Status epilepticus

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Chapter 43 Status epilepticus

Status epilepticus (SE) is a medical emergency requiring prompt intervention to prevent the development of irreversible brain damage.

The duration of seizure activity required to define SE has not been universally agreed upon. Most authors have defined SE as more than 30 minutes’ duration of either a single seizure, or intermittent seizures with no regaining of consciousness between seizures.¹^–⁴ This definition is most useful for epidemiological research and is based on experimental studies that show that irreversible neuronal damage occurs after 30 minutes of seizure activity.^5,⁶

More recently an operational definition of SE as 5 minutes of continuous seizure activity, or two or more discrete seizures with no intervening recovery of consciousness, has been used.⁷ This definition promotes earlier diagnosis and treatment of SE. It has arisen from the generally accepted need to initiate treatment for SE rapidly and the observation that seizures persisting beyond this duration are unlikely to remit spontaneously.⁸

Refractory SE is defined as failure of initial therapy, such as benzodiazepines and phenytoin, with seizures persisting beyond 1–2 hours and usually requiring agents that induce general anaesthesia to control them.^9,¹⁰ Refractory SE is associated with a worse prognosis.^9,¹¹

SE is commonly separated into two categories:

1 Generalised convulsive SE (GCSE). Seizures are primary or secondarily generalised and the patient has generalised tonic and/or clonic convulsive movements with loss of consciousness.

2 Non-convulsive SE (NCSE). There is altered consciousness without convulsive movements but electroencephalography (EEG) evidence of seizures. NCSE may evolve from GCSE when electrical seizure activity continues with loss of motor manifestations. NCSE includes absence SE and complex partial SE.

The incidence of SE is U-shaped, being greatest under 1 year and over 60 years of age.²

PATHOPHYSIOLOGY

Ongoing or recurrent seizures result from failure of normal seizure-terminating mechanisms or excessive excitation causing seizure activity to persist. The major inhibitory mechanism in the brain is γ-aminobutyric acid A (GABA_A) receptor-mediated inhibition. Glutamatergic excitatory synaptic transmission is important in sustaining SE.¹²

The pathophysiological effects of seizures on the brain are thought to result from both direct excitotoxic neuronal injury and secondary injury due to systemic complications such as hypotension, hypoxia and hyperthermia. Ongoing excitation results in excessive intracellular calcium flux through the opening of NMDA (N-methyl-D-aspartate) receptor-mediated calcium channels, inducing a cascade of intracellular neurochemical events that damage or kill the cell.

AETIOLOGY

SE may occur de novo (approximately 60% of presentations) or, less commonly, in a previously diagnosed epileptic.² The aetiologies of SE, in decreasing order of frequency as they occur in adults, are given in Table 43.1.²

Table 43.1 Causes of status epilepticus in adults

Low antiepileptic drug levels (poor compliance, recent dose reduction or discontinuation)

Temporally remote causes (previous central nervous system injury e.g. stroke, trauma, tumour, meningitis)

Stroke – vascular occlusion or haemorrhage

Cerebral hypoxia/anoxia

Metabolic disturbances (electrolyte abnormalities, uraemia, hyperglycaemia, hypoglycaemia)

Alcohol – withdrawal or intoxication

Central nervous system tumours – primary or secondary

Systemic infection

Idiopathic

Central nervous system infection – meningitis, encephalitis

Head trauma

Drug toxicity (tricyclic antidepressants, phenothiazines, theophylline, isoniazid, cocaine, amphetamine)

For SE that has its onset in the intensive care unit (ICU), the following should be considered as possible causes:

• drug withdrawal (narcotics, benzodiazepines, omission of anticonvulsant medications)

• metabolic disturbance (hyponatraemia, hypocalcaemia, hyperglycaemia, hypoglycaemia, uraemia, hepatic encephalopathy)

• drug toxicity (pethidine, theophylline, ciclosporin, tacrolimus, antibiotics, e.g. penicillins, cephalosporins, ciprofloxacin, imipenem in renal failure)

• stroke – vascular occlusion or haemorrhage

GENERALISED CONVULSIVE STATUS EPILEPTICUS

GCSE is the most common and dangerous type of SE and accounts for approximately 75% of cases.² It encompasses a broad spectrum of clinical presentations, from overt generalised tonic-clonic seizures to subtle convulsive movements in a profoundly comatose patient.¹³

CLINICAL

Typically, early in the evolution of seizures, patients are unresponsive with obvious tonic (sustained contractions) and/or clonic (rhythmic jerking) movements (overt GCSE). Motor manifestations may be symmetrical or asymmetrical.

With time, the clinical manifestations may become subtle, and patients have only small-amplitude twitching movements of the face, hands or feet or nystagmoid jerking of the eyes (late or subtle GCSE).¹³

Later still some patients will have no observable repetitive motor activity and the detection of ongoing seizures requires EEG (electrical GCSE). Most authors classify this as a form of NCSE.¹⁴^–¹⁶ Such patients are still at risk of central nervous system (CNS) injury and require prompt treatment.

EEG CHANGES

Just as there is a progression from overt to increasingly subtle motor manifestations, there is also a predictable sequence of EEG changes during untreated GCSE. Initially, discrete electrographic seizures merge to a waxing and waning pattern of seizure activity, followed by continuous monomorphic discharges, which become interspersed with increasing periods of electrographic silence and, eventually, periodic epileptiform discharges on a relatively flat background.^13,¹⁷ The presence of any of these EEG patterns should suggest the diagnosis of GSCE.

ENDOCRINE AND METABOLIC EFFECTS

Early in GCSE there is a marked increase in plasma catecholamines, producing systemic physiologic changes that resolve if SE is stopped early (Table 43.2). However, if seizures continue, many of these early physiologic changes reverse and the resultant hypotension and hypoglycaemia may exacerbate neurological injury.¹⁸

Table 43.2 Physiological changes in generalised convulsive status epilepticus ^18,⁵⁶

Hypoxia

Respiratory acidosis

Lactic acidosis

Hyperpyrexia

Hypertension (early)/hypotension (late)

Hyperglycaemia (early)/hypoglycaemia (late)

Tachycardia

Cardiac arrhythmias

Blood leukocytosis

Cerebrospinal fluid pleocytosis, increased cerebrospinal fluid protein

Intracranial hypertension

Neurogenic pulmonary oedema

Aspiration pneumonitis

Rhabdomyolysis

Hyperthermia is due to both muscle activity and central sympathetic drive, and thus may still occur when paralysing agents prevent motor activity. In early SE, both cerebral metabolic activity and cerebral blood flow (CBF) are increased. In late SE, although cerebral metabolic activity remains high, CBF may fall due to hypotension and loss of cerebral autoregulation, leading to cerebral ischaemia.

An important differential diagnosis of generalised convulsive epilepsy is pseudoseizures. These can occur in patients with or without a history of epilepsy.¹⁹ Clinical features suggestive of pseudoseizures are listed in Table 43.3. Distinction between the two may be extremely difficult, and can only be made with complete certainty using EEG monitoring.¹⁹ Pseudo-status, misdiagnosed as true SE, is often refractory to initial therapy and can lead to patients receiving general anaesthesia and mechanical ventilation.

Table 43.3 Features suggestive of pseudoseizures

Lack of stereotyped seizures, with behavioural manifestations varying from event to event

Lack of sustained convulsive activity – ‘on–off’ appearance

Increase in movement if restraint is applied

Abolition of motor movements with reassurance or suggestion

Resistance to eye opening and gaze aversion

Poor response to treatment, refractory status epilepticus

Absence of pupillary dilatation

Normal tendon reflexes and plantar responses immediately after convulsion

Lack of metabolic consequences despite some hours of apparent fitting

NON-CONVULSIVE STATUS EPILEPTICUS

This may account for approximately 25% of SE, though its incidence is probably underestimated because of failure to recognise and diagnose the condition.

The diagnosis of NCSE should be considered in any patient with an unexplained altered conscious state, particularly those with CNS injury, metabolic disturbance, hepatic encephalopathy and sepsis. Series where EEG has been performed in critically ill patients with an unexplained depressed conscious state have found a high incidence of NCSE (8–18%).²⁰^–²² EEG monitoring is required in patients with GCSE who do not recover consciousness after resolution of overt convulsive activity; in one study more than 14% of such patients had NCSE.¹⁴

Considerable debate exists regarding the precise criteria for diagnosing NCSE and published reports often describe diverse cohorts of patients. The diagnosis of NCSE generally requires a change in behaviour and/or mentation from baseline for at least 30 minutes, no overt seizure activity and an EEG with epileptiform discharges. A response to intravenous antiepileptic drugs (e.g. benzodiazepines), with clinical improvement and resolution or improvement in EEG epileptic activity, is helpful in confirming the diagnosis.²³

Various classifications for NCSE have been suggested.^4,²³^–²⁵ Traditionally NCSE is divided into absence SE (ASE) and complex partial SE (CPSE), though it may not always be possible to differentiate between the two types.^23,²⁴

ASE is characterised by bilateral diffuse synchronous seizures.²³ Typical ASE has generalised 3-Hz spike-wave discharge EEG activity occurring with altered behaviour or loss of responsiveness and is seen in children with idiopathic generalised epilepsy who are otherwise normal. This form of SE is relatively benign. Atypical ASE is a heterogeneous syndrome occurring in patients with mental retardation and epilepsy with multiple seizure types, or with other forms of diffuse cerebral dysfunction. The prognosis is usually poor and is related to the underlying condition.

CPSE, also referred to as ‘epileptic twilight state’ and ‘temporal-lobe SE’, is accompanied by lateralised seizure activity on EEG.²³ A wide variety of clinical features and degree of impairment of consciousness is possible and includes confusion, agitation, bizarre or aggressive behaviour and coma. Behavioural accompaniments such as lip smacking, automatisms and gaze deviation may occur, depending on the seizure origin within the brain. Debate exists over whether the seizure activity causes brain injury and much of the morbidity appears attributable to the underlying illness.

NCSE is often mistaken for other conditions, resulting in a delay in diagnosis and treatment. A high index of suspicion must therefore be present to trigger investigation with an EEG.

The differential diagnosis of NCSE is:

• metabolic encephalopathy

• drug intoxication

• cerebrovascular disease

• psychiatric syndromes (dissociative reactions, acute psychosis)

• postictal confusion

EPILEPTIFORM ENCEPHALOPATHIES

Some variants of SE deserve mention, such as comatose patients with epileptiform patterns on EEG who do not fit into the traditional classification of NCSE. Some of these cases may be late GCSE but many occur without prior clinical convulsions. In such situations it is unclear whether the abnormal discharges seen on the EEG are responsible for, or contribute to, the altered consciousness and abnormal movements, or are merely a reflection of a severe cerebral insult.²⁴

Myoclonic SE that follows a hypoxic insult falls into this category. Patients have incessant, at times asynchronous, rhythmic jerks that may involve the entire body. This clinical appearance after an anoxic insult is associated with an extremely poor outcome.²⁶

INVESTIGATIONS

Not all of the investigations listed in Table 43.4 need to be performed in every patient. The selection of tests depends on both the patient’s history and presentation.

Table 43.4 Investigations in status epilepticus

Initial studies

Blood glucose, electrolytes (sodium, potassium, calcium, magnesium), urea

Oximetry Spo₂ or arterial blood gases

Anticonvulsant drug levels

Full blood count

Urinalysis

Further investigations after stabilisation

Liver function tests, lactate, creatine kinase

Toxicology screen

Lumbar puncture

Electroencephalogram