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Address correspondence to: Stefan Lorenzl, MD, Interdisciplinary Center for Palliative Care, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany.
Nonconvulsive status epilepticus (NCSE) is rarely considered as a cause of confusion in terminally ill patients. The clinical presentation varies from altered mental status to coma, without visible convulsions. Electroencephalogram is the most important diagnostic tool to identify epileptiform activity. Treatment should be initiated following a stepwise model, avoiding intubation and transfer to the intensive care unit. Although mortality rates are high, in some patients NCSE can be reversed by treatment. NCSE should be considered in a differential diagnosis of all terminally ill patients with sudden mental status changes. We present two cases and discuss treatment options and the borders of therapy.
Epileptic seizures are typically brief and self-limited because of endogenous inhibitory mechanisms. In contrast, nonconvulsive status epilepticus (NCSE) is characterized by progressive sequential or simultaneous failure of these endogenous anticonvulsant barriers. It usually does not cease without therapeutic intervention. NCSE is a diagnostic and therapeutic challenge. Clinical symptoms may include only altered mental status or behavior without convulsive activity. The treatment options in a palliative care setting are limited, if admission to the intensive care unit is to be avoided.
There are many reasons for terminally ill patients to develop a status epilepticus. Besides primary brain tumors and brain metastases, metabolic changes may be the most common underlying reasons. NCSE has been reported in about 6% of patients with systemic cancer without evidence of central nervous system (CNS) involvement and in up to 20% of patients with primary brain tumors or metastases.
Although epileptic seizures are common in patients with brain tumors or metastases, little is known about the incidence and outcome of status epilepticus in patients on palliative care units. In this article, we describe two cases of NCSE in the palliative care setting, and review the clinical and diagnostic criteria as well as treatment options for terminally ill patients with NCSE.
Case Reports
Case 1
A 53-year-old patient with a multifocal astrocytoma was admitted to the palliative care unit because of progressive personality changes and mild aphasia with anomia. Focal epileptic seizures were known and he was already treated with lamotrigine. Three days after admission, the patient showed an acute confusional state, with sudden onset of global aphasia and tendency to leave the hospital. A computed tomography (CT) scan did not show any change and laboratory values were still in normal range. Therefore, NCSE was suspected and an electroencephalogram (EEG) was done, which showed a left temporal status pattern (Fig. 1). Initially, the seizure activity was successfully interrupted with intravenous (IV) lorazepam up to 4 mg. The patient was subsequently treated with lorazepam and levetiracetam orally, and NCSE ceased after one day of treatment. The patient could be discharged home and died at home four weeks later without recurrence of NCSE.
Fig. 1Figure shows parts of the EEG of the two patients described in the case reports. In Case 1, frontal epileptic activity is seen, and in Case 2, left temporal spike wave complexes indicate seizure activity.
A 52-year-old patient with renal carcinoma and brain metastases was admitted to the palliative care unit in a comatose state. One week previously, he had felt completely well and had been able to play tennis, before being found comatose in his apartment. He was first admitted to a nearby hospital where he had received cancer treatment previously. There was no history of seizures and he had not received antiepileptic drug treatment. A CT scan of the brain revealed progression of multifocal brain metastases. After one week, the patient was transferred without further electroencephalographic evaluation to our palliative care unit. On admission, NCSE was clinically suspected because of intermittent subtle tonic head and clonic eye movements (suggestive of epileptic nystagmus) and confirmed by EEG on the same day (Fig. 1). On treatment with IV lorazepam up to 6 mg, the patient regained consciousness intermittently. A three-day high-dose IV phenytoin treatment following IV phenytoin loading showed no additional effect. The medication was changed to valproic acid IV at 4 mg/kg/h, which again showed no further improvement despite therapeutic plasma levels and was discontinued. On the first day without treatment, the seizure activity ceased spontaneously and the patient was able to communicate with his brothers. He wished a continuation of antiepileptic drug treatment but refused transfer to the intensive care unit (ICU). After a further three days, NCSE reappeared and could not be reversed despite treatment with midazolam, valproic acid, and levetiracetam in maximum doses. The patient died four days later.
Comment
Etiology, Pathophysiology, and Clinical Picture
The most common etiologies of NCSE of patients in the palliative care unit are likely to be primary brain tumor or metastases, especially when edema is present. In a systematic survey in older patients, ischemic stroke and intracranial hemorrhage were the underlying cause of 40% of status epilepticus, 17% were due to hypoxia, and 14% to metabolic disturbances, whereas brain tumors accounted for 10% of cases.
Importantly, 20% of cases resulted from reduced plasma levels of anticonvulsant drugs. This points to the importance of monitoring blood levels of anticonvulsants, which also applies to the palliative care setting.
Several explanations of the therapy refractory nature of status epilepticus have been proposed. Prolonged synaptic excitation and ineffective repolarization of neurons are discussed.
Because gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter, it may be possible that the loss of postsynaptic GABAA receptors is an important mechanism for the compromised GABAergic transmission and the consecutive neurotransmission failure. Because neurotransmitter receptors exhibit a high degree of plasticity, it has recently been suggested that GABA receptors are internalized into the cytoplasm during status epilepticus.
Additionally, an activation of N-methyl-d-aspartate receptors has been demonstrated, which move in the opposite direction from the cytoplasm into the cell membrane.
Automatisms may be present. In comatose patients, unilateral tonic head and eye movement is often observed. Other symptoms include myoclonic contractions of the angle of the mouth, mild clonus of an extremity or, rarely, epileptic nystagmus.
However, the motor phenomena per definition do not represent the predominant semiology. Typical signs of epileptic motor seizures (generalized tonic-clonic seizures) like tongue bite and urinary incontinence are usually missing.
Important differential diagnoses include delirium (e.g., due to renal failure), metabolic disturbances (e.g., hypercalcemia, hyponatremia), or drug overdose (e.g., morphine). The acutely altered mental status is the most common first symptom of NCSE. Therefore, in patients with sudden behavioral changes of unknown etiology, an EEG is recommended.
Technical Evaluation
Although cortical enhancement on diffusion-weighted magnetic resonance imaging has been reported in NCSE,
and its presence is not relevant for treatment decisions. Status epilepticus may be the presenting sign of tumor progression or formation of new metastases,
as well as of stroke and brain hemorrhage. In the palliative care setting, the condition of the patient has to be considered and possible treatment options evaluated before brain imaging is recommended. In most cases, this will not be necessary.
Lumbar puncture is recommended if the patient shows signs of CNS infection, such as meningism and/or fever, because antibiotic treatment may be necessary to alleviate symptoms. It is contraindicated if increased intracranial pressure is present or suspected.
The most important diagnostic investigation for NCSE is the EEG. EEG evaluation requires expert analysis. Fig. 1 gives two examples of EEG status patterns of the patients presented in the case reports. Concurrent EEG monitoring while attempting to break the status should be done at the time of diagnosis. Continuous EEG evaluation during drug treatment of the seizures can be useful in selected cases but is not generally recommended in the palliative care setting. However, there are portable EEG systems, which can be used in the patient's room (and even in the home care setting) without the need to transport the patient to a specialized EEG unit.
Treatment
There are currently no guidelines for the treatment of NCSE in terminally ill patients. Because NCSE is potentially responsive to therapy, treatment should be considered in all patients and started as soon as possible. A recent study showed that aggressive treatment of status epilepticus in patients with cancer is effective, especially in younger patients.
Delay of treatment may reduce the chances for a reversal of NCSE and worsen the outcome. We propose a stepwise approach to treatment (Fig. 2). The initial treatment of NCSE (Step I) is a combination of benzodiazepines and phenytoin. Benzodiazepines should be used at the time of initial EEG evaluations while attempting to break the NCSE. However, treatment with benzodiazepines alone is not recommended if epileptic activity does not cease. In a randomized controlled trial in 134 patients,
status epilepticus was successfully treated in only 8%–24% of cases with IV administration of lorazepam (0.1 mg/kg) or diazepam (0.15 mg/kg), followed by 18 mg/kg phenytoin. Benzodiazepines commonly used are lorazepam, clonazepam, midazolam, and diazepam. We do not recommend the use of diazepam because it may be more sedative, has a longer half-life than the other benzodiazepines, and its antiepileptic effect is short lived due to its highly lipophilic character, which leads to rapid redistribution in the body fat. The use of clonazepam can result in increased upper airway secretions. If possible, initial IV treatment should be started with lorazepam or midazolam.
Fig. 2Figure illustrates the stepwise treatment options of NCSE of terminally ill patients. The first step includes benzodiazepines and phenytoin, followed in the next step with valproic acid. Midazolam might be given in both steps. The third step consists of lidocaine and levetiracetam, which can be given in addition to valproic acid. The time gap between steps should not be more than 24–48 hours.
If this treatment shows no effect after a maximum of 24 hours, valproic acid and/or barbiturates should be given in non-narcotic doses (Step II). The last step under nonpalliative conditions is the use of IV anesthesia (e.g., with propofol). The rationale for this treatment is that prolonged seizure activity results in brain damage as shown in animal models.
Although treatment of NCSE with anesthesia is rarely warranted in terminally ill patients, a trial of general anesthesia might be considered in single patients if the goals of care suggest that it would be appropriate. Monitoring of the side effects of this treatment will usually require a transfer to the ICU.
There are three randomized placebo-controlled studies looking at the Step I therapy.
Phenytoin may cause severe arrhythmias. When given together with corticosteroids, plasma levels of both drugs may be reduced by a factor of two or more. Furthermore, IV administration of phenytoin may cause painful local inflammatory reactions, and accidental extravasation can cause severe tissue damage.
Valproic acid is less sedative than the other available IV anticonvulsants, and causes less respiratory suppression, arterial hypotension, and cardial arrhythmias. It has been recently described to be effective in generalized status epilepticus and NCSE.
and has been used in two prospective investigations, which included a total of 42 patients with status epilepticus, of whom 19 were in a therapy refractory state.
Patients received a bolus of 1.5–2 mg/kg lidocaine, which immediately stopped seizure activity in 74% of cases. Additional bolus administrations and, in some cases, the continuous infusion of 2–4 mg/kg/h ended seizures in 40 of 42 patients. Due to its characteristics as an antiarrhythmic drug, monitoring of heart rate and blood pressure may be necessary. However, a relevant blood pressure decrease does not seem to happen below doses of 6 mg/kg.
Recently, the new antiepileptic drug levetiracetam has become available for IV administration, but there are yet no controlled data on treatment of status epilepticus available. In a recent uncontrolled trial, levetiracetam has been given enterally as an add-on antiepileptic drug for refractory status and stopped seizure activity in 23% of patients.
In nonterminally ill patients, the rapid progression of treatment to the infusion of anesthetics under intubation is recommended because of the risk of brain and systemic damage. In the palliative care setting, we recommend as Step III the use of lidocaine and levetiracetam (Fig. 1). Additionally, midazolam might be given as a continuous infusion. Levetiracetam might already be used as add-on drug during valproic acid infusion. The suggested dosages are detailed in Table 1. Although we have focused our analysis on drugs administered IV, there is also the potential to use oral antiepileptic drugs (via nasogastric tube). However, because treatment of NCSE should be instituted as rapidly and effectively as possible after diagnosis, initial IV administration of antiepileptic drugs is recommended.
Table 1Commonly Used Drugs and Their Doses of Administration
Drug name
Initial dose
Administration rate
Maximum dose/24 h
Evidence
Lorazepam
0.1 mg/kg
2 mg/min
10 mg
↑
Clonazepam
0.25 mg/kg
5 mg/min
6 mg
↑
Midazolam
0.1 mg/kg
0.05–0.1 mg/kg/h
20 mg
↑
Phenytoin
50–250 mg
15–20 mg/kg
30 mg/kg (plasma levels 20–30 μg/mL)
↑↑
Valproic acid
15 mg/kg
0.5–4 mg/kg/h
1,500–3,000 mg
↑
Lidocaine
1.5–2 mg/kg
2–4 mg/kg/h
400–600 mg
↑
Levetiracetam
500–2,000 mg
2–5 mg/kg/h
5,000–10,000 mg
↔
The arrows indicate the study evidence for the use of this drug in nonconvulsive status epilepticus: ↑=evidence is supported by at least one controlled trial; ↑↑=evidence is supported by more than one placebo-controlled study; and ↔=no clear evidence from controlled studies.
The most important prognostic factor is the underlying cause of NCSE. Despite the relatively low mortality of 10%–20% in the general population, patients with severe underlying illnesses or metabolic disturbances may have a higher mortality rate of up to 80%.
In status epilepticus, independently from the etiology, the duration of the status is an important predictor for mortality. If seizures last for one hour, the mortality is 36%; if they last for more than three hours, the mortality is about 50%.
An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an investigation of variables associated with mortality.
Separate data for NCSE are unfortunately not available. Some patients may be transferred to the palliative care unit having been in unrecognized NCSE for days. Although chances of full recovery from NCSE are slim in such cases, there may be a possibility to halt the epileptic activity for hours or days and enable the patient to spend conscious time with their relatives, as seen in Case 2.
There are a number of ethical issues to consider when attempting to reverse NCSE in palliative care patients. Treatment with antiepileptic drugs may be associated with serious side effects,
which can be difficult to monitor in a patient in NCSE. IV phenytoin can cause hypotonia or arrhythmias, and the course of action in the case of such complications needs to be agreed upon in advance with the patient's health-care proxy or relatives. To avoid overdosing, regular analysis of drug plasma concentrations is required. Because response to treatment is often delayed, the minimum duration of therapy should be four to five days. Beyond this time, remissions are unlikely. The rationale and consequences of withdrawal of the antiepileptic medication should be carefully explained to the relatives and team members. The potential benefit of the treatment needs to be constantly reevaluated and weighed against the side effects. In patients whose death is judged to be imminent, treatment with adequate doses of benzodiazepines and careful vigilance for potentially distressing symptoms will usually be the preferred course of action.
Conclusion
NCSE is an important neurological condition in palliative care units. Its incidence may be underestimated due to the lack of diagnostic evaluation. Reliable clinical evidence for treatment options on palliative care units is lacking. We propose a stepwise approach based on available data and clinical experience, and adapted to the special needs of palliative care patients. Because no evidence-based algorithm is possible at present, treatment decisions must be made on a case-by-case basis and constantly reevaluated. More research into this syndrome and its treatment in terminally ill patients is urgently needed.
An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an investigation of variables associated with mortality.
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