Status Epilepticus

Context and Definition

Status epilepticus (SE), a state of prolonged, uncontrolled seizures, is a common emergency department (ED) presentation that is potentially life-threatening. Mortality dependents on the aetiology of SE, ranging between 16% to 20% in patients with the first episode of generalized SE and between 35% to 60% in the case of refractory SE. [1] Following evidence-based, validated treatment algorithms can significantly improve outcomes.

Presentations may vary from clinically obvious tonic-clonic convulsions, to subtle focal seizures, to seemingly bizarre sensory alterations associated with partial seizures. An awareness of the existence and presentations of these different forms is required.

Status epilepticus refers to a prolonged seizure of any type. It is a neurological emergency that requires prompt assessment and treatment to avoid severe complications or death. [1] SE is far more common in adults than children.

Whilst most presentations are clinically obvious, typically with tonic-clonic seizures affecting all four limbs, some seizures may be far more subtle and require a high index of suspicion for diagnosis.

Rapid diagnosis and emergent treatment is essential to terminate the seizure and to minimise the risk of any long term neurological damage. Various treatment strategies are available but the mainstays of treatment are benzodiazepines.

Traditional definitions of SE refer to either:

• A single seizure persisting for more than 30 minutes
• Multiple seizures of shorter duration without a full neurological recovery in between seizures

Revised definition of SE refers to seizures that persist for more than five minutes without intervention or recurrent seizure activity without recovery between episodes. [1-6]

This relates to evidence demonstrating that:

• A significant proportion of seizures that continue for five minutes will persist for longer than 30 minutes
• The average seizure duration in adults is less than one minute

Hence, seizures that persist beyond five minutes represent a significant deviation from the norm.

Further to this, there is evidence that neuronal injury can result after just five minutes of seizure activity.

Established SE refers to clinical or electrographic seizures that persist for 30 minutes or longer without full neurological recovery in between.

Refractory SE is defined as the persistence of convulsions despite adequate doses of two intravenous anticonvulsant agents.

SE may be subdivided into convulsive and non-convulsive forms. These will be discussed in greater detail.

Basic Science and Pathophysiology

Seizures result from rapid abnormal electrical discharges from cerebral neurones. This is thought to arise from an imbalance between excitatory and inhibitory neurotransmitters, most commonly between glutamate and gamma-aminobutyric acid (GABA), leading to a failure of the inhibitory process. [7]

Numerous systemic and metabolic changes occur in association with prolonged seizures. These include:

• Tachycardia
• Hypertension
• Hyperglycaemia
• Lactic acidosis

Most of these changes are thought to result from a surge in catecholamine release that accompanies the seizure and the changes will resolve with seizure resolution.

Beyond 30 minutes of seizure duration, cerebral autoregulation may become impaired and cerebral perfusion will fall as hypotension occurs, with potential for ischaemic injury and cerebral oedema.

Aetiology

The incidence of SE varies by age, with the highest risk seen in infants and individuals over 50 years old. [8]

In children, the most common aetiologies are infective. In adults, the most common aetiology is cerebrovascular disease.

The underlying aetiology of SE can be divided into three groups:

1.Chronic epilepsy

In one-third of patients, there will be an underlying background of chronic epilepsy.

In patients with a pre-existing history of epilepsy, SE most commonly results from:

• Drug non-compliance
• Drug withdrawal
• Drug therapy alteration

However, it may also occur in the presence of:

• Intercurrent illness
• Metabolic abnormalities
• Co-ingestion of drugs that lower the seizure threshold [5]

2. Future epilepsy onset

In one-third of patients, the episode will represent the onset of future epilepsy.

3. No prior or future history

In one-third of patients, the episode occurs with no prior or future history of epilepsy.

In the absence of an established diagnosis of epilepsy, SE may result from:

• Drug withdrawal syndromes (alcohol, barbiturates, benzodiazepines)
• Acute structural brain injury (e.g. stroke, subarachnoid haemorrhage, trauma and cerebral hypoxia)
• CNS infection (meningitis, encephalitis and abscess)

These may also be the causes of SE in a patient without epilepsy and should always be borne in mind when assessing patients.

Clinical Assessment and Risk Stratification

There are numerous forms of SE, and classification is important to help direct the appropriate level of treatment and investigation.

Broadly speaking, SE may be categorised as being either:

• Convulsive
• Non-convulsive

The classification depends on the presence, or absence, of regular focal or generalised contractions of the muscles.

Convulsive status may be further classified as:

• Generalised (involving the entire brain) [1]
• Partial (involving only part of the brain) [9]

However, other forms exist but these relate to less common presentations:

• Absence
• Myoclonus, or pseudo-status epilepticus, which is characterised by tonic-clonic jerks in the absence of true altered consciousness

Generalised tonic-clonic SE

Generalised tonic-clonic SE is the most clinically obvious presentation of SE.

It begins with a sudden powerful contraction of the muscles (tonic phase) often associated with a fall to the floor, followed by regular rhythmic contraction and relaxation (clonic phase) of the musculature of all limbs.

This is invariably associated with alterations in the level of consciousness.

Partial SE

Partial SE is defined by seizures originating from a specific area of the cortex without any impairment of consciousness.

Presentation may be far more subtle than for generalised seizures and may involve:

• Motor symptoms (e.g. regular rhythmic contractions of a single limb or muscle group)
• Sensory symptoms (e.g. illusions, hallucinations and depersonalisation)

Complex partial seizures are associated with a degree of conscious impairment and arise from a single region of the brain. Symptoms may include:

• Aphasia
• Apraxia
• Focal limb weakness

Complex partial seizures may often be associated with motor or verbal automatisms.

All ED patients with SE should have an intravenous cannula sited, and blood should be sent for:

• Blood sugar
• Urea
• Electrolytes
• Magnesium
• Calcium
• Full blood count (FBC)
• A blood gas, either venous or arterial to demonstrate the patients metabolic status

Further investigations

Further investigations will be dictated according to the specific circumstances of individual cases. These may include:

• Computerised Tomography (CT) brain
• Blood cultures
• Serum anticonvulsant levels
• Lumbar puncture for cerebrospinal fluid (CSF) evaluation [3-5]

An electroencephalogram (EEG) is rarely required in the acute setting. However, it may be of value in patients with suspected non-convulsive status, or in those patients who are paralysed and sedated. [10]

Clear ictal activity may not be seen on the EEG during simple partial status epilepticus.

Introduction

SE is a medical emergency that requires urgent aggressive therapy in order to limit any long-term damage. The following principles must be recognised:

• Early initiation of anticonvulsants is key to successful treatment
• Outcomes worsen with increasing duration of SE
• Loss of responsiveness to benzodiazepines will occur with time

Effective treatment can be effected in two phases:

• Pre-hospital
• In hospital

Pre-Hospital

Treatment should begin with attention to airway, breathing and circulation (ABC), with

the application of high-flow oxygen where available.

Blood glucose should be checked, and intravenous dextrose used to treat the patient if hypoglycaemia is found or suspected.

There is a good amount of evidence to support the use of benzodiazepines in the pre-hospital setting. Use either:

• Diazepam (rectal) or
• Midazolam (buccal or intranasal) [11]

In Hospital

The following agents may be used in the management of patients with SE:

1st line treatment

Benzodiazepines

This group represents the first line of agents for treating SE, preventing the propagation of the seizure rather than affecting the original focus. [12]

All have a rapid onset of action due to their lipid solubility and consequent ability to cross the blood-brain barrier.

The agents used most frequently are:

• Diazepam
• Lorazepam
• Midazolam

Both diazepam and lorazepam are lipid-soluble, the former being available as both intravenous and rectal preparations. Rectal diazepam will terminate seizures in 70% of patients; intravenous diazepam will terminate seizures in 60-80% of patients in SE.

Lorazepam is less lipophilic, has a smaller volume of distribution and a longer intracerebral half-life (12 hours) than diazepam. It may therefore provide more prolonged suppression of seizures. Intravenous lorazepam will terminate seizures in 60-90% of patients in SE.

Midazolam is water-soluble making it available for buccal or intranasal use, primarily in the pre-hospital setting.

All benzodiazepines carry the risk of respiratory depression and hypotension.

2nd line treatment

• levetiracetam
• phenytoin
• sodium valproate

Levetiracetam: Take into account that levetiracetam may be quicker to administer and have fewer adverse effects than the alternative

Hydantoins

Phenytoin is a long-acting drug whose advantage is the prevention of seizure recurrence over an extended period of time.

Its delayed onset (10 to 30 minutes) necessitates use in combination with a rapidly acting agent, typically a benzodiazepine.

Phenytoin is not water-soluble and is formulated with propylene glycol, which has the potential to cause significant side-effects including:

• Local infusion site reactions
• Arrhythmias mandating cardiac monitoring during infusion
• Hypotension

Phenytoin is associated with the ‘purple glove syndrome’ characterised by local oedema, skin discolouration and pain distal to the infusion site. Skin necrosis and limb ischaemia have been reported.

Complications are reduced by keeping infusion rates below 50 mg per minute and by avoiding co-infusion with dextrose-containing fluids which can lead to the formation of precipitates.

Fosphenytoin is the inactive prodrug of phenytoin which is broken down into the active drug by serum phosphatases. It has the advantage that it is water-soluble and hence is associated with fewer of the local side-effects. It may also be infused at a faster rate. However, the time taken for the active metabolite to be formed means that the time taken to achieve therapeutic phenytoin levels is similar for both.

Paraldehyde

Paraldehyde is recommended in many treatment algorithms as a second-line agent to be used after benzodiazepines in the absence of intravenous access.

It is given via the rectal route, mixed with an equal volume of olive oil.

Whilst there is little published evidence to support its use, there is a large body of anecdotal evidence.

3rd line Treatment

• phenobarbital or
• general anaesthesia.

Barbiturates

Barbiturates have a similar mode of action to benzodiazepines by modification of the actions of GABA.

These agents are not standard first-line drugs but may be used for patients with refractory SE.

Side-effects include respiratory depression and sedation, particularly if used after benzodiazepines.

Agents used include:

• Phenobarbital
• Thiopental
• Pentobarbital, a short-acting agent with a rapid onset of action that is very effective at terminating seizures.

Other Agents

Intravenous Pabrinex or thiamine should be given in patients with known, or suspected, alcohol abuse or poor nutritional status.

The evidence base for the use of agents other than first-line drugs is limited, hence numerous other drugs are used for the treatment of refractory SE without any clear standardisation. These include:

• Propofol: an intravenous anaesthetic agent with rapid onset and short duration of action that has been shown to be effective in terminating seizures. Use is limited in children due to a risk of ‘propofol infusion syndrome’ – not seen in adults – and also by hypotension resulting from the high doses required to produce burst suppression on the EEG
• Levetiracetam: a new antiepileptic drug, with a unique pharmacological profile not metabolised in the liver. [13] This has been shown to be a useful adjunct in the treatment of refractory SE in several case series, having the benefit of causing less cardiovascular and respiratory depression than other agents
• Midazolam: whilst often used as a first-line agent, particularly in the pre-hospital setting, midazolam may also be useful for the treatment of refractory SE. It has been shown to be capable of rapidly controlling seizures when given as a continuous infusion.

Note: An acidosis is commonly seen in status epilepticus. This is seen more frequently in the setting of single prolonged seizures rather than in that of recurrent seizures without full recovery in between.

The acidosis has both metabolic and respiratory components, the former resulting from lactic acid production with continued muscle contraction, and the latter resulting from hypoventilation.

The induced acidosis does not correlate with any degree of neuronal injury and is thought to act as an anticonvulsant contributing to the termination of seizures.

Procedure Management

These images provide a step-by-step management protocol for patients. Find out more about each step.

• The majority of seizures will be self-limiting and will cease spontaneously within five minutes. Seizures persisting beyond five minutes should be treated as SE
• Failure to treat patients with convulsions on the basis that they may actually represent pseudo-seizures. It represents a far greater danger to fail to treat a patient who may have genuine SE than it does to assume the seizure is functional rather than organic
• Leaving too short a time for an agent to have its effect before instituting treatment with a further agent. This may compound any adverse effects. For patients with impending SE, 10 minutes should be allowed between subsequent drug doses
• Prescribing intravenous sodium bicarbonate for patients in SE with a profound metabolic acidosis. This acidosis will usually resolve spontaneously and may contribute to the cessation of convulsions.

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