Nonconvulsive Status in Clinical Decision Making

Nonconvulsive status epilepticus (NCSE), like convulsive status epilepticus, is a state of continuous or almost continuous intermittent seizure activity lasting more than 30 minutes without a return to baseline function. NCSE is characterized by an alteration of mental status associated with epileptogenic changes seen on the electroencephalogram (EEG).Because of the wide range of clinical presentations, it is at times difficult to recognize NCSE clinically; indeed, sometimes it is not even considered in the differential diagnosis of patients with altered mental status. At this time, there are no good data to indicate the true incidence of this entity; the current literature indicates that it is significantly underdiagnosed.The clinical presentation can vary considerably from one case to another. Symptoms can be non-specific and bizarre in origin, and can fluctuate over time. The varying manifestations of NCSE contribute to the difficulty in diagnosing the condition and affect clinical decision making. A large body of literature mentions patients who are initially described as having a psychiatric condition, only to later have the correct diagnosis of nonconvulsive status identified, either by EEG or by the onset of a convulsive component to the status.1-3When associated with a mild impairment in mental status, NCSE has a low morbidity and mortality.4,5 However, outcomes may worsen in patients with comorbidities and acute medical conditions that contribute to the clinical presentation may occur.6-10CLASSIFICATIONPrimarily 2 types of nonconvulsive status are described in the literature: absence status epilepticus (ASE) and complex partial status epilepticus (CPSE). Absence seizures have clinical characteristics that help differentiate them from complex partial seizures; however, once status occurs, it becomes difficult to differentiate these 2 entities on clinical grounds alone. As already stated, the hallmark of NCSE, whether it is absence or complex partial, is altered mental state and therefore, unless it is suspected, the diagnosis can easily be missed. The change in behavior can be sudden or gradual in both types of NCSE.11 The duration and intensity of the episodes can vary in both types, as can the duration of postictal confusion. Electrographically, they are both associated with EEG changes, but ASE is characterized by diffuse abnormal cortical electrical activity at onset with generalized discharges on EEG, while the EEG in CPSE is focal at onset with secondary generalization, which can be slow or rapid.ETIOLOGYNCSE has been reported in all age groups and in both sexes. It can be the first manifestation of a seizure disorder.1,2,11-14 A number of causes of NCSE have been described in the literature. Among others, they include metabolic abnormalities, drug toxicity or withdrawal, traumatic brain injury, infections, structural CNS lesions, hormonal abnormalities, and electroconvulsive treatment.There appears to be a distinct subgroup of patients in whom ASE develops in later life. Lee2 reported on 11 patients, aged 42 to 76 years, who presented with mild disorientation to confusion caused by ASE. Of these 11 patients, 10 had no past seizure history. Three of Lee's patients had hyponatremia, 2 were taking lithium, and 1 had psychogenic polydipsia.Thomas and colleagues15 reported on 11 patients with de novo ASE in midlife and found that 8 had onset of status related to benzodiazepine withdrawal. Other cofactors related to the new onset of ASE were psychotropic drug use, hypocalcemia, hyponatremia, and chronic alcoholism.Extrapolating from the data presented by Lee and Thomas's group, new-onset ASE in later life, without a preceding seizure history, should encourage an aggressive search for underlying metabolic or pharmacologic causes. Tomson and colleagues12 reported that the 2 most common factors contributing to the onset of NCSE were generalized tonic-clonic seizures and changes in antiepileptic drug (AED) therapy.The true incidence of NCSE is not clear, although some series report that about 25% of patients in status actually had NCSE.16 Towne and colleagues17 reported that EEG findings met the criteria for NCSE in 8% of 236 comatose patients who did not have clinical evidence of seizure. Privitera and Strawsburg18 reported that 37% of 198 patients who presented to the emergency department with a change in mental status had clinical and EEG manifestations of NCSE.At the present time, it is unclear whether untreated NCSE results in significant morbidity, although it has been hypothesized that morbidity and mortality are related to an underlying cause. There is some evidence that NCSE is associated with the release of biomarkers related to neuronal injury; however, a clinical correlation is difficult to make.19Confounding the difficulty in drawing conclusions on the impact on outcome from NCSE is that few of these patients had neuropsychologic testing done before the event.1 Clearly, there is a need for a well-designed prospective study to investigate outcomes in NCSE because the findings would have a profound impact on treatment decision making.CLINICAL CHARACTERISTICSThe mental status changes reported in NCSE may be subtle to the degree that only family or friends notice them, or they may manifest as marked changes in behavior, psychosis, and even coma.1,11,17,20,21 The variety of clinical presentations includes speech disturbance, which can vary from verbal perseveration to aphasia, to cognitive disturbances that can affect attention, memory, or both.1,21,22 The cognitive disturbances can be mild or result in prolonged confusional states2,23 (see Table).Affective and psychotic changes also have been described and sometimes are confused with primary psychiatric illnesses.2,23,24 Frequently, fluctuations in the clinical presentation make diagnosis difficult. 2Automatisms, myoclonic jerks, abnormal motor activity, and eye twitching or deviation may be minimally present, although motor activity is normal in most cases. It is important to emphasize that patients in NCSE can appear to be functioning "normally" and that manifestations of the status may be as subtle as decreased attention or slight clumsiness; therefore, when the patient or family observes that the patient is not at baseline, it should raise suspicion and prompt an investigation.DIAGNOSISBecause of the wide range of clinical presentations, lack of or minimal motor activity, and fluctuation of symptoms, it is easy to understand how the diagnosis of NCSE can be missed or confused for a psychiatric disorder or nonepileptic neurologic disorder. A detailed history including past medical conditions, social history, medications, and changes in medications is essential. The history should include information from family members or caregivers whenever possible.Information about changes from baseline, onset and duration of the events, presence or absence of postictal symptoms, and presence or absence of fluctuating symptoms all help develop the differential diagnosis. A history of a seizure disorder, especially when the patient's symptoms are temporally related to a convulsive event, is a red flag that needs to be investigated. Prolonged postictal periods or persisting aphasic, somatosensory, or psychic findings after the ictus should raise suspicion of possible ongoing epileptogenic activity.The physical examination of a patient in whom NCSE is suspected begins with the assessment of the patient's vital signs, oxygenation, and serum glucose level. The vital signs and the pupil and skin examinations can help identify toxic syndromes that may point to underlying causes of the patient's condition.Evidence of head trauma should be sought and the thyroid, heart, lungs, and abdomen carefully examined. Subtle motor activity may provide the key to the diagnosis, so the physical examination must focus on automatisms, eye deviations, persisting twitches, lip smacking, or dystonic postures. Unless these findings are sought after, they may easily be missed and important diagnostic clues left unappreciated. All patients with altered mental status require a careful neurologic examination, including an assessment of cognition. Neuroimaging is generally part of the evaluation of a patient in nonconvulsive status.In general, noncontrast CT is recommended in emergent situations because of its ready availability and high sensitivity for acute hemorrhage. In other situations, MRI is generally preferred because of its high sensitivity for underlying structural lesions.Electroencephalography NCSE should be suspected in any patient who exhibits a change in mental status of uncertain origin, in which case an EEG is indicated. In ASE, the EEG changes are typically characterized by continuous or nearly continuous generalized, rhythmic, bilaterally synchronous spike-wave discharges at 3-per-second, with a maximum over the frontal regions. However, variations in the EEG pattern can occur, including 2- to 3-second spike and wave or polyspike activity, rhythmic slowing, and bursts of fast activity at 10 to 20 cycles per second.12,13,25Ictal EEG findings in complex partial seizures are varied and can be characterized by rhythmic spike, rhythmic sharp and slow waves, or rhythmic slowing.2,12,15 The clinician should remember that if the EEG is performed at the onset of a complex partial seizure, a focal abnormality might be present; conversely generalization may occur so quickly that the focal onset is missed and the patient is at risk for receiving a misdiagnosis of ASE.12TREATMENTIn cases of NCSE, before beginning treatment, it is important that precipitating factors be identified and that the clinical and EEG characteristics be assessed. Correlation of clinical and EEG data is needed to make a diagnosis of NCSE, to identify the type of NCSE, and to determine the appropriate long-term management strategies.Intravenous benzodiazepine therapy, in particular lorazepam or diazepam therapy, has been used during EEG monitoring to ascertain the correlation between clinical and EEG findings. Benzodiazepines also have proved helpful in de novo ASE when the underlying cause is benzodiazepine withdrawal and in cases of mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes.23,26Once the diagnosis of NCSE is determined and the seizure is controlled, long-term treatment should be considered. Several AED options are available.Phenytoin, valproic acid, or phenobarbital can be given intravenously in addition to benzodiazepines when an AED is needed to terminate an acute event; they can be given orally as a standard long-term treatment when needed. Carbamazepine, primidone, and the new-generation AEDs including lamotrigine (Lamictal, GlaxoSmithKline), levetiracetam (Keppra, UCB Pharma), and topiramate (Topamax, Ortho-McNeil) are also considerations for long-term treatment. The role of the new-generation AEDs as first-line agents is still evolving, and one needs to personalize treatment to individual needs based on the type of seizures, present and past history, side-effect profile, and drug-drug interactions.Valproic acid is the drug of first choice in treating patients with absence seizures.27,28 Ethosuximide and clonazepam also have been used for this indication.3 Vigabatrin and tiagabine are not recommended at this time because of possible adverse reactions.29CONCLUSIONNCSE should be included in the differential diagnosis of patients who present with a change in mental status of undetermined cause. When NCSE is suspected, an EEG is indicated to confirm the diagnosis. When the EEG demonstrates NCSE, therapy should be started. In general, NCSE responds to benzodiazepine therapy. In cases in which a precipitant is not identified and seizure recurrence is a concern, a longer-acting anticonvulsant can be used. The choice of the anticonvulsant depends on the EEG characteristics and whether the EEG findings are suggestive of a focal or a generalized mechanism and on the underlying cause. Well-designed prospective studies and multidisciplinary investigations are needed.SILVANA RIGGIO, MD, is associate professor in the Department of Psychiatry at Mount Sinai School of Medicine and Bronx Veterans Medical Center in New York City.REFERENCES1. Guberman A, Cantu-Reyna G, Stuss D, Broughton R. Nonconvulsive generalized status epilepticus: clinical features, neuropsychological testing and long-term follow-up. Neurology. 1986;36:1284-1291.2. Lee SI. Nonconvulsive status epilepticus. Ictal confusion in later life. Arch Neurol. 1985;42:778-781.3. Berkovic SF, Bladin PF. Absence status in adults. 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Epilepsia. 2005;46:1625-1632.---Table Clinical signs of NCSEBEHAVIORAL CHANGES:Impaired attentionDisorientation or confusionMood disturbancePsychosisBizarre behaviorSPEECH DISTURBANCE:Verbal perseverationDecreased verbal fluencyMutenessSpeech arrestEcholaliaAphasiaMOTOR:NormalDecreased response timeFocal jerksAutomatisms