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Nonconvulsive status epilepticus: Treatment and prognosis

Nonconvulsive status epilepticus: Treatment and prognosis
Authors:
Jeffrey Jirsch, MD, MSc., FRCPC
Lawrence J Hirsch, MD
Section Editor:
Paul Garcia, MD
Deputy Editor:
John F Dashe, MD, PhD
Literature review current through: Dec 2022. | This topic last updated: Jul 20, 2021.

INTRODUCTION — Nonconvulsive status epilepticus (NCSE) was originally described in patients with chronic epilepsy, but it is now recognized with increased frequency in other patient populations, especially the critically ill. The diagnosis and treatment of NCSE are not straightforward and depend on many variables, including the clinical setting and etiology, electroencephalography (EEG) findings, and the clinical status of the patient.

This topic reviews the treatment and outcomes of NCSE. Other aspects of NCSE are discussed separately. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis".)

Convulsive status epilepticus is reviewed elsewhere. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis" and "Convulsive status epilepticus in adults: Management" and "Clinical features and complications of status epilepticus in children" and "Management of convulsive status epilepticus in children".)

APPROACH TO PHARMACOLOGIC THERAPY — Unlike convulsive status epilepticus, which is a relatively uniform entity that is amenable to standard treatment algorithms, NCSE is more heterogeneous. Treatment must be tailored to the perceived urgency and morbidity of the underlying condition and the individual patient.

How aggressively should one treat? — There is considerable controversy about whether to treat NCSE as aggressively as convulsive status epilepticus, and there are no randomized studies upon which to base treatment decisions [1]. Most of the literature deals with critically ill patients and those in the aftermath of convulsive status epilepticus, with sparse data on treatment approaches for NCSE in patients who have only mild alteration in consciousness, such as those with focal SE with or without alteration in consciousness (previously known as simple or complex partial status epilepticus, respectively).

Treatment of NCSE is not covered in status epilepticus guidelines published by the Neurocritical Care Society [2] or the American Epilepsy Society [3]. Guidelines of the European Federation of Neurological Societies simply recommend treating NCSE like convulsive status epilepticus, but with additional attempts at non-coma-inducing treatment with before moving to the use of anesthetic drugs [4]. Most medications used for the treatment of NCSE are not formally approved by regulatory agencies for any type of status epilepticus

Whether or not patients benefit from treatment for certain EEG findings, including intermittent, brief nonconvulsive seizures, is currently unknown [1,5]. How aggressively to treat depends in part upon how likely it is that the neurologic deficit is a consequence of the EEG findings; this relationship is not always clear, particularly in the critically ill.

Rationale for aggressive treatment – The rationale for aggressive treatment (ie, using multiple antiseizure medications, including consideration of intubation and anesthetic medications) is based on animal data suggesting that NCSE superimposed on acute brain injury is injurious to neurons [6,7], as well as the following data in humans:

Small studies in patients with traumatic brain injury support the notion that the acutely symptomatic brain may be more susceptible to injury from seizures, as measured by elevations in various markers of brain injury, including extracellular glutamate and lactate-to-pyruvate ratio [8-13], and, later, hippocampal atrophy on magnetic resonance scans [14].

Nonconvulsive seizures after intracerebral hemorrhage have been associated with hematoma expansion and increased midline shift [8,15], and nonconvulsive seizures after subarachnoid hemorrhage and traumatic brain injury may result in transient brain hypoxia, metabolic crisis, and increased intracranial pressure [13,16].

Nonconvulsive seizures have been associated with elevated neuron-specific enolase (NSE), a key enzyme for energy metabolism and a marker of acute brain injury as well as damage to the blood brain barrier, in the absence of other causes of brain injury beyond seizures [17,18]. In addition, absolute levels of NSE correlated with the duration of status epilepticus, suggesting that early treatment of nonconvulsive seizures may be beneficial [18].

Multiple observational studies in adults and children have found that NCSE and nonconvulsive seizures are independent predictors of poor outcome [7,19-22] and later epilepsy [23]. Several studies have also demonstrated that higher seizure burdens are associated with worse short- and long-term outcomes, including disability and cognition [24,25]. In addition, seizure duration and delay in diagnosis have been associated with higher mortality.

Rationale against aggressive treatment – The argument against aggressive treatment of some forms of NCSE is based primarily on observations that the prognosis of patients with nonconvulsive seizures or NCSE largely depends on many factors other than seizure control, of which etiology and age are probably most important [26-29]. One retrospective study compared critically ill older patients with NCSE treated aggressively with intravenous (IV) benzodiazepines in an intensive care unit (ICU) with those treated less aggressively outside of the ICU because their advance directives mandated avoidance of aggressive care and intubation [27]. The use of IV benzodiazepines was associated with prolonged hospitalization and increased mortality despite similar severity of illness.

Initial therapy for patients presenting with NCSE — For the initial treatment of adults who present with NCSE, we suggest an IV benzodiazepine in combination with a non-coma-inducing IV antiseizure medication. Suggested loading doses are provided in the table (table 1); reloading (not to exceed the total daily [24-hour] maximum dose) may be required, as guided by continuous EEG monitoring; in some cases, repeat dosing may be required within minutes if ictal activity is not immediately aborted; in other cases, repeat dosing may be required at the next scheduled EEG interpretation hours later if ictal activity is detected.

A typical initial regimen is lorazepam 2 to 4 mg combined with any one of the following antiseizure medications:

Fosphenytoin (15 mg phenytoin equivalents [PE]/kg at a maximum rate of 150 mg PE/minute; maximum dose 2000 mg)

Valproate (30 mg/kg IV at a maximum rate of 5 mg/kg per minute; maximum cumulative dose after reloading of 4000 mg)

Levetiracetam (40 mg/kg IV bolus, maximum 4500 mg, over 15 minutes)

Lacosamide (200 mg IV bolus over 15 minutes)

Note that doses used for NCSE are lower than those used for convulsive SE as there is time to give a lower dose, assess the acute response, and give more if needed; in convulsive SE, there is no time for this, and the full loading doses should be given immediately.

Therapy for NCSE should be administered under close clinical supervision and with continuous EEG monitoring in most cases. In patients with preexisting epilepsy, optimization of antiseizure medications currently utilized may be of value, especially when nonadherence to the outpatient regimen is suspected.

If NCSE persists after IV doses are given, repeat doses can be given without significant delay (within minutes) of any of the above at the same or lower dose.

A concerted effort should be made to diagnose and treat NCSE as quickly as possible but with minimal sedation, in order to avoid inducing or prolonging coma and intubation. This practice places a high value on avoidance of harm associated with risks of deep sedation and prolonged intubation (eg, deep venous thrombosis, pneumonia, sepsis), since these risks may be higher than the risk of neuronal injury from NCSE itself in most cases. Potential exceptions include patients with acute brain injury and those with NCSE in the aftermath of convulsive status epilepticus. (See 'How aggressively should one treat?' above and 'Refractory nonconvulsive status epilepticus' below.)

Support for the use of benzodiazepines and other antiseizure medications for NCSE is primarily extrapolated from data in patients with convulsive status epilepticus.

Benzodiazepines – In clinical trials, the use of benzodiazepines for convulsive status epilepticus is associated with shorter seizure duration and a lower risk of cardiorespiratory complications compared with placebo [30]. However, some observational data suggest that overtreatment (defined as using doses >130 percent of the recommended doses) might be associated with a higher need of intubation [31].

Antiseizure medications – Any of the IV antiseizure medications used for convulsive SE can also be used for NCSE, such as levetiracetam, fosphenytoin/phenytoin, valproate, and lacosamide. The first three of those antiseizure medications were shown to be equivalent in efficacy and tolerability for treatment of CSE in a large prospective randomized controlled trial [32]. In genetic generalized epilepsy, valproate is clearly preferred, as fosphenytoin/phenytoin (as well as other sodium channel-blocking agents) may exert a paradoxical effect.

Data from randomized clinical trials specifically to the treatment of nonconvulsive seizures or NCSE are limited. In one trial of 74 patients with refractory nonconvulsive seizures (NCSE was an exclusion), lacosamide was noninferior to fosphenytoin, with a seizure control rate of 63 percent (versus 50 percent with fosphenytoin) and a similar rate of adverse events [33].

Likelihood of response to initial therapy — The likelihood of success with initial pharmacologic treatment of NCSE varies according to the subtype of NCSE [31,34,35]:

Absence status epilepticus – Typical, atypical, and myoclonic absence status epilepticus are most often aborted with benzodiazepines or valproate, without need for anesthetic sedation, even after long delays in treatment initiation [36].

Focal NCSE without impairment of consciousness – Focal status epilepticus without impairment of consciousness (previously known as simple partial status epilepticus) usually has an adequate treatment response with standard IV antiseizure medications; aggressive coma-inducing anesthetics are usually either not necessary or avoided nonetheless, even in cases that are difficult to treat.

Focal NCSE with impairment of consciousness Focal status epilepticus with impairment of consciousness (previously known as complex partial status epilepticus) typically has a good response to initial therapy, but clinical improvement may be delayed.

NCSE in coma – NCSE in coma, often seen after convulsive status epilepticus, may be resistant to initial therapy and subsequent therapies, especially if treatment is delayed, and may require additional treatment with intubation and coma-inducing anesthetic agents.

An approach to further decision making in the setting of refractory NCSE is discussed below. (See 'Refractory nonconvulsive status epilepticus' below.)

Treating the underlying cause — As with other types of seizures and status epilepticus, identifying and treating the underlying etiology of the NCSE is a necessary component of successful management. This includes careful review of the medication list to identify potential causative drugs, such as a beta-lactam antibiotic in a critically ill patient with renal dysfunction. Frequently, the concomitant use of supportive medical strategies (eg, glucocorticoids for vasogenic edema, acyclovir for herpes simplex virus encephalitis) or surgical interventions (eg, draining of brain abscess, resection of brain tumor) are crucial in the treatment of NCSE. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis", section on 'Etiology'.)

Refractory nonconvulsive status epilepticus — Refractory status epilepticus (RSE) refers to status epilepticus that continues despite administration of therapeutic doses of two or more antiseizure medications.

Most experts are reluctant to advocate the use of anesthetic agents for NCSE except in certain circumstances. Examples of situations that may warrant aggressive therapy and iatrogenic coma:

Aggressive treatment warranted – For patients with definite NCSE, we suggest ongoing treatment that includes the use of coma-inducing anesthetic medications in the following situations:

NCSE in the aftermath of convulsive status epilepticus, which has consistently been associated with worse outcomes than CSE without subsequent NCSE [37,38].

NCSE and frequent refractory nonconvulsive seizures in patients with acute brain injury (eg, intracranial hemorrhage, traumatic brain injury), which have been associated with increased brain injury, metabolic stress, and worse outcomes [8,12-16,39] (see 'How aggressively should one treat?' above).

NCSE in the setting of cryptogenic new-onset refractory status epilepticus (NORSE) [40], which defines a clinical presentation, not a specific diagnosis, of RSE for which no etiology is identified within the first 72 hours after admission in a patient without active epilepsy or other preexisting, relevant, active neurologic disorder.

This typically requires continuous infusions of midazolam, propofol, ketamine, or pentobarbital in the intensive care unit. This approach is presented in detail elsewhere. (See "Convulsive status epilepticus in adults: Management".)

Aggressive treatment rarely required – Certain situations rarely require the use of sedation and intubation; these are important to identify early so that inherent complications (eg, sepsis, thrombosis) can be avoided:

Absence (typical or atypical) status epilepticus and focal status epilepticus without impairment of consciousness generally respond well to initial therapies and have good neurologic outcomes, provided that adequate dosages of nonsedating antiseizure medications are used; sedation and intubation are very rarely required.

Focal status epilepticus in patients with impaired awareness, but who are not comatose, is most often successfully managed with nonsedating IV antiseizure medications alone, although repeated trials of multiple medications may be required.

In cases where sedation and coma are to be avoided, a typical approach to refractory NCSE includes sequential trials of non-coma-inducing IV antiseizure medications not previously administered (phenytoin/fosphenytoin, valproate, lacosamide, and levetiracetam) (table 1). Of note, most medications in critically ill patients have altered pharmacokinetics due to organ failure and/or low protein levels associated with a catabolic state. Higher doses and more frequent dosing may be required in some patients to achieve therapeutic steady state drug levels, particularly for valproate and levetiracetam.

Administration of certain oral antiseizure medications not available in IV form, such as topiramate [41], pregabalin [41], clobazam [42], oxcarbazepine [43], perampanel [44,45], brivaracetam [46], vigabatrin, or stiripentol [47], may also be of some value as add-on therapies, although the evidence for these treatments is limited to uncontrolled case series. Of note, oral/enteral bioavailability may be limited in critically ill patients due to ileus, intestinal wall edema, and visceral hypoperfusion; IV formulations are preferred when available.

OUTCOME AND PROGNOSIS — There are seemingly conflicting data on the morbidity and mortality associated with NCSE, but this is primarily because NCSE includes two quite distinct groups of patients:

Ambulatory patients, usually with a history of epilepsy, have a relatively good prognosis

Acutely ill, stuporous, or comatose patients with NCSE have a much poorer prognosis

The prognosis for typical, atypical, and myoclonic absence status epilepticus (ASE) is usually excellent without evidence of neuronal damage or sequelae on later examination [36].

Predictors of poor outcome – Risk factors for worse outcome include acute brain disease, severe mental status impairment, and longer seizure duration [7,28,37,48,49]. In a series of 100 patients with NCSE, 18 percent of patients died [28]. Worse outcome was seen in patients with an acute medical (systemic or neurologic) cause of NCSE (27 percent mortality) as compared with those without an acute medical cause (3 percent). Patients with severe mental status impairment had a mortality rate of 39 percent.

Among the acutely ill, non-ambulatory patients, NCSE appears to be associated with a worse prognosis compared with convulsive status epilepticus [37,50]. In a large randomized trial comparing four different treatment regimens for status epilepticus, 30-day outcomes were significantly worse for patients with NCSE compared with those with clinically overt status epilepticus (hospital discharge 9 versus 50 percent; mortality 65 versus 27 percent) [50]. NCSE in the aftermath of convulsive status epilepticus is also associated with higher mortality compared with those whose EEG does not show ongoing seizures (51 versus 13 percent) [37].

Refractory status epilepticus – Outcome in refractory status epilepticus (RSE), which almost always becomes nonconvulsive even if it began as CSE, is poor. Mortality is almost 50 percent, and only a minority of patients return to their premorbid functional baseline, primarily those with preexisting epilepsy and no acute brain process [48,51-53]. Similar to status epilepticus in general, mortality in RSE is associated with older age, etiology (especially anoxic injury and subarachnoid hemorrhage), long seizure duration, and high Acute Physiology and Chronic Health Evaluation-2 (APACHE-2) scale scores (calculator 1) [7,54,55].

Despite these data, some patients with very prolonged RSE (requiring weeks to months of iatrogenic coma) still recover with an excellent outcome [56,57].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in adults".)

SUMMARY AND RECOMMENDATIONS

In the critically ill coma population, there is considerable controversy about whether to treat nonconvulsive status epilepticus (NCSE) as aggressively as convulsive status epilepticus. In all patients with NCSE, a concerted effort should be made to diagnose and treat seizures as quickly as possible but with minimal sedation, trying to avoid inducing or prolonging coma and intubation. (See 'How aggressively should one treat?' above.)

For patients presenting with NCSE, we suggest treatment with an intravenous (IV) benzodiazepine under closely monitored conditions with continuous electroencephalography (EEG), combined with an IV non-coma-inducing antiseizure medication (Grade 2C). Dosing is lower than that used for convulsive status epilepticus (SE), with repeat doses given as needed (table 1). (See 'Initial therapy for patients presenting with NCSE' above.)

The likelihood of success with initial pharmacologic treatment of NCSE varies according to the subtype of NCSE. Absence status epilepticus and focal status epilepticus without impairment of consciousness usually have a good response to treatment without the need for aggressive coma-inducing anesthetics. Focal status epilepticus with impairment of consciousness (but without coma) typically has a good response to initial therapy, although clinical improvement may be delayed. In contrast, NCSE in coma, which can develop de novo or after convulsive SE, may be refractory to multiple initial therapies and require intubation and coma-inducing anesthetic agents. (See 'Likelihood of response to initial therapy' above.)

Treatment of refractory NCSE must be individualized. We favor ongoing aggressive treatment in patients with NCSE in the aftermath of generalized status epilepticus, in those with acute brain injury, and in those with cryptogenic new-onset refractory status epilepticus (NORSE), assuming the patient's underlying condition does not preclude a chance for neurologic recovery. Such treatment typically requires continuous infusions of midazolam, propofol, ketamine, or pentobarbital in the intensive care unit. (See "Refractory status epilepticus in adults", section on 'Definition and etiology'.)

Ambulatory patients with NCSE, usually with a history of epilepsy, have a good prognosis, whereas acutely ill, stuporous, or comatose patients with NCSE have a poorer prognosis. (See 'Outcome and prognosis' above.)

Refractory status epilepticus (RSE), which is usually nonconvulsive, is associated with a mortality rate of up to 50 percent. Poor outcomes are driven primarily by the underlying acute process associated with NCSE rather than the seizures themselves, although prolonged nonconvulsive seizure activity may cause secondary neuronal injury and worse outcomes, especially in those with acute brain injury. (See 'Outcome and prognosis' above.)

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References