Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepticus

Frank W. Drislane, M.D.1

Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, KS-477, 330 Brookline Avenue, Boston, Massachusetts 02115
Received August 7, 2000; revised August 9, 2000; accepted August 9, 2000

Nonconvulsive status epilepticus (NCSE) is much more common than is generally appreciated. It is certainly underdiagnosed, but its presentation is protean. Diagnostic criteria and treatment are controversial. Absence status is characterized by confusion or diminished responsiveness, with occasional blinking or twitching, lasting hours to days, with generalized spike and slow wave discharges on the EEG. Complex partial status consists of prolonged or repetitive complex partial seizures (with a presumed focal onset) and produces an "epileptic twilight state" with fluctuating lack of responsiveness or confusion. There is a clear overlapping of syndromes. Other confused, stuporous, or comatose patients with rapid, rhythmic, epileptiform discharges on the EEG may have "electrographic" status and should be considered in the same diagnostic category. NCSE typically occurs following supposedly controlled convulsions or other seizures, but with persistent neurologic dysfunction despite apparently adequate treatment. Confusion in the elderly or among emergency room patients is also a typical setting. The diagnosis of NCSE usually involves an abnormal mental status with diminished responsiveness, a supportive EEG, and often a response to anticonvulsant medication. All patients have clinical neurologic deficits, but the EEG findings and response to seizure medication are variable and are more controversial criteria. The response to drugs can be delayed for up to days. Experimental models and pathologic studies showing neuronal damage from status epilepticus pertain primarily to generalized convulsive status. Most morbidity from NCSE appears due to the underlying illness rather than to the NCSE itself. Some cases of prolonged NCSE or those with concomitant systemic illness, focal lesions, or very rapid epileptiform discharges may suffer more long-lasting damage. Although clinical studies show little evidence of permanent neurologic injury, the prolonged memory dysfunction in several cases and the similarities to convulsive status suggest that NCSE should be treated expeditiously. The diagnosis is important to make because NCSE impairs the patients health significantly, and it is often a treatable and completely reversible condition.
2000 Academic Press

Key Words: nonconvulsive status epilepticus; status epilepticus; absence; complex partial seizures; seizures; electroencephalogram; neuropathology; cognitive effects; treatment; antiepileptic drugs.

Nonconvulsive status epilepticus (NCSE) causes many different neurologic deficits, particularly in alertness and cognitive function, and is usually a treatable and reversible illness. Nevertheless, its presentation is protean and it may be mistaken for many other
To whom correspondence should be addressed. Fax: (617) 667- 7919. E-mail:
1

conditions. Indeed, NCSE may be one of the most frequently missed diagnoses in patients with altered neurologic function. The missed diagnosis occurs in part because NCSE arises often in patients with other serious illnesses but also because the diagnosis is often not entertained. This may be because descriptions in the medical literature are so varied that no particular syndrome is anticipated or

fdrislan@caregroup.harvard.edu.
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considered. Definitions of
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nonconvulsive status are controversial, and not all papers describe the same entity. Part of the reason for the confusion and controversy surrounding NCSE is its relative youth as a diagnostic and clinical entity. Convulsive seizures, and probably seizures prolonged enough to constitute convulsive status epilepticus (SE), were known in antiquity, and convulsive status has been described in the medical literature for the past few centuries. NCSE, however, was unknown to early epileptologists. There are clearly many other causes of altered consciousness and behavior, and the relationship between spells of altered consciousness and epilepsy (recognized primarily by the repetitive stereotyped, involuntary motor activity of convulsions) was not obvious. The connection became understandable when briefer episodes of nonconvulsive seizures such as absence seizures became recognizable and diagnosable through the development of EEG technology in the 1930s and 1940s (1). Only then could it be recognized that epileptic seizures and these spells of staring, immobility, and unresponsiveness had a related physiologic basis. This also made it clear that both conditions could be treated with antiepileptic medications. It may have been postictal confusion that first suggested the connection between epileptic convulsions and prolonged episodes of altered mental status. A century ago, Charcot in Paris and Gowers in England speculated on whether episodes of altered behavior in patients with epilepsy represented seizures or a postictal state (2). It was only after the development of the EEG decades later that this question could be answered.

TABLE Absence Status Epilepticus: Clinical Features

Confusion but wakefulness, with blinking or occasionalmyoclonus May start or end with a generalized convulsion Can last days Minimal focal features; generalized discharges on EEG Often prior absence, myoclonic, or convulsive seizures Typical precipitants: benzodiazepine or other medication withdrawal, generalized convulsions, infection, trauma, metabolic aberrations

vidual cases may have features of one or the other, or both; overlap is substantial and is a source of major confusion. There are other possible types of NCSE that do not fit neatly into one of these categories. Absence SE may be considered those cases similar to "status epilepticus in petit mal" described by Schwab (3) (Table 1). They have no features of a focal epilepsy and have rapid, generalized 3-Hz epileptiform discharges on the EEG (Fig. 1). Pure cases represent very prolonged absence seizures. Patients often have a history of absence, myoclonic, or generalized convulsive seizures. Typical clinical manifestations include confusion with occasional blinking or myoclonus, with episodes lasting up to days. They may start with a generalized convulsion. Medication withdrawal and other precipitants may prompt an episode of absence SE. Such patients were described well by Andermann and Robb (5). More recently, relatively frequent episodes have been reported in elderly patients with no prior epilepsy ("de novo SE"), in association with withdrawal of benzodiazepines, at times used for anxiety or sleep (6). Other than absence seizures, there are

Lennox's studies of absence seizures and their prolongation to the state of absence status epilepticus effectively established the existence of NCSE. Schwab described SE of a nonconvulsive variety in the 1950s (3). Niedermeyer and Khalifeh described "spike wave stupor" in 1965 (4), and it was only in the 1970s that more case reports and larger series began to make NCSE known to most neurologists. The history of nonconvulsive status has been summarized in greater detail by Kaplan (2).

I. TYPES OF NCSE
NCSE has generally been divided into two types: absence SE, characterized by generalized spike and slow wave discharges, and complex partial SE, usually with focal discharges and considered the equivalent of prolonged or repetitive complex partial seizures. IndiCopyright 2000 by Academic Press All rights of reproduction in any form reserved.

several types of generalized seizures that can be so prolonged as to constitute status epilepticus. These others, including myoclonic status (7) and tonic, clonic, and generalized tonic clonic seizures, all have substantial motor manifestations, and are not "nonconvulsive." Complex partial status epilepticus (CPSE) is NCSE with a presumed focal onset (Table 2). CPSE was reported less often than absence SE until recently, perhaps because of some very stringent definitions (described later). Clinical manifestations include an "epileptic twilight state" with a lack of responsiveness or confusion, and bizarre, and particularly fluctuating, behavior (8 11). At times there are oral or manual automatisms. Cases include both prolonged repetitive complex partial seizures and continuous seizure activity. Possibly because of the association with vascular

Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepticus

FIG. 1. Rapid generalized epileptiform spikes and slow waves following a few seconds of a normal EEG. Recorded on a 30 year-old woman who walked in for follow up of her epilepsy. She was confused but ambulatory and able to speak.

disease and prior focal epilepsy, CPSE appears somewhat harder to treat than absence SE and is more likely to recur. Some NCSE studies are restricted to pure absence SE, some to CPSE, and many include all varieties of NCSE. Logically, there are many forms of focal seizures without convulsions or other dramatic motor presentations, depending on where in the brain they start and develop. Prolonged focal seizures from sensory or association areas of the brain may constitute other forms of NCSE.

Other forms of focal NCSE are discussed later with respect to their presentations. One of the most interesting is a disturbance of language (without confusion or stupor) termedaphasic status epilepticus. This can appear quite similar to the new-onset aphasia from a stroke. The location of epileptiform discharges corresponds at times very well to the classic location of vascular lesions causing similar aphasias. For example, left-frontalonset focal seizures may produce more of a Broca aphasia with preserved comprehension (12), while more posterior and inferior TABLE 2 seizures may produce an aphasia more akin to Complex Partial Status Epilepticus: Clinical Features a Wernicke aphasia (13, 14). Aphasia is most Confusion to unresponsiveness properly diagnosed when the seizures remain "Epileptic twilight state" with fluctuating mental status focal rather than extend to involve an Recurrent or prolonged complex partial seizures alteration in consciousness (15), which would
Observed or presumed focal onset, often temporal or

frontal; focal slowing and discharges on EEG Often prior epilepsy and vascular disease in the elderly Can last up to months; often recurrent May produce severe amnesia following

be a complex partial seizure. Speech arrest alone, however, is not properly considered aphasia, and seizures causing speech arrest may arise in many different areas of the brain. Overlap. The definite overlap of absence SE and CPSE confuses the classification of NCSE and may explain why reported cases of absence SE outnumber those of CPSE while complex partial seizures are far
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Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepti

FIG. 2. EEG from an 83 year-old woman found unresponsive after admission to the medical service with a urinary tract infection and "failure to thrive", with no clinical seizures observed during the entire hospitalization.

more common than absence seizures in overall adult clinical practice. Both exhibit confusion or other mental status changes along with minimal motor activity and usually no systemic physiologic disturbances. A history of primary generalized epilepsy and rapid rhythmic, generalized EEG discharges argue in favor of absence SE, while a history of

medical illnesses or, perhaps most commonly, following clinically evident convulsions or generalized convulsive SE. Seldom are the EEG discharges or seizures the only clinical problems. Many of these patients have serious cerebrovascular disease or toxic and metabolic encephalopathies, or both (18, 19). Figure 2 illustrates an example. These patients might be

focal seizures or other focal neurologic disease and a fluctuating course suggest CPSE. Nevertheless, an individual seizure may start focally and generalize rapidly. Cases considered as atypical absence SE may well be complex partial seizures with generalization and prolongation. This concept is buttressed by work correlating EEGs with the clinical presentation. Tomson and colleagues (16) studied 32 patients with NCSE, 14 with focal EEG changes (thus labeled CPSE), and 18 with generalized discharges, 6 of whom had primary generalized epilepsy. Patients could not be differentiated by clinical features alone. Similarly, Granner and Lee (17) noted a predominance of generalized EEG discharges in NCSE, but many of these patients had focal discharges on interictal EEGs or after antiepileptic drug (AED) treatment. There are additional confused, stuporous, or comatose patients found to have rapid, rhythmic, continuous epileptiform discharges on the EEG, with or without clinically evident seizures, in the setting of severe
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termed in electrographic status epilepticus (ESE) or as having epileptic encephalopathies. These cases may be included as types of NCSE, whatever the response to AEDs, but this is controversial.

II. EPIDEMIOLOGY
More than 20 years ago, Celesia (20) stated that NCSE constituted nearly a quarter of SE cases in a moderate-sized series. Subsequently, Shorvon (21) estimated, from the prevalence of different types of epilepsy and the incidence of episodes of SE in each, that there were approximately 3.5 cases of complex partial SE and 15 cases of other nonconvulsive SE per 100,000 population per year. Interestingly, DeLorenzo and colleagues (22) estimated, from ascertainment of actual cases, an incidence of about 60 cases of SE per 100,000 per year in the United States. Together with Shorvons figures, this would corroborate Celesias estimate of

Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepticus

one-quarter of all SE cases. Still, the diagnosis is often missed, and any ascertainment must be an underestimate. Tomson and colleagues (16) found 1.5 cases of NCSE per 100,000 per year in Sweden, about one-tenth the estimated incidence. Clearly, NCSE is not a rare condition, but it is often not noticed or misdiagnosed. There are certainly many more cases waiting to be diagnosed.

III. PRESENTATION
NCSE presents in protean ways, accounting in part for its underrecognition and

diagnosed with NCSE have not had epilepsy earlier in life but have had benzodiazepine withdrawal or other significant effects of medications on the brain (6). Confusion is a common problem in emergency rooms. NCSE is a possible explanation and is probably missed frequently. In one larger series of patients with NCSE seen in emergency rooms, agitation, lethargy, disruptive behavior, mutism or other language disturbances, delirium, staring, oral automatisms, inappropriate laughter or crying, rigidity, and several other types of bizarre behavior were presenting signs (33). Mistaken diagnoses included metabolic

underdiagnosis. Some patients present with typical absence or complex partial SE, as described earlier, but many other unusual alterations in consciousness, behavior, and neurologic function can be manifestations of NCSE. Focal SE confined to nonmotor areas of the brain may be particularly deceptive. Focal weakness or sensory changes, including visual field abnormalities, may be the manifestation of focal NCSE (23). Visual hallucinations and visual loss similar to those of migraine can be an unusual manifestation of focal NCSE (24). Catatonia (25) and atonia (26) have been described as manifestations of NCSE. Speech difficulties due to dysarthria rather than aphasia can be caused by SE arising in the opercular regions (27). Prolonged somasthetic or visceral sensory disturbances may represent sensory status (28). NCSE may produce diminished responsiveness following electroconvulsive therapy (29). Among the most likely settings for NCSE is following supposed control of convulsive or other SE, but with persistent neurologic dysfunction despite apparently adequate treatment (e.g., Fig. 3). Fagan and Lee (30) described eight patients who had ongoing NCSE after treatment for convulsive status. SE was generalized on the EEG. The patients conditions ranged from confused to comatose, and all improved with treatment. It was surmised that patients might have fared poorly had the NCSE not been discovered. DeLorenzo and colleagues (31) found that nearly half of the patients with apparent control of convulsive SE demonstrated persistent electrographic seizures when followed by EEG and that 14% of the total population monitored warranted a diagnosis of ongoing NCSE. Patients were comatose, but with no overt motor signs, and the diagnosis was made possible by EEG alone. Confusion in the elderly is also a relatively common setting for NCSE (32), but there are

encephalopathies, postictal states, psychiatric disorders, intoxication, and hyperglycemia. Many of the patients had some suggestions that NCSE was a possibility through earlier epilepsy or other neurologic dysfunction, such as strokes. Renal disease and medication or other intoxication were common precipitants.

IV. DEFINITIONS
Making a diagnosis of NCSE is clearly dependant on the definition of the illness or criteria we use for determining that NCSE is a proper label for the patients illness. Definitions have not been accepted uniformly, so different studies describe different clinical entities, leading to some confusion in diagnosis. The underdiagnosis of NCSE and the difference of opinions on appropriate definitions of NCSE surely reinforce one another. Though there is a lack of universally accepted definitions, some features are common to most diagnostic criteria. There are three main features to the diagnostic criteria for NCSE in clinical studies (Table 3). All patients will have clinical neurologic deficits, particularly alterations in alertness and responsiveness. The associated EEG findings and a rapid response to AEDs, particularly benzodiazepines, are variable and are more controversial components of the criteria. Early definitions were particularly demanding. To diagnose complex partial SE, Mayeux and Lueders (34) required prolonged complex partial seizures with continuous focal or secondarily generalized seizures on the EEG or repeated complex partial seizures with a focal EEG. Treiman and Delgado-Escueta (11) required recurrent or persistent complex partial seizures, fluctuating neurologic signs, recurrent epileptiform EEG patterns, and a prompt clinical and EEG response to AEDs. Few patients in more recent series would meet

of course many other possible causes. Many of the elderly patients

these criteria. More recently, Cockerell and colleagues (35) diagnosed CPSE in patients with
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Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepti

FIG. 3. EEG showing persistent generalized epileptiform spike and polyspike discharges in a 29 year-old woman admitted with generalized convulsions; thought to be under control but remained lethargic and did not respond appropriately to questions.

confusion lasting at least 30 minutes, with allowance for persistent or continuous

to 60 minutes with some form of seizure activity on the EEG. Neither required an

epileptiform discharges on the EEG and with no definite requirement of medication responsiveness. For NCSE, Tomson and colleagues (16) required impaired consciousness for an hour and an EEG with continuous seizure activity, while Kaplan (2) sought impaired consciousness for 30

immediate response to AEDs to make the diagnosis. Several papers demonstrate that a response to AEDs may be delayed even up to days (30, 33), and a clinical diagnosis must often be made before there is a clear response to medications. Many astute clinicians have also TABLE 3 made the diagnosis of NCSE and treated Criteria for Diagnosis of NCSE patients successfully, all without an EEG ever 1. Diminished level of consciousness or other being obtained. neurologic deficit There are certain clinical conditions or 2. Epileptiform EEG: typical discrete seizures or situations in which one should retain a high continuous discharges index of suspicion that NCSE may explain the 3. Response to anticonvulsants: clinical and patients altered neurologic function (Table 4). EEG (controversial, often after long delay) By far the most common is following recognized seizures or convulsive SE when the patient has not recovered to baseline despite apparently sufficient treatment. Altered mental status in the
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Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepticus

TABLE Clues to the Recognition of NCSE

Following generalized convulsions or GCSE Subtle signs such as twitching, blinking, and nystagmus in a stuporous patient Otherwise unexplained stupor or confusion, especially in the elderly Altered mental status in the elderly, particularly after benzodiazepine withdrawal History of seizures and a new medical or surgical stress "Stroke plus"

elderly should always prompt a consideration of medication toxicity or medication withdrawal. In the case of benzodiazepine withdrawal (such as after stopping sleep medications) NCSE is not rare. Certainly, patients with altered mental status who have "subtle" signs such as blinking or twitching or

zures, merging seizures, continuous seizures, continuous seizures with brief "flat" periods on the EEG, and prolonged flat periods with periodic discharges. The later stages (4 and 5) are often unaccompanied by actual convulsions and could be considered a type of NCSE. Still, whether these later stages of GCSE are considered actual seizures or SE at the time is quite controversial, and different clinical examples of these stages might fit into one diagnosis of NCSE and not another. Continuous, rapid generalized epileptiform discharges with occasional "flat" periods ("stage 4") are usually associated with a significant clinical deficit and will be considered NCSE or "subtle" SE by most. Subsequent longer-interval periodic discharges ("stage 5") are not accepted by all as evidence of ongoing SE. Still, there is no simple and universally accepted way to distinguish one of these situations from the

spontaneous nystagmus must be considered for the diagnosis. Patients with a history of epileptic seizures may have NCSE precipitated by a new medical illness, trauma, or surgery. Finally, patients who seem to a neurologist to be faring worse or recovering less rapidly than typical from a stroke may have intermittent seizures or NCSE as a partial explanation of the deterioration or lack of improvement.

other, and it is clear that neither responds particularly well to AEDs.

Periodic Lateralized Epileptiform Discharges (PLEDs)

PLEDs are not considered by most epileptologists to be a manifestation of clinical seizures or SE, at least at the time of the EEG recording. Clinical seizures have occurred in at least 80% of PLED patients before the EEG (37 40). Many had prior SE. PLEDs are associated with stroke (the most common cause in many reports), tumors, infections, metabolic disturbances, and earlier epilepsy. Head injury, subdural hematomas, anoxia, brain abscess, congenital lesions, cysts, tuberous sclerosis, multiple sclerosis, and Creutzfeld Jakob disease have all been reported as causes. There is usually acute, serious neurologic illness, and the mortality is highup to 50% within 2 months (41). Almost all reports of PLEDs show EEGs with epileptiform discharges at a frequency of 1 Hz or slower, often every 1 to 2 seconds, some with intervals of up to 10 seconds. The discharge frequency declines over days in a given patient, and most PLEDs will resolve after days to weeks (37). In the largest study of PLEDs to date, Snodgrass and colleagues (40) found that almost 90% of patients had clinical seizures, usually a few days before the EEG showing PLEDs, and two-thirds had some form of SE before the PLEDs. PLEDs may not be a manifestation of seizures at the time, but they are certainly a risk for more seizures, and half the surviving patients without prior epilepsy developed subsequent epilepsy. Snodgrass and colleagues considered PLEDs to be
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V. THE EEG IN NCSE

Making a diagnosis of NCSE traditionally involves the clinical picture of an abnormal mental status with diminished responsiveness, a supportive EEG, and often a response to anticonvulsant medication. Complexities and controversies arise in each area. In particular, a tremendous variety of EEG samples have been offered as supporting a diagnosis of NCSE in scores of cases in the medical literature. The EEGs vary strikingly, and many would probably be rejected by individual epileptologists as insufficient to diagnose NCSE in isolation, though they may be acceptable given the clinical history and course. Some features seem more reliable than others.

EEG Stages in Status Epilepticus

From experimental animal studies and clinical samples from patients with generalized convulsive SE (GCSE), Treiman and colleagues (36) proposed that the EEG in GCSE typically follows a standard evolution through five characteristic stages: discrete sei-

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"the terminal phase of status epilepticus." Most investigators agree. More rapid periodic discharges are typically seen in EEG recordings of actual clinical seizures. The discharge frequency may distinguish between these clinical entities. Most recordings of PLEDs, as described above, would not be considered clinical seizures although those with more rapid discharges (at least >1 Hz and certainly >1.5 Hz) would be read as seizures by most electroencephalographers. No absolute frequency criterion can be used to distinguish PLEDs from seizures. One report of seven patients over the age of 60 described recurrent confusional episodes associated with PLEDs (43). Discharge intervals were as long as 4 seconds. Clinical deficits resolved with a slowing of the EEG discharges, whether spontaneously or prompted by benzodiazepines. Carbamazepine appeared to prevent recurrences, but they did occur when the medication was decreased. The authors considered PLEDs an "unusual status epilepticus of the elderly." PLEDs are generally not considered seizures or SE by themselves, but clinicians must keep an open mind about rules specifying what is and what is not NCSE.

to be no clear difference between continuous and intermittent electrographic seizure activity.

Electrographic Status Epilepticus (ESE)

ESE should be considered as "true" status though treatment is often unsuccessful in effecting a clinical improvement. Many of these recordings appear similar to Treiman's "stage 4" and also to EEGs published in a wide variety of case reports of NCSE. As always, the clinical outcome is determined primarily by the etiology. Many cases are caused by anoxia or sepsis with multiple medical problems, and the outcome is usually poor. Nevertheless, considering such cases as not representing SE because of the inadequate response to medication is analogous to insisting on a successful outcome with antibiotics before diagnosing an infection. Several clinical series have demonstrated that the response to AEDs in NCSE is often delayed or very slow such that clinical decisions must be made long before this evidence is available (30, 33, 45). ESE should be considered a type of SE for several reasons. First, the EEG discharge appearance, rhythmicity, and frequency are characteristic for many clinical reports of SE and similar to those from the study of Granner and Lee (17) (below). Second, the very large majority of patients with ESE have had clinical seizures recently, and most will have clinical seizures following the ESE recording (18, 19, 46), indicating that this is not simply a sign of "burnt out" seizures. For example, patients with ESE, on emergence from pentobarbital treatment, will usually go on to have clinically evident seizures (47). Finally, while many patients with ESE have catastrophic neurologic and medical illness and may not respond to AEDs, many others (especially those without anoxia) will have

Continuous versus Intermittent Discharges

Almost all definitions of NCSE include EEGs with epileptiform spike or sharp wave discharges or slowing and a rapid, rhythmic appearance. These may be included within two or more electrographic seizures with a discrete onset of typical ictal discharges or with continuous discharges throughout the recording. Recurrent electrographic seizures without clinical recovery between them clearly indicate status epilepticus. Continuous discharges are more controversial. Slower discharges constitute PLEDs or PEDs (as

discussed above), but faster discharges would be read by most electroencephalographers as an ongoing seizure. There was no significant clinical difference between intermittent electrographic seizures and continuous discharges (with a discharge frequency of 1 Hz) in the diagnosis of focal SE in one study (23), but this study included all focalSE and not just NCSE. In the large series of SE patients from Richmond, Virginia, intermittent SE (of all types) had a lower mortality than continuous SE, but this was with convulsive clinical activity rather than for NCSE alone (43). Another study found that continuous and intermittent seizures in all forms of SE (not just NCSE) had no difference in outcome (44). For purposes of diagnosis, there appears
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EEG and clinical improvement on medication (So). In the end, it makes most sense to consider ESE as a manifestation of status epilepticus (usually NCSE) and treat accordingly (keeping in mind that some of the causative illnesses are devastating) rather than stating that something is not an epileptic seizure because we might fail to fix it.

Clinical Guidance
Finally, rather than debate what should be seen with NCSE, we can be guided by the EEG patterns actually found in patients with a secure clinical diagnosis. Granner and Lee (17) reviewed EEGs from 85 episodes of NCSE in 78 patients with the clinical diagnosis

Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepticus

TABLE Status Epilepticus: EEG Criteria 1. 2. 3. Epileptiform sharp waves slowing Rhythmicity Rapid discharges: 13.5 Hz

confirmed by EEG and response to AEDs. EEG waveform morphologies were quite variable and included typical and atypical spike wave discharges, multiple or polyspike wave discharges, and rhythmic delta activity with intermixed spikes. Discharge frequency was always 1 to 3.5 Hz (mean 2.2 Hz), and only 4% were 3 Hz or faster. Two-thirds were generalized and 13% focal, with another 18% generalized with a focal emphasis. In summary, EEGs in a wide variety of cases of NCSE share three typical features, shown in Table 5.

trical activity of SE damaged these neurons independent of systemic and metabolic factors. These latter experiments also provided a model of NCSE, but with persistent and very rapid epileptiform discharges. Lothman and colleagues found that kainic acid (whether applied systemically or locally in the hippocampus) particularly affected limbic structures, producing seizures that could be nonconvulsive (51, 52). To overcome concern that the neuronal injury was a direct toxic effect they also used electrodes implanted in the rat hippocampus (53, 54). Rapid repetitive stimulation for 30 to 90 minutes led to seizures and self-sustaining SE persisting for 12 to 24 hours after the stimulation ceased. Electrographic seizures included rapid discharges, often over 10 Hz. Animals with frequent limbic seizures or SE sustained hippocampal neuronal loss, but those with briefer and less frequent seizures did not (55).

VI. MORBIDITY: DAMAGE FROM NCSE

Neurologists agree that NCSE should be avoided, but the exact long-term risk from an episode of NCSE is far less certain. In trying to discern the longerlasting risks one must consider both experimental and clinical information.

Experimental Results
The pathology of GCSE was detailed by Meldrum and colleagues in the 1970s, just as NCSE was becoming recognized clinically. Their landmark studies laid the foundation for our understanding of the neuronal and neurologic effects of convulsive status. They induced episodes of GCSE lasting up to 5 hours in baboons (48). The typical EEG showed brief runs of 10- to 20-Hz spikes followed by 2- to 3-Hz polyspikes. After hours of seizures it still showed rapid epileptiform discharges punctuated by flat periods. Subsequent pathologic studies showed neuronal damage in the neocortex, cerebellar Purkinje and basket cells, and hippocampus (49). Much of the damage appeared to correlate with the associated hyperpyrexia, hypotension, hypoxia, acidosis, and hypoglycemia. Paralysis and artificial ventilation in baboons with similar seizures and EEG activity led to reduced neuronal damage, indicating that control of systemic factors provided some protection (50). Nevertheless, even with maintenance of normal homeostasis, SE led to hippocampal neuronal loss, suggesting that the elec-

Chemical and electrical methods of inducing SE may damage neurologic tissue independent of the subsequent seizures, leaving open the question of whether it is the seizures and SE or the precipitant itself that damages neurons. To address this, Sloviter (56) showed that indirect electrical stimulation via the perforant pathway (the primary afferent excitatory pathway to the hippocampus) induced damage restricted to hippocampal neurons in rats. The typical stimulations used to provoke experimental SE have been intense, and the intensity of the resulting epileptiform discharges appears to correlate with the likelihood of neuronal damage. Lowenstein and colleagues (57) used flurothyl to induce seizures in paralyzed ventilated rats and found evidence of neurologic damage in the amygdala and pyriform cortex strongly associated with prolonged, "high-frequency" (ca. 10 Hz) discharges, but there was no damage following discharges slower than 1 Hz. Damage was directly related to the duration and intensity of electrographic seizure activity. The electrical activity of different types of SE varies considerably. Many of these experiments used prolonged, high-frequency stimulation to provoke SE, and the resultant electrographic seizure discharges were also of high frequency and often sustained for hours. Discharges greater than 3 Hz are common in generalized clinical seizures (58), and many of these models produced sustained discharges of 615 Hz, possibly more representative of GCSE than of NCSE, with its usually less dramatic electrographic patterns. Human NCSE is not simply generalized convulsive SE without the convulsions. It may be sustained for hours or days but seldom includes the high-frequency
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Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepti

discharges characteristic of generalized convulsions in humans or in the experimental paradigms discussed. Many of the models establish a clear correlation between the intensity of the electrical seizure activity on one hand and the extent of neuronal damage on the other. With less intense seizure activity, neuronal damage may be minimal or even absent. If the electrical activity of NCSE is often insufficient to cause lasting neuronal damage, it becomes unclear exactly how well these high-intensity stimulation models can be extrapolated to human NCSE, and we must turn to clinical studies. Human pathologic studies of the effects of SE have been scarce, in part because fatal cases are often associated with acute, severe brain-injuring illnesses such as ischemic strokes, hemorrhages, and encephalitis, all of which may cause damage independently. One case control study (59) examined hippocampal cell densities in patients who died after episodes of GCSE in comparison to those of matched patients with epilepsy but no SE and to normal controls. SE patients had significantly decreased hippocampal densities compared with normals and somewhat less than in epilepsy controls, suggesting that the episodes of SE were responsible for the additional damage. Episodes of NCSE are seldom fatal unless they occur in association with GCSE or other acute, severe neurologic illnesses, in which case it is difficult to sort out the offending agent. For the most part, pathologic studies of patients with pure forms of NCSE remain unavailable.

Clinical Morbidity
Lothman (51) has summarized the many physiologic changes (such as acidemia and hypotension) that occurduring SE, but most apply to GCSE. Studies of the long-term

ment. No long-term sequelae were noted in several prominent series (46). CPSE. Early reports on CPSE included very few patients. Most returned to normal or "baseline cognitive function" (10, 34, 61), but not all were studied thoroughly with subsequent neuropsychologic tests. In a more recent CPSE series (35), none of 20 patients had cognitive deterioration, and 5 had meticulous neuropsychologic assessment. Krumholz and colleagues (62) reported 10 patients with CPSE for 36 hours or longer, all of whom had lasting neurologic deficits. Two patients each had strokes or encephalitis, and another three had multiple medical problems that may have contributed to the deficits. Three patients had refractory epilepsy, and all sustained prolonged memory deficits, lasting 3 to 24 months, but at least 2 improved. CPSE occurred more frequently in medically sick patients, raising the question of synergistic harmful effects of NCSE and medical illnesses. Other individual reports (9, 11) also found prolonged memory deficits after NCSE; it is uncertain whether they are permanent. NCSE. Reports of NCSE not necessarily specifying absence SE or CPSE are more numerous (16, 32, 63 65). They show few long-term sequelae, but most include limited follow-up. That of Guberman and colleagues (63) is exceptional by including 5-year followup on 8 patients, showing no intellectual, memory, or behavioral deterioration. Scholtes and colleagues (65) evaluated 65 patients and found good outcomes in all but one. ESE. Patients with ESE in the setting of serious medical illness have a terrible prognosis, but it is not possible to dissect out that portion of the long-term harm done by epileptiform discharges or NCSE (18, 19, 46, 66). Most clinical studies of the effects of SE are pediatric and retrospective. Several have found negative consequences, but it is very

effects of SE must assess clinical consequences, including subsequent seizure frequency and cognitiveneuropsychologic function following an episode of SE. Seldom can a baseline be assessed before the SE to see if there is a change. Most studies are of GCSE, and it correlates with worsened seizure control, but this may be due to the underlying illness causing SE rather than to the episode itself (60). Nevertheless, there may be a subset of patients with a worsened clinical course following SE. Absence SE. Most authors have found little longterm morbidity from absence SE. Nevertheless, this conclusion usually rests on clinical impressions in moderate-sized series rather than on actual measure
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difficult to control for many variables. Comprehensive neurologic and neuropsychologic evaluations before and after SE are seldom available. Also, patients with a progressive illness worsen, whether or not related to the SE, and many patients with neurologic deficits fluctuate with time. Finally, it is difficult to control for the influence of AEDs. Medications, doses, serum levels, and drug interactions may change frequently in patients with refractory epilepsy, including at the time of testing. Dodrill and Wilensky (67) obtained neuropsychologic testing on 143 adults with epilepsy. Nine had episodes of SE over a 5year interval, and these patients worsened neuropsychologically while some

Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepticus

control patients improved, but SE patients had an average 14-point lower IQ score before the SE and were taking an average of 2.8 AEDs versus 1.7 AEDs for controls. Maytal and colleagues (68) studied 193 children with SE, almost all convulsive. Seventeen had cognitive and other deficits after the SE, usually attributed to an acute illness such as a stroke. They concluded that "the major neurologic sequelae are usually due to the underlying insult rather than to the prolonged seizure itself."

VII. TREATMENT
Although clinical studies show little evidence of permanent neurologic injury from episodes of NCSE it would be unwise to ignore the prolonged memory dysfunction in several well-reported cases, and NCSE has some similarities to convulsive SE (69). It is possible that a minority of episodes of NCSE

biturates, benzodiazepines, and ethosuximide can be effective (5). Intravenous phenytoin can also help (3). Absence SE due to benzodiazepine withdrawal (e.g., de novo absence status in the elderly) usually responds to brief courses of benzodiazepines, although barbiturates may also be helpful (6). With such an acute precipitant, long-term treatment may be unnecessary. When longer treatment is necessary, valproate has been effective in preventing recurrences (72), but this does not mean that other medications would be ineffective, especially given the overlap syndromes and the possibility that many episodes of absence SE are actually focal-onset, secondarily generalized seizures. Infrequently, AEDs, including vigabatrin and tiagabine, have been reported to precipitate or worsen generalized NCSE (73, 74). Complex partial SE may be interrupted and controlled by traditional intravenous medications, phenytoin and phenobarbital (9) or oral carbamazepine (10). More frequently,

might lead to significant deficits. From case reports and by analogy to GCSE, the more prolonged cases may be worse (70), and NCSE may last for days without proper diagnosis. Concomitant systemic factors such as infection, metabolic disturbances, hypotension, and medications might increase the likelihood of damage in a synergistic fashion (62). Episodes associated with focal lesions such as strokes may involve two processes, with a greater chance of lasting harm (71). Finally, by extrapolation from experimental studies (57) episodes of NCSE with more rapid (and presumably excitatory) epileptiform discharges may be more worrisome. Patients with NCSE should be treated quickly with AEDs for several reasons. They are clearly ill with ongoing seizures and have impaired consciousness and other neurologic deficits that are potentially reversible and certainly treatable. Also, NCSE, like other forms of SE, entails the attendant morbidity of incidental trauma, aspiration pneumonia, etc. Additionally, many episodes of NCSE begin with and may end with generalized convulsions, in turn potentially harmful. Finally, we must remain alert to the possibility that some prolonged episodes might cause lasting damage. NCSE remains an underdiagnosed, treatable condition and one well worth both diagnosing and treating. Treatment of NCSE is often easier than diagnosis, but when the initial treatment is unsuccessful subsequent treatment can become far more complicated and difficult. Straightforward absence SE may be terminated by benzodiazepines relatively quickly. Other treatments such as carbon dioxide inhalation, oral bar-

intravenous benzodiazepines are used to interrupt the NCSE once it is recognized (75). Nevertheless, CPSE is often recurrent (35), and patients are much less likely to remain off medication. In occasional cases of NCSE, patients recover spontaneously (16). Benzodiazepines are used nearly uniformly in the attempt to interrupt NCSE in the rest of patients, and they are often successful (16, 63). Lorazepam may be the preferable drug (33). Nevertheless, there are clearly many cases in which the NCSE proves resistant (35, 76). In a recent series of patients with NCSE where the foci were found to be primarily in frontal areas (45) there was often a delay of 2 days before diagnosis. In most of these refractory patients, intravenous benzodiazepines were unsuccessful in breaking the SE. Most responded to intravenous phenytoin, but one required pentobarbital. Electrographic status or the NCSE discovered after known convulsions or GCSE can be even more refractory (46). In one large series, only 60% of patients with NCSE had an initial response to benzodiazepines (17). Benzodiazepines often improve the EEG without leading to clinical improvement. Higher doses of longacting intravenous medication such as phenytoin and phenobarbital (30, 77) or increasing levels of already used AEDs (33) may be helpful. In the end, even patients with periodic discharges or PEDs (whether considered SE or not) actually did reasonably well, as long as anoxia was not the cause (78), and most returned to baseline. In the idealized case, any form of NCSE is diagnosed readily and responds immediately to intravenous benzodiazepines. This is not a rare scenario, but
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312

Presentation, Evaluation, and Treatment of Nonconvulsive Status Epilepti

it is unlikely to cover most patients. Fortunately, given the relatively minimal evidence of ongoing damage and rapid establishment of lasting neurologic deficits due to NCSE, treatment probably need not be as aggressive as for continuing convulsive SE. Many of the treatments cited above occurred over days though this is not the recommended plan. It is relatively rare that patients will need such aggressive treatment as pentobarbitalinduced coma or treatment with such substitutes as propofol, ketamine, and much higher doses of benzodiazepines such as lorazepam and midazolam. Still, there are many reasons for treating NCSE expeditiously. Treatment should be individualized and judicious (2) but should not be delayed. NCSE presents in remarkably varied ways but often in typical situations such as following other seizures or in the setting of acute stroke. Because there are no motor manifestations, the diagnosis is missed frequently, but it is also made frequently by astute neurologists and other clinicians. The diagnosis is well worth making because NCSE impairs the patients health significantly, and it is often a treatable and completely reversible condition.

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