Treatment of non-convulsive status
epilepticus



Matthew C Walker



Department of Clinical Neurology, Institute of Neurology, Queen Square,
London, and National Society for Epilepsy, Chalfont St Peter, Bucks

Introduction



Seizures of any type can continue unabated and they are then considered as a
separate entity, status epilepticus. This is of great importance, as in certain
circumstances a persistent seizure can result in neuronal damage irrespective of
any physiological compromise.



Among the diagnoses of status epilepticus are a number that can are considered
as non-convulsive status epilepticus including absence status epilepticus,
atypical absence status epilepticus, electrical status epilepticus during
slow-wave sleep (including Landau-Kleffner syndrome), complex partial status
epilepticus and status epilepticus in coma. Indirect estimates for the incidence
of non-convulsive status epilepticus have been as high as 14 - 24 per 100,000
population per year (the majority of these are non-convulsive status epilepticus
in the setting of learning difficulties). Although non-convulsive status
epilepticus includes a number of very different conditions, these forms of
status epilepticus share two important qualities: difficulty in making the
diagnosis, and uncertainty about the best mode of treatment.



Diagnosis



The diagnosis of non-convulsive status epilepticus can be difficult, and is
dependent on EEG. In patients with a previous diagnosis of epilepsy, any
prolonged change in personality, prolonged post-ictal confusion (greater than 20
minutes) or recent onset psychosis should be investigated with EEG as these can
all be presentations of non-convulsive status epilepticus . If new onset
developmental delay occurs in the setting of epilepsy then a sleep EEG should be
considered to look for status epilepticus during slow-wave sleep (see below). In
non-comatose patients with no history of epilepsy, non-convulsive status
epilepticus can present as confusion or personality change (almost invariably in
the setting of a metabolic derangement, encephalitis or other acute
precipitant). Rarely, non-convulsive status epilepticus can present as autism
and if suspicions are raised (usually a fluctuating course) then EEG is
indicated .



Non-convulsive status epilepticus can follow convulsive status epilepticus, and
is an important treatable cause of persistent coma following convulsive status
epilepticus . This and status epilepticus with subtle manifestations such as
twitching of the limbs, or facial muscles or nystagmoid eye jerking, which can
result from hypoxic brain damage, are often collectively referred to as subtle
motor status epilepticus. Up to 8% of patients in coma who have no outward signs
of seizure activity are in non-convulsive status epilepticus, thus emphasising
the importance of EEG in the investigation of comatose patients. Similarly,
non-convulsive status epilepticus is underdiagnosed in the confused elderly in
whom the confusion is frequently blamed on other causes .



Although EEG interpretation is usually straightforward, with regular repetitive
discharges occurring in some patients in a cyclical fashion, difficulties can
occur in differentiating non-convulsive status epilepticus from an
encephalopathy of other cause. Thus electrographic definitions of non-convulsive
status epilepticus should include: unequivocal electrographic seizure activity;
periodic epileptiform discharges or rhythmic discharge with clinical seizure
activity; and rhythmic discharge with either clinical or electrographic response
to treatment. There is uncertainty about the relevance of periodic lateralised
epileptiform discharges (PLEDs). This is most notable following severe
encephalitis or hypoxic injury in which discharges can occur with such
periodicity so as to be confused with periodic discharges seen following
prolonged status epilepticus. Some have argued that such discharges represent
ongoing seizure activity, and should be treated thus. The general consensus,
however, is that a multitude of aetiologies can underlie PLEDs, and that they
should only be treated as epileptic if there is other evidence of ictal
activity.



Neuronal damage and non-convulsive status epilepticus



It has long been recognised that ongoing electrographic seizure activity can
result in neuronal damage, so-called excitotoxic neuronal damage. This damage
occurs in animal models of non-convulsive status epilepticus. These animal
models, however, involve the induction of status epilepticus in non-epileptic
animals with either powerful chemoconvulsants or prolonged high frequency
repetitive stimulation. This is very different from the human situation.
Furthermore, non-convulsive status epilepticus in humans tends to have lower
frequency discharges, which if reproduced in animal models produces
substantially less neuronal damage.



Another important finding has been that epileptic animals, animals pretreated
with antiepileptic drugs (AEDs) and young animals are all resistant to
chemoconvulsant induced neuronal damage. Thus young age, AEDs and prior history
of epilepsy probably all confer some degree of neuroprotection. Lastly, in
humans non-convulsive status epilepticus often results from an acute precipitant
such as an encephalitis and, in such circumstances, the status epilepticus only
minimally contributes to any resultant pathology.



There have been reports of prolonged memory problems, hemiparesis and death
occurring following complex partial status epilepticus although, in most of
these cases, the outcome relates to the underlying aetiology. Indeed, the degree
to which non-convulsive status epilepticus contributes to neuronal damage in
humans is unclear. Since aggressive treatment is not entirely benign, and can
lead to hypotension and respiratory arrest, then the best approach to treatment
will only be determined in randomised studies of aggressive versus more
conservative management.





Specific forms of non-convulsive status epilepticus

Typical absence status epilepticus



This entity needs to be distinguished from complex partial status epilepticus
and atypical absences seen in mental retardation. This term should perhaps be
reserved for prolonged absence attacks with continuous or discontinuous 3 Hz
spike and wave occurring in patients with primary generalised epilepsy. The EEG,
however, may also include irregular spike and wave, prolonged bursts of spike
activity, sharp wave or polyspike and wave.



Although absence epilepsy has its peak in childhood and commonly remits in
adolescence, absence status epilepticus commonly occurs in later life. Absence
status epilepticus can be divided into childhood absence status epilepticus
(those usually already receiving treatment), late-onset absence status
epilepticus with a history of primary generalised seizure (often a history of
absences in childhood) and late-onset absence status epilepticus developing de
novo (usually following drug or alcohol withdrawal).



There is no evidence that absence status induces neuronal damage, and thus
aggressive treatment is not warranted. Treatment can either be intravenous or
oral. Absence status epilepticus responds rapidly to intravenous
benzodiazepines, and these are so effective that the response is diagnostic.
Lorazepam at 0.05 - 0.1 mg/kg is the benzodiazepine of choice. The effect may
only be transient and a longer acting AED may need to be given. If intravenous
treatment is required, but either benzodiazepines are ineffective or
contraindicated then intravenous valproate (20 - 40 mg/kg) can be given. In
cases of primary generalised epilepsy treatment should be continued with a
suitable AED. If a precipitating factor can be identified in late-onset de novo
cases, then long-term therapy is not usually indicated.



Complex partial status epilepticus



Complex partial status epilepticus has to be differentiated not only from other
forms of non-convulsive status epilepticus, but also from post-ictal states, and
other neurological and psychiatric conditions. EEG can be helpful, but often the
scalp EEG changes are non-specific and the diagnosis is very much clinical in
nature . The definition as ‘a prolonged epileptic episode in which focal
fluctuating or frequently recurring electrographic epileptic discharges, arising
in temporal or extratemporal regions, result in a confusional state with
variable clinical symptoms' is suitably vague and is necessary to emphasise that
complex partial status epilepticus can originate in any cortical region and can
fluctuate in a cyclical fashion. A further factor is importantly included in
this definition, and that is the absence of coma; electrographic status
epilepticus in coma is considered separately, partly because of its poor
prognosis.



How aggressively complex partial status epilepticus needs to be treated depends
upon: the prognosis of the condition; and if treatment improves the prognosis.
As in all epilepsies the prognosis relates partly to the prognosis of the
underlying aetiology and any concomitant medical conditions. Complex partial
status epilepticus in someone with epilepsy is probably a more benign condition
than acute precipitated status epilepticus, and should perhaps be treated thus.
The medication used to treat status epilepticus is not without adverse effects
and can result in hypotension, respiratory depression and, sometimes,
cardio-respiratory arrest . This is more so with intravenous administration with
its resultant rapid, high serum levels. At present, early recognition of the
condition and treatment with oral or rectal benzodiazepines is recommended; oral
clobazam has proven to be an effective treatment. In patients who have
repetitive attacks of complex partial status epilepticus, oral clobazam (10 - 20
mg/day) over a period of 2 - 3 days given early at home can usually abort the
status epilepticus, and such strategies should be discussed with patient and
carers.



Early recognition is a critical goal, as the delay in treatment comes not from
therapeutic strategy, but from failure to diagnose the condition in the first
place. For more persistent or resistant complex partial status epilepticus
intravenous therapy should be used, and lorazepam followed by phenytoin are the
drugs of choice . In contrast to absence status epilepticus, the response to
benzodiazepines can be disappointing, and often there is a resolution of the
electrographic status epilepticus without concomitant clinical improvement
(possibly due to post-ictal effects). Whether general anaesthesia is ever
justified remains a matter for speculation; since most complex partial status
epilepticus is self-terminating often without any serious neurological sequelae,
then such aggressive therapy should, in most instances, be avoided. Treatment of
the underlying cause (e.g. encephalitis or metabolic derangement) is of course
paramount, and can often lead to resolution of the status epilepticus.

Electrical status epilepticus during sleep



Electrical status epilepticus during sleep (ESES) is characterised by spike and
wave discharges in 85 - 100% of non-REM sleep . This phenomenon is associated
with certain epilepsy syndromes including Landau-Kleffner and Lennox-Gastaut
syndromes, continuous spikes and wave during sleep and benign epilepsy with
centrotemporal spikes . The spectrum, response to treatment and definition of
these syndromes are still debated. ESES can also occur in the setting of an
autistic syndrome alone without overt clinical seizures. There is a spectrum of
developmental delay and deterioration associated with ESES from none to severe,
and patients with benign epilepsy with centrotemporal spikes with ESES can have
marked associated neuropsychological problems (belying the term ‘benign') that
resolve with AED treatment. ESES has a poor response to treatment; phenytoin,
phenobarbitone and carbamazepine, can precipitate or worsen this condition .
This is especially important, as these drugs are often used first-line in the
treatment of partial epilepsy. Low-dose oral clobazam and clonazepam have been
reported to result in a marked improvement in the ESES, and an associated
neuropsychological improvement. If benzodiazepines fail, then treatment with
steroids or, in some severe cases, subcortical transection should be considered
. Recognition of the condition is paramount, and an overnight sleep EEG should
be performed in all children with epilepsy who show regression of language,
unexplained behavioural changes or neuropsychological regression.



Atypical absence status epilepticus



Atypical absence status epilepticus is associated with the epileptic
encephalopathies such as Lennox-Gastaut syndrome. This entity can be difficult
to diagnose, but should be considered if there is change in personality,
decrease in cognition or increased confusion in a patient with one of these
epilepsies. The EEG characteristics are usually that of continuous or frequent
slow (< 2.5 Hz) spike and wave. This condition is usually poorly responsive to
intravenous benzodiazepines, which should, in any case, be given cautiously, as
they can induce tonic status epilepticus in these patients. Oral rather than
intravenous treatment is usually more appropriate, and the drugs of choice are
valproate, lamotrigine, topiramate, clonazepam and clobazam. Sedating
medication, carbamazepine and vigabatrin have been reported to worsen atypical
absences.



Non-convulsive status epilepticus in coma



Electrographic status epilepticus in coma is not uncommon and is seen in up to
8% of patients in coma with no clinical evidence of seizure activity. The
diagnosis is often debatable as in many instances burst-suppression patterns,
periodic discharges and encephalopathic triphasic patterns have been proposed to
represent electrographic status epilepticus, while these mostly indicate
underlying widespread cortical damage or dysfunction. Non-convulsive status
epilepticus in coma consists of three groups: those who had convulsive status
epilepticus, those who have subtle clinical signs of seizure activity and those
with no clinical signs. Convulsive status epilepticus has, as part of its
evolution, subtle status epilepticus in which there is minimal or no motor
activity but ongoing electrical activity . This condition should be treated
aggressively with deep anaesthesia and concomitant AEDs. The association of
electrographic status epilepticus with subtle motor activity often follows
hypoxic brain activity and has a poor prognosis, but aggressive therapy with
benzodiazepines, phenytoin and increased anaesthesia is perhaps justified, since
the little evidence available indicates that such treatment improves prognosis.



Lastly electrographic status epilepticus with no overt clinical signs is
difficult to interpret – does it represent status epilepticus or widespread
cortical damage? Since these patients have a poor prognosis, aggressive
treatment is recommended in the hope that it may improve outcome. Lastly there
is a group of patients in whom there are clinical signs of repetitive movements,
but no electrographic seizure activity, and in these patients antiepileptic
treatment and aggressive sedation is not recommended.

Conclusion



Non-convulsive status epilepticus is an all-encompassing term that covers a
variety of conditions with very different prognoses from the entirely benign to
the fatal (although this is mainly due to the underlying aetiology). These
conditions are poorly replicated by available animal models, and this together
with the lack of randomised treatment trials has meant that the best treatment
options are unknown. It is important to remember that aggressive AED treatment
is not benign especially when deep anaesthesia is proposed.



Further reading



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POHLMANN-EDEN B, HOCH DB, COCHIUS JI et al (1996) Periodic lateralized
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SHORVON SD (1994) Status Epilepticus: Its Clinical Features and Treatment in
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September 2005

This article is reproducible for educational purposes

Source: http://www.e-epilepsy.org.uk/pages/articles/show_article.cfm?id=118