Seizures in palliative care

History and physical examination

Mr J.K. does not relate any recent changes in his medications except for the decrease in dexamethasone during the past 2 weeks and the addition of hypoglycemic agents 3 weeks ago for the glucose intolerance he developed since taking the steroid. He has had a declining appetite during the past 14 days. He has been having some left-sided paresis, which preceded the diagnosis of the cerebral tumours, but it seems to have worsened since last night. This finding is confirmed on the physical examination.

When a patient develops a seizure, a prompt history and physical examination are useful to determine the cause. A structural cause can be suspected if there was an aura before the seizure, if the seizure was focal, if there were versive eye movements during the seizure, or if the physical examination revealed focal neurologic findings. These latter neurologic findings might disappear within a few hours after the seizure event. A review of the patient’s medications should be conducted; for example, determine whether the patient is taking drugs that can lower the seizure threshold, experiencing withdrawal from benzodiazepines or alcohol, or weaning from steroids, or has subtherapeutic levels of anticonvulsants. Rarely, a patient might develop severe opioid-induced neurotoxicity accompanied by convulsions. Investigations might be warranted; a complete blood count and a biochemical workup might reveal further potentially reversible anomalies. Cerebrospinal fluid can be cultured for infectious causes and be submitted for cytologic examination.² Radiologic investigations such as computed tomographic scan with contrast or preferably magnetic resonance imaging of the brain might reveal a previously unsuspected mass, leptomeningeal disease, progression of brain tumours, or an ischemic or hemorrhagic stroke. Some strokes are secondary to cancer complications or to its treatments (hypercoagulable or hypocoagulable states, tumour cell embolization, occlusion of cerebral arteries, etc).^1,2 An electroencephalogram is warranted if there is the suspicion of subtle seizure activity; however, normal electroencephalogram results will not completely exclude such a diagnosis.¹ Investigations might reveal more than 1 cause of seizures.¹

Prophylaxis

Anticonvulsant prophylaxis is not recommended in patients with brain tumours, whether primary or metastatic, if the patient has never had any seizures. This is because of the relatively low risk of developing convulsions for most tumours, and the considerable potential burden of antiseizure side effects (drug-drug interactions, sedation, cognitive impairment, etc). However, brain metastases from melanoma, choriocarcinoma, renal cell carcinoma, thyroid papillary cancer, and cancer of the testis might be exceptions, as these cancers might have a higher risk of causing seizures owing to their increased risk of bleeding.^1,5 A small study by Forsyth et al⁴ did not show any benefit of seizure prophylaxis, as patients still developed convulsions due to tumour progression or subtherapeutic levels of anticonvulsants on the same order as those patients not taking prophylaxis. Patients should take dexamethasone before, during, and immediately after cerebral radiotherapy to prevent the edema secondary to acute radiation toxicity, which could otherwise provoke seizures.¹

Treatment

The treatment of seizures will vary according to the frequency of the convulsive episodes, the duration of each episode, and whether there is a reversible cause. Indeed, a first-time seizure with a reversible cause does not require long-term anticonvulsants. On the other hand, a first episode of seizure in a patient with a brain lesion should warrant the institution of long-term anticonvulsants. When this lesion is a known brain tumour (primary or metastatic) and no other reversible cause of seizure activity has been identified, the institution or increase in dosage of a steroid, such as dexamethasone, could be considered as the first-line treatment alongside long-term anticonvulsant treatment.^5,6 If the brain tumour, whether primary or secondary, can be excised surgically, then anticonvulsants might be weaned off after surgery.⁵

If patients require long-term anticonvulsants but are candidates for further chemotherapy, then institution of antiseizure medications with little risk of interaction with the chemotherapeutic agents should be considered. These include levetiracetam, gabapentin, lamotrigine, topiramate, and pregabalin, as they do not induce cytochrome P450 activity.² Enzyme-inducing medications to avoid include phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and topiramate.²

Table 2^3,5 shows the anticonvulsants usually prescribed for partial and generalized seizures. Table 3^3,5 presents the starting doses, therapeutic doses, and side effects of these anticonvulsants. Moribund patients will need to have their usual anticonvulsants changed when the oral route is lost; then the choices are to give medications through sublingual (SL) administration, such as with lorazepam (0.5 to 1 mg every 8 hours); per rectum (PR) with diazepam (10 to 20 mg twice a day), carbamazepine, valproic acid, or phenobarbital (check dosing with a pharmacist)^3,7; or subcutaneous (SQ) administration with midazolam (30 to 60 mg per 24 hours in a continuous infusion), lorazepam (0.5 to 1 mg every 8 hours), or phenobarbital (200 to 600 mg per 24 hours in a continuous infusion or divided doses).

Status epilepticus

Status epilepticus has traditionally been defined as either seizure activity, convulsive or nonconvulsive, lasting longer than 30 minutes, or 3 episodes without return of consciousness within a 30-minute span.^5,6 It carries a mortality risk of 11% to 34%,³ with acidosis, rhabdomyolysis, and cerebral damage as further complications. With a prolonged convulsive episode, neuronal injury will make pharmacoresistance more likely and anti-convulsants less effective.^5,8 Because the probability of spontaneous resolution of the seizure decreases with time, treatment of status epilepticus should be instituted when a convulsion lasts 5 minutes or more. The treatment might vary according to the patient’s location: home care, hospice, or hospital.

In hospital, intravenous (IV) access, blood pressure monitoring, and electrocardiogram can be the routine of the initial handling of status epilepticus. Patients should be positioned in such a way that they cannot hurt themselves; airways should be maintained; and supplemental oxygen should be provided as necessary. In a palliative care population, it is not always possible to obtain venous access and medications will be given by an alternate route, mostly by SQ, SL, intranasal, or PR administration. It is also not always indicated to have such aggressive monitoring, which might be the case on a palliative care unit or in home care.

In all settings, lorazepam is the drug of choice,^7,9 for its speed of activity (3 minutes via IV administration⁵), duration of effectiveness (8 to 24 hours⁵), and ease of administration. Dosage recommendations vary, but a 2-mg dose can be given by IV, SQ, SL, or PR administration,⁷ and repeated 10 minutes later if the seizure continues. Alternatively, administer 10 mg of diazepam PR or by IV and repeat every 5 minutes until it is effective—a maximum total dose of 40 mg^3,7 could be used. Midazolam is also a very good alternative, 5 to 10 mg^3,7 either IV or SQ, and possibly by buccal or intranasal (0.2 mg/kg)³ administration as some research seems to show.⁹ Midazolam could be repeated every 15 minutes up to a total of 3 times.³ At this step, some would suggest the simultaneous initiation of IV phenytoin.³ Others would recommend phenytoin only if there is no response to the benzodiazepine.^5–7 The phenytoin dose is 15 to 20 mg/kg every 24 hours, at a rate not exceeding 50 mg per minute.^5–7 Another choice of anticonvulsant at this third step could be phenobarbital. Phenobarbital carries a risk of respiratory failure, especially after the use of benzodiazepines.^5,6 The phenobarbital dose is 10 to 15 mg/kg infused at a rate of 100 mg per minute,⁷ for a maximum total dose of 1 g. Alternatively, 20 mg/kg of phenobarbital infused at a rate of 60 mg per minute has also been recommended.⁵ Phenobarbital can also be given by SQ administration,³ which makes it easier to use in a hospice or home-care setting. If the seizure is refractory, persisting despite the use of 2 or 3 different anticonvulsants, the recommendation is intubation and transfer to the intensive care unit for treatment with propofol or pentobarbital,^3,5,7,8 should the patient’s prognosis and goals of care allow for aggressive treatment.

A differential diagnosis of status epilepticus should include syncope, transient ischemic attacks, arrhythmia, Munchausen syndrome, and other psychiatric disturbances, parasomnias, and deliriums.⁵ Another complicating factor for diagnosing status epilepticus is the existence of nonconvulsive partial complex status epilepticus. These seizures are more often secondary to metabolic disorders, presenting as confusion that might be continuous or recurring, with partial complex seizures and recovery of consciousness between episodes—the entire status lasting 1 to 10 days. Nonconvulsive partial complex status epilepticus might resemble delirium with automatisms or psychotic behaviour or affective changes. Unlike convulsive status epilepticus, it does not lead to cerebral damage and therefore its treatment can be more progressive.⁵