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Nonconvulsive Status Epilepticus in Palliative Care Patients

Open AccessPublished:July 01, 2010DOI:https://doi.org/10.1016/j.jpainsymman.2010.01.019

      Abstract

      Altered mental status and reduced level of consciousness are common among patients admitted to palliative care units. However, nonconvulsive status epilepticus (NCSE) has rarely been considered as a possible cause, and electroencephalographic confirmation of the epileptic status is sparse. The clinical presentation of patients with NCSE varies from altered mental status to coma, with no or only minimal convulsions. We report a prospective evaluation of patients with altered mental status on admission to our palliative care unit in the year 2007. Of 290 patients admitted in 2007, 49 patients showed signs of confusion or delirium and/or a reduction in their level of consciousness. NCSE was suspected clinically in 22 of these patients, and epileptic activity could be confirmed in 15 (5.2%) of 290 patients. Nine of 15 patients could be effectively treated with anticonvulsants and regained communication ability before death. NCSE appears to be an important, often unrecognized, and potentially treatable cause of altered mental status in palliative care patients. Pharmacological treatment might restore communicative abilities even in severely ill patients.

      Key Words

      Introduction

      Confusion, delirium, and reduced level of consciousness are common among patients on admission to a palliative care unit.
      • Grewal J.
      • Grewal H.K.
      • Forman A.D.
      Seizures and epilepsy in cancer: etiologies, evaluation, and management.
      There are many causes for altered mental status in terminally ill patients, but one important and treatable cause might be nonconvulsive status epilepticus (NCSE). Diagnosis of NCSE is more challenging than diagnosis of convulsive seizures because the clinical presentation ranges from minimally altered mental status to coma without tonic-clonic activity.
      • Jirsch J.
      • Hirsch L.J.
      Nonconvulsive seizures: developing a rational approach to the diagnosis and management in the critically ill population.
      Although few data are available, NCSE has been reported in 6% of patients with systemic cancer without evidence of central nervous system involvement and in up to 20% of patients with primary brain tumors or metastases.
      • Cocito L.
      • Audenino D.
      Altered mental status in patients with cancer.
      The most common etiologies of NCSE in palliative care patients treated on a palliative care unit are likely to be primary brain tumors and metastases, especially when edema is present. In a systematic survey in older patients suffering from status epilepticus, ischemic stroke, and intracranial hemorrhage were the underlying cause in 40%; 17% were because of hypoxia; and 14% because of metabolic disturbances; whereas brain tumors only accounted for 10% of cases.
      • Waterhouse E.J.
      • DeLorenzo R.J.
      Status epilepticus in older patients: epidemiology and treatment options.
      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, and NCSE remains poorly understood in this population. Its response to treatment and the outcome after treatment have never been investigated prospectively. To determine the prevalence of NCSE in patients with delirium and its course after a standardized treatment, an observational prospective study was conducted in all consecutive patients with unexplained changes in mental or behavioral status who were admitted to our palliative care unit in the year 2007.

      Patients and Methods

      We identified patients with clinical signs of confusion or delirium, and/or reduced level of consciousness, who were admitted to the Interdisciplinary Center for Palliative Medicine at the Munich University Hospital in the year 2007. After a complete neurological examination, each patient with a clinical presentation suggesting NCSE received a 36-channel electroencephalographic (EEG) evaluation. Clinical signs suggesting NCSE were mild myoclonic jerks of facial muscles (e.g., angle of the mouth) or epileptic nystagmus. Treatment was initiated if epileptic activity was confirmed by the EEG. A second EEG was obtained in eight of our patients who showed prolonged clinical improvement after therapy. In the remaining patients, response to treatment was assessed clinically by daily neurological examination. Effective treatment was defined as clinical resolution of NCSE with regained consciousness and ability to communicate.

      Results

      A total of 290 patients were admitted to the Acute Palliative Care Unit of the Interdisciplinary Center for Palliative Medicine in 2007. We identified 49 patients with altered mental status on admission. Of this group, 22 patients showed clinical signs and symptoms suggestive of NCSE, such as mild myoclonic jerks of the angle of the mouth and/or nystagmus. In the EEG recording, 15 of these 22 patients displayed epileptiform discharges (e.g., sharp and slow waves, repetitive sharp waves, intermittent sharp waves, intermittent sharp and slow waves, and intermittent spikes) (Fig. 1).
      Figure thumbnail gr1
      Fig. 1An example of an EEG of a patient with NCSE. It shows anteriorly dominant sharp and slow wave complexes with a very prominent positive component and a longer duration slow wave, which could be atypical triphasic waves. Although encephalopathy might be a differential diagnosis, this patient improved on antiepileptic treatment. The figures show the 1a) baseline and 1b) recordings 10 seconds and 1c) 20 seconds later.
      The diagnoses of the patients are shown in Table 1. Nine of the 15 patients had documented primary or metastatic neoplasms in the brain. The duration of NCSE could not be determined retrospectively because only eight patients had had an EEG recording before admission on our unit, which in five cases was suggestive of NCSE. Clinically, it was known that six patients had been comatose for at least one week before admission.
      Table 1Data of the 15 Patients with NCSE
      Age, yearsGenderDiagnosisPresentationMidazolamPhenytoinOthersOutcome
      79MCerebral ischemiaSomnolence++Valproic acid, levetiracetamNo effect, died four weeks later
      76MGlioblastomaComaLevetiracetamInitial effect for two weeks, died three weeks later (NCSE recurrence)
      77MGlioblastomaAwake/somnolence++LevetiracetamInitial effect for one week, died six weeks later (NCSE recurrence)
      53MAstrocytoma IIAwake/confusion++LevetiracetamInitial effect for seven weeks, died eight weeks later (NCSE recurrence)
      52MMelanoma with brain metastasesComa++LevetiracetamInitial effect for five days, died six days later (NCSE recurrence)
      42FOligoastrocytomaSomnolence++LevetiracetamNo effect, died three weeks later
      71MLiver cirrhosisSomnolence+LevetiracetamNo effect, died two weeks later
      52MHIV, PMLSomnolence+Valproic acidNo effect, died two weeks later
      96FBilateral thalamic ischemiaComa+Valproic acid, levetiracetamNo effect, died one week later
      67FMelanoma with brain metastasesComa++Valproic acid, levetiracetamInitial effect for six days, died one week later (NCSE recurrence)
      81FBronchial carcinoma with brain metastasesSomnolence+Valproic acid, levetiracetamNo effect, died one week later
      24FAstrocytoma IIISomnolence+LevetiracetamInitial effect for seven days, died two weeks later (NCSE recurrence)
      54MAstrocytomaConfusion++LevetiracetamEffect after one day, lasted until death four weeks later
      62MGlioblastomaConfusion, aphasia+Valproic acid levetiracetamEffect after one day, effect lasted for 32 days
      67FOligoastrocytomaConfusion, aphasia, and hemiparesis++Valproic acid, levetiracetamEffect after eight days, lasted for 184 days, and died six days later (NCSE recurrence)
      M=male; F=female; HIV=human immunodeficiency virus; PML=progressive multifocal leukoencephalopathy.
      All patients were treated with intravenous (IV) antiepileptics according to a previously published stepwise model.
      • Lorenzl S.
      • Mayer S.
      • Noachtar S.
      • et al.
      Nonconvulsive status epilepticus in terminally ill patients—a diagnostic and therapeutic challenge.
      We used IV phenytoin as the first-choice drug, but none of our patients improved on it. Seven patients were then switched to valproic acid and eight patients directly to levetiracetam. Of the seven patients treated with valproic acid, only one showed clinical improvement. In the remaining six patients, levetiracetam was subsequently given as an add-on treatment.
      Overall, clinical resolution of NCSE was observed in nine of 15 patients and lasted between five and 92 days. Patients with clinical resolution of NCSE fully regained consciousness and were able to communicate. A follow-up EEG was performed in two patients, which showed no EEG pattern suggestive of NCSE. The time lag between initiation of antiepileptic drug treatment, and clinical response ranged from four hours to six days.
      All but one patient suffered recurrence of seizures or NCSE, which proved refractory to further treatment, and eventually died. Only one patient with an astrocytoma survived for another 184 days. In seven patients who presented with coma, four patients became awake and responsive after treatment.

      Discussion

      We report a case series of 15 patients with NCSE who were prospectively investigated and treated at our Interdisciplinary Center for Palliative Medicine. Although there is a limited number of reports on NCSE in terminally ill patients, this is, to our knowledge, the first prospective study in this patient group.
      In our population, 19% of patients with brain tumors or brain metastases presented with NCSE, which is consistent with earlier reports.
      • Grewal J.
      • Grewal H.K.
      • Forman A.D.
      Seizures and epilepsy in cancer: etiologies, evaluation, and management.
      Astrocytomas accounted for most primary brain tumors in our population (five patients). These low-grade tumors are known to be even more epileptogenic than high-grade gliomas.
      • Smith D.F.
      • Hutton J.L.
      • Sandemann D.
      • et al.
      The prognosis of primary intracerebral tumors presenting with epilepsy: the outcome of medical and surgical management.
      • Whittle I.R.
      • Beaumont A.
      Seizures in patients with supratentorial oligodendroglial tumors. Clinicopathological features and management considerations.
      These patients had been transferred to the palliative care unit for treatment of delirium, which turned out to be because of potentially treatable NCSE.
      Among our patients, NCSE developed in their last days of life. Seizures in patients with primary brain tumors or brain metastases normally develop at time of diagnosis or tumor progression.
      • Whittle I.R.
      • Beaumont A.
      Seizures in patients with supratentorial oligodendroglial tumors. Clinicopathological features and management considerations.
      Thirteen of the 15 patients had a history of seizures, and all were taking antiepileptic drugs, a higher proportion than in other reports.
      • Shneker B.F.
      • Fountain N.B.
      Assessment of acute morbidity and mortality in nonconvulsive status epilepticus.
      Discontinuation or noncompliance is considered to be the greatest risk for NCSE in this population.
      • Kaplan P.W.
      Nonconvulsive status epilepticus.
      This point was not investigated in our patients because drug level monitoring was not performed. Other possible factors leading to NCSE in palliative care patients may be metabolic derangement (hypercalcemia, hyponatremia), addition of new drugs (antipsychotics, antidepressants, and diuretics), or progression of the underlying disease.
      The time until diagnosis is an important predictor of the outcome and, therefore, of the value when deciding on treatment. Because response to treatment is often delayed, the minimum duration of therapy should be four to five days. Beyond this time, remissions are unlikely. If the treatment requires higher doses of sedative drugs, the potential benefit of the treatment has to be weighted against the side effects. The rationale and consequences of withdrawing the antiepileptic medication should be carefully discussed with the relatives and team members.
      Most of our patients were noncommunicative or even comatose on admission. In these patients, the diagnosis of NCSE is challenging because the differential diagnosis is broad and includes drug intoxication and many other causes of encephalopathy. Subtle myoclonic movements or nystagmus may be suggestive of NCSE but are often absent.
      • Jirsch J.
      • Hirsch L.J.
      Nonconvulsive seizures: developing a rational approach to the diagnosis and management in the critically ill population.
      Myoclonic jerks can also be misdiagnosed as opioid intoxication in these patients, and ocular movements like epileptic nystagmus
      • Pfefferkorn T.
      • Holtmannspötter M.
      • Querner V.
      • et al.
      Epileptic nystagmus.
      might not be investigated when lids are closed. Therefore, a thorough neurological examination is mandatory for all patients with delirium to detect signs of NCSE.
      Almost 90% of NCSE of all hospital inpatients is unrecognized at the bedside and is only diagnosed by continuous EEG.
      • Claassen J.
      • Mayer S.A.
      • Kowalski R.G.
      • et al.
      Detection of electrographic seizures with continuous EEG monitoring in critically ill patients.
      Therefore, the actual number of NCSE in terminally ill patients might be significantly underestimated. In 22 of 49 patients, we suspected NCSE clinically and 15 of them showed EEG patterns consistent with NCSE (Fig. 1). However, because the EEG pattern of NCSE can be highly variable and sometimes difficult to distinguish from encephalopathy (Fig. 2), even clinically suspected NCSE cases without typical EEG patterns might warrant an antiepileptic treatment trial.
      • Jirsch J.
      • Hirsch L.J.
      Nonconvulsive seizures: developing a rational approach to the diagnosis and management in the critically ill population.
      Figure thumbnail gr2
      Fig. 2The EEG pattern of the 42-year-old female with right frontal oligoastrocytoma. She presented with an NCSE after a right frontotemporal trepanation. The status did not respond to treatment. This bipolar longitudinal recording shows a right frontotemporal status pattern.
      Although levetiracetam has a wide spectrum of action and a favorable pharmacokinetic profile, few data exist regarding its use in NCSE. There are only retrospective reports on its use in status epilepticus.
      • Rupprecht S.
      • Franke K.
      • Fitzek S.
      • et al.
      Levetiracetam as a treatment option in non-convulsive status epilepticus.
      • Nau K.M.
      • Divertie G.D.
      • Valentino A.K.
      • et al.
      Safety and efficacy of levetiracetam for critically ill patients with seizures.
      Importantly for the patients in this study, levetiracetam does not interact with corticosteroids,
      • Brown E.S.
      • Frol A.B.
      • Khan D.A.
      • et al.
      Impact of levetiracetam on mood an cognition during prednisone therapy.
      which is a major disadvantage of phenytoin and valproic acid. Our results suggest that treatment should be started with levetiracetam and combined with other drugs when NCSE is not treated effectively. Because of its pharmacological profile, levetiracetam is particularly suited for the treatment of elderly patients,
      • Alsaadi T.M.
      • Koopmans S.
      • Apperson M.
      • et al.
      Levetiracetam monotherapy for elderly patients with epilepsy.
      patients taking multiple medications, and tumor patients.
      • Rupprecht S.
      • Franke K.
      • Fitzek S.
      • et al.
      Levetiracetam as a treatment option in non-convulsive status epilepticus.
      The downside of levetiracetam is its high cost, especially when given intravenously.
      Patients with severe underlying diseases like cancer or major metabolic disturbances and NCSE have a mortality rate of up to 80%.
      • Drislane F.W.
      • Schomer D.L.
      Clinical implications of generalized electrographic status epilepticus.
      Of the 15 patients treated in our series, 13 died within the first three months, with survival ranging from five to 184 days. Yet, these were all patients with terminal diseases where death was expected to follow within days to months. As this study was not controlled, we cannot say whether survival time was actually prolonged by NCSE treatment. The most obvious treatment effect, however, was the regained ability to communicate. Retrospective analysis of available data did not identify patient features predictive of treatment outcome. This may be because of the overall small number of patients in this study. Changes in neuropsychiatric performance could not be evaluated because of the lack of baseline data. None of the patients could remember what happened during the time of NCSE.
      Two patients with ischemic stroke have been included in this study. One patient had a hemispheric infarction in the territory of the right middle cerebral artery and the other had bilateral thalamic infarctions. In both patients, treatment did not show any effect, and they died soon after. The patient with the thalamic infarctions was the oldest patient in our study (96 years), but effective treatment of NCSE in stroke patients has been reported in this age group.
      • Bateman B.T.
      • Claassen J.
      • Willey J.Z.
      • et al.
      Convulsive status epilepticus after ischemic stroke and intracerebral hemorrhage: frequency, predictors, and impact on outcome in al large administrative dataset.

      Conclusion

      NCSE is an important neurological condition in patients on palliative care units. Its incidence may be underestimated because of the lack of diagnostic evaluation. In our observational prospective study, we have shown that treatment of NCSE can restore communicative abilities even in severely ill patients. This might even be important when the remaining life span is very short. Treatment decisions must be made on a case-by-case basis and constantly reevaluated. More research into this syndrome, its treatment, and ethical implications in terminally ill patients are urgently needed.

      Acknowledgments

      The authors thank Claudia Schneider for secretarial assistance.

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