In recent years, there have been increasing attempts by physicians to better define and classify NCSE, in order to establish treatment paradigms for different subtypes. Instead of the traditional dichotomy, some clinicians suggest that classification should be more elaborated. First, NCSE can be divided into two categories: the generalized and the focal NCSEs. The generalized NCSE comprises typical absence SE, atypical absence SE and late-onset absence SE. The focal NCSE consists of simple partial SE (SPSE), complex partial SE (CPSE) and subtle SE [10]. Regardless of the type, the classification scheme is mainly based on clinical symptoms and EEG features. However, in fact, it is sometimes quite difficult to distinguish between generalized and focal NSCE, especially when there is no EEG available. Even with the availability of EEG data, it is still hard to differentiate these subtypes because the EEG pattern can be a transient phenomenon. For example, it can be focal initially and transform to be generalized later, or the opposite [11]. Therefore, clinicians should take advantage of all information available to determine the subtypes, with at least diagnosis of NCSE in extreme difficulties.
Unlike convulsive status epilepticus which is easy to diagnose from the clinical manifestations, NCSE is often misdiagnosed, sometimes even undetected because of its protean symptoms. Therefore, NCSE was used to be considered as a rare condition. In this report, the 4 cases were diagnosed as NCSE according to the 2017 ILAE classification [12], and most of them presented with impaired consciousness (confused, slow reaction and lags in response) and some strange behaviors (being upset and restless or washing hands repeatedly). None of them had any obvious motor symptoms like tonic or clonic movements. Notably, the clinical signs of case 4 were so mild that spectators may overlook these abnormities and come to a conclusion of “Nothing wrong with her. Maybe she is just a little tired”. Indeed, the semiology of NCSE is diverse and daedal. Some patients present with typical absence or complex partial SE, whereas some may display other unusual alterations of consciousness (varying from mildly inattentive, confused, somnolent to unresponsive), affect (euphoric, anxious, amused, etc.), behavior (agitated, bizarre and inappropriate; Fugue states), speech and language (slow or decreased speech and volume; dysarthria, speech arrest), motor (staring, blinking, bradykinesia; automatisms like chewing, grimacing, licking, kissing, picking, and ambulation; subtle facial, perioral, and limb myoclonus, tremor, apraxia, clumsiness; head deviation) and autonomic/vegetative symptoms [2, 8]. Even comatose patients without overt seizure activity may meet the diagnosis criteria of NCSE [9, 13]. Most symptoms of NCSE are so inconspicuous that they can be easily neglected by others, even the family members. Moreover, it is not uncommon for some clinicians to mistake NCSE for postictal confusion after a generalized tonic-clonic seizure [14], transient global amnesia, hysterical fugue states, acute psychosis, migraine aura, posttraumatic amnesia, and severe depression, which may result in the underrecognition and underdiagnosis of NCSE [3, 10].
Apart from the above clinical manifestations, EEG also plays an important role in the diagnosis of NCSE. Under some circumstances where clinical signs are subtle or even absent, EEG is becoming especially valuable. However, we have to note that EEG interpretation is a subjective “art”, and diagnosis of NCSE based on it may not come to consistency among interpreters. Furthermore, EEG of NCSE can have various forms, which makes it more difficult to interpret. Some clinicians suggest that the typical EEG features of NCSE are typical spike-and-wave, atypical spike and wave, multiple spike-and-wave, and rhythmic delta with intermittent spikes. These discharges may be continuous or persistent with brief pauses of a few seconds, or intermittent [15]. Some have also mentioned that different subtypes may show different EEG patterns. ASE usually manifests with continuous or frequently recurring generalized spike and wave discharges during ictal period, and the number of spikes per wave is > 1 [16]. CPSE manifests with continuous or persistent sharp wave and spike-and-wave discharges, which can have a generalized onset or a focal onset which frequently progresses into the generalized pattern [17]. In this report, EEG of the 4 cases initially manifested with either a focal or a generalized onset, then evolved into spike-and-wave pattern gradually. Three cases, except for case 2, all presented with focal predominance. To facilitate clinicians to recognize and diagnose NCSE, the following EEG diagnostic criteria have been suggested: frequent or continuous focal electrographic seizures; the amplitude, frequency and spatial distribution can be changing with time; patients without a pre-existing epilepsy history manifest with frequent or continuous generalized spike wave discharge; in patients with an epileptic encephalopathy/syndrome, EEG presents with frequent or continuous generalized spike wave discharges which are significantly different in intensity or frequency (usually a faster frequency) from baseline EEG; patients who are in coma after a generalized tonic-clonic SE show periodic lateralized epileptiform discharges or bilateral periodic epileptiform discharges [18].
According previous studies, the underlying causes and medical conditions of NCSE may include pre-existing epilepsy, metabolic disorders, alcohol withdrawal, the use of some neuroleptic/psychotropic drugs, cerebral infarction or hemorrhage, infection like meningitis and encephalitis, sepsis, carbon monoxide and toxic [10, 19]. There are even some case reports of NCSE associated with AEDs, like tiagabine [20]. Among the 4 cases, three had a history of complex partial epilepsy but none of them experienced any other medical conditions, so the pre-existing epilepsy may be the possible cause for the NCSE. Case 4 did not have a pre-existing history of epilepsy, but she was diagnosed as diabetes mellitus several years ago. Metabolic disorders have been reported as the underlying causes of NCSE in previous studies, so we inferred diabetes mellitus contributed to NCSE of this patient.
As far as is concerned, the most challenging work for clinicians is to diagnose NCSE rather than to treat it. Nevertheless, there is still debate over how aggressive the treatment should be. The most widely-accepted opinion is that the treatment should be individualized, due to the diverse causes and types. Typical ASE is usually treated by intravenous administration of 10 mg of diazepam or 4 mg of lorazepam, which can be repeated if the seizures continue 10 min after the treatment [10]. Atypical ASE may not have a favorable response to benzodiazepines. Valproic acid and phenobarbital are reasonable alternatives. In patients with pre-existing epilepsy, SPSE and CPSE may respond to benzodiazepines rapidly, sometimes even spontaneously terminate without any medical therapy. In this report, the first three patients with pre-existing partial epilepsy all responded well to benzodiazepines (diazepam) in both clinical and EEG aspects. As for those without a history of epilepsy but with other underlying causes and medical conditions, SPSE and CPSE are usually refractory to the first-line treatments. In that case, subsequent intravenous phenobarbital or valproic acid should be added [21]. However, here we found that in the case 4 patient who did not have a previous history of epilepsy, the clinical signs gradually disappeared after an oral administration of levetiracetam, without intravenous medicine like benzodiazepines, phenobarbital or valproic acid. Therefore, it remains unknown whether the NCSE terminated spontaneously or because of the medicine, though levetiracetam has also been proved to be an effective treatment in recent years [22, 23]. Although medical treatment has been proved to be helpful, in some occasions aggressive treatment can have a greater risk on morbidity and mortality [24, 25]. For example, comatose NCSE patients treated with benzodiazepines may worsen [26], so caution should be taken with drug administration.
The outcome assessment of NCSE is challenging for clinicians because it is difficult to separate the effects of ongoing seizure activity from those of an underlying course and complications which occur in the clinical course. The prognosis of NCSE remains controversial. Some case series have reported high mortality and morbidity rates. Shneker et al. found that 18 NCSE patients in their series died (18%), and suggested that the mortality is significantly associated with the underlying etiology, severe mental status impairment, and development of acute complications [27]. Kjersti and his colleagues reported a poor outcome in 48 NCSE patients: 3 died (6.3%), 4 had severe sequelae (8.5%) and 7 had cognitive sequelae (14.9%). They concluded that the absence of previous seizures is a predictor for a worse outcome than the patients with epilepsy before NCSE [28]. Also, some clinicians have emphasized that NCSE, especially CPSE, can lead to a poor outcome: death, persistent or permanent cognitive or memory loss, and motor and sensory dysfunction [29]. Furthermore, some researchers have confirmed that serum neuron-specific enolase (s-NSE), a marker for acute neuronal injury, is increased significantly in NCSE patients, indicating that NCSE can cause brain injury [30,31,32], so these authors insist that the aggressive therapy is indeed necessary and worthy. On the contrary, some clinicians have suggested that NCSE is a kind of “benign” condition and the outcome is quite good, especially for ASE. They suggest that even inadequate treatment can lead to good favorable prognosis [33]. Some researchers believe that NCSE would not cause damage to the brain, and the high morbidity in some case series of NCSE may be due to the underlying disease of the patients rather than the NCSE per se [34]. In this report, all the 4 patients had a good prognosis without any cognitive and severe sequela. The favorable prognosis may be associated with the pre-existing epilepsy, satisfactory response to medication (the first 3 cases), and the extreme mild clinical signs (case 4).
