission.
When managing an inpatient with epilepsy who is nil by mouth, always contact the patient's primary epileptologist if possible, in order to determine the ideal medications for their epilepsy syndrome.
For people with well-controlled epilepsy on one AED who will be nil by mouth for <48 hours, a benzodiazepine bridge (eg, 1 mg of intravenous lorazepam three times per day) can be considered unless the patient is elderly or otherwise prone to delirium.
For people taking a high dose of a single AED or low doses of two AEDs without intravenous formulations, clinicians should consider substituting with one intravenous AED (eg, levetiracetam).
For people taking high doses of two or more AEDs or low doses of three or more AEDs without intravenous formulations, clinicians should consider substituting with two intravenous AEDs (eg, levetiracetam and lacosamide).
Contributors AMB drafted and revised the manuscript. JWL, PK and ALB revised the manuscript.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed. This paper was reviewed by Mark Manford, Cambridge, UK, and Sanjay Sisodiya, London, UK.