Acute symptomatic seizures occur in close temporal proximity to a documented neurological or systemic insult. They are a common reason for seeking an emergency neurological opinion. We discuss their important causes, treatment and prognosis, discuss a practical approach to their clinical assessment and investigation, and offer thoughts on treatment.
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Acute symptomatic seizures are defined as clinical seizures occurring at the time of, or in close temporal relationship with, a documented central nervous system (CNS) or systemic insult, which may be metabolic, toxic, structural, infectious or inflammatory.1 They differ from unprovoked seizures in terms of underlying aetiology, investigations, treatment and should be separately categorised for epidemiologic purposes. The risk of seizure recurrence following an acute symptomatic seizure depends on the underlying aetiology, but in general is significantly lower than that following a single unprovoked seizure. Some neurologists prefer to view acute symptomatic seizures as a result of interacting factors including genetic predisposition, structural lesions and provoking insult. The term ‘provoked seizures’ is sometimes used, including in the Driver and Vehicle Licensing Agency (DVLA) guidelines; however, this can lead to confusion with, for example, seizures in idiopathic generalised epilepsy provoked by sleep deprivation.
Acute symptomatic seizures are a common reason for medical admission and require thoughtful investigation. We review their clinical presentation in adults (box 1, table 1), their important causes and appropriate investigations (box 2, table 1), and their treatment and prognosis (box 3). Although childhood febrile convulsions are, by definition, acute symptomatic seizures, they are not covered here.
Important clinical features
A detailed history is crucial in establishing the underlying cause. Important points to consider in the history include:
A witness account is extremely valuable and should always be sought. This may provide information about the location of seizure onset and help to distinguish seizures from other causes of transient loss of consciousness, for example, syncope and psychogenic non-epileptic attacks. Examples of conditions easily mistaken for seizures include rigors in the acutely unwell febrile patient, panic attacks, shaking limb transient ischaemic attacks, sudden reduced vigilance following thalamic infarcts and dyskinesias in anti-n-methyl d-aspartate encephalitis.
Associated neurological features
These are important in distinguishing from unprovoked seizures and in guiding further investigations:
■ Headache, which may be severe or relatively non-specific. It may be present in intracranial haemorrhage, venous thrombosis, space occupying lesion, infective and inflammatory disorders
■ Meningism features, for example, fever, photophobia, neck stiffness
■ Altered consciousness
■ Head trauma: minor head trauma may lead to subdural haematoma particularly in the older people, those on anticoagulants or antiplatelets and people who are heavy consumers of alcohol
■ Focal neurological symptoms
■ Myoclonus, dystonia or other movement disorders
Speed of onset of any prodromal symptoms
Although the seizures are of sudden onset (by definition), the tempo of preceding symptoms may point to the underlying aetiology. Abrupt onset implies a vascular or traumatic event; symptoms evolving over days to weeks imply an infective or inflammatory pathology; evolution over weeks or months suggests a space-occupying lesion.
■ Intercurrent illness or infection
■ Foreign travel and sexually transmitted infection history
■ Alcohol intake, illicit drug use
■ Concomitant medication including ‘over-the-counter’ medication
■ Relevant past medical history including malignancy, stroke, diabetes mellitus, recent surgery, systemic inflammatory conditions, cardiovascular and respiratory disease and metabolic disorders
■ Temperature, blood pressure, plasma glucose
■ Skin: for purpuric or vasculitic rash, or features suggesting a neurocutaneous disorder
■ Joints: for evidence of arthropathy
■ Cardiovascular: for example, heart murmurs
■ Chest and abdomen: for evidence of sepsis (consolidation or abdominal tenderness)
■ Reduced level of consciousness or impaired alertness may reflect a postictal state or may imply significant intracranial pathology
■ Signs of raised intracranial pressure, such as dilated pupil, sixth nerve palsy, papilloedema
■ Meningism, for example, neck stiffness, photophobia, Kernig's and Brudzinski's signs
■ Focal neurological signs
■ Evidence of ongoing seizure activity, for example, myoclonus, focal twitching, fluctuating conscious level, nystagmus
Alcohol-related seizures, through intoxication or withdrawal, account for up to 40% of emergency seizure presentations.29 Acute intoxication causes direct neuronal toxic effects, reducing inhibitory activity. Alcohol is a sedative; its acute withdrawal can provoke seizures through a hyperexcitable state from downregulation of γ-aminobutyric acid (GABA)-ergic activity during chronic alcohol use. Several metabolic abnormalities associated with alcoholism can trigger acute seizures; hypomagnesaemia (through poor nutrition) and hypoglycaemia (through depleted liver glycogen) can both accompany chronic alcohol abuse, and hyponatraemia can develop in liver disease. Patients abusing alcohol more likely suffer vascular events (traumatic haematomas, stroke, hypertensive haemorrhage) and head trauma leading to acute symptomatic seizures, as well as increasing the risk of subsequent epilepsy. They also more likely abuse other substances and seizures may result from intoxication with another agent.
Alcohol withdrawal seizures respond best to benzodiazepines. Clinicians should seek and treat electrolyte abnormalities, acute intracranial pathology, infection and drug overdose. There is little evidence regarding starting antiepileptic drugs in patients with recurrent alcohol-related seizures not clearly caused by alcohol withdrawal or other secondary cause; this decision must be individualised and it is important to consider the possibility of head injury, metabolic derangements and infection. For patients who understand the importance of good compliance, treatment should be offered. Using antiepileptic drugs that are not liver metabolised seems logical, although there is no evidence to support this.
Investigation of acute symptomatic seizures
The term acute symptomatic seizures specifically imply seizures occurring at the time of the initial illness, which do not recur, and in general do not require long term treatment with antiepileptic medication. The conditions listed below can cause either complex partial or tonic-clonic seizures, and may present with status epilepticus. They may also cause recurring, unprovoked seizures, that is, epilepsy, as well as acute symptomatic seizures. The occurrence of acute symptomatic seizures increases the risks of future unprovoked seizures, in some instances.
Stroke causes both acute symptomatic seizures and epilepsy. Recent studies have suggested 2.5%–5.0% of patients develop early seizures and these suggest a worse prognosis.2 3 The seizure risk is higher with larger infarctions, especially if involving the cortex; seizures are less likely with deep white matter ischaemic lesions. Acute symptomatic seizures in stroke do not consistently influence the outcome or the risk of subsequent poststroke epilepsy.2 A seizure at stroke onset is a relative contraindication to thrombolysis, and is more suggestive of other diagnoses, such as venous sinus thrombosis or intracerebral haemorrhage.
Cerebral venous sinus thrombosis is an uncommon cause of cortical infarction and intracerebral haemorrhage (figure 1). It is slightly more common in women than in men. It presents with headache (either non-specific or with raised pressure features), encephalopathy, focal neurological symptoms or seizures, and there may be papilloedema. Seizures may be difficult to control. As yet, there is no evidence to support or refute using antiepileptic drugs (AEDs) for the primary or secondary prevention of seizures following cerebral venous sinus thrombosis;4 however, we discuss our own practice later.
The risk of acute symptomatic seizures is higher with intracerebral haemorrhage than with ischaemic stroke; occurring in 16% of patients in a recent study.3 It is greatest following haemorrhage into frontal, temporal and parietal lobes, and is less when involving the deep white matter or occipital lobes. Haemorrhage secondary to a vascular malformation (cavernoma or arteriovenous malformation) carries a higher seizure risk than spontaneous haemorrhage or haemorrhage secondary to hypertension.5
Subarachnoid haemorrhage from aneurysmal rupture carries a 10% risk of seizure; most occur at the onset. Early onset of seizures carries a poor prognosis. In one study, 7% of patients subsequently developed epilepsy, the risk increasing with ischaemia and large subdural collections.6
Hypertensive encephalopathy and the posterior reversible encephalopathy syndrome
Posterior reversible encephalopathy syndrome is a clinico-radiological diagnosis. It most commonly occurs with hypertension and previously was known as hypertensive encephalopathy. There are several other aetiological factors, including renal disease, immunosuppression, organ transplantation, eclampsia, autoimmune disease and infection. The underlying pathophysiology is unclear: the several proposed theories include altered blood–brain barrier due to breakdown in cerebral autoregulation, focal vasospasm and endothelial dysfunction. Common clinical features are headache, altered mentation, seizures and visual disturbance. Characteristic MR brain scan changes develop in the parietal and occipital lobes (figure 2). The management is to treat any underlying disorder and to treat blood pressure aggressively, with intravenous agents if necessary. The limited evidence suggests that long term antiepileptic therapy is not usually required.7
Seizures complicate the acute stage of bacterial meningitis in 17%–24% of cases; these patients have a higher mortality.8 9 Seizures tend to occur early in the disease and are significantly more likely in patients with tachycardia, low Glasgow coma score, Streptococcus pneumoniae infection and focal neurological abnormalities.8 Bacterial meningitis in adults is most commonly caused by S pneumoniae and Neisseria meningitis. The long term risk of developing epilepsy (overall 2.7%) has been shown to be higher in those who experience acute symptomatic seizures (8%) than in those without (1.6%).9
Tuberculous meningitis has a subacute and subtle onset; patients may be withdrawn or have subtle personality change as well as having the slow onset of meningeal features. With progression of the disease, patients become more obtunded and develop focal neurological signs. Seizures can result from tuberculomata within the cortex from direct spread of the infection.
Encephalitis presents indolently with headache, altered mental status and personality change. Meningism and fever may also occur. Herpes simplex virus encephalitis has a predilection for the temporal lobes; temporal lobe seizures develop in a quarter of cases (figure 3). Treatment depends upon identifying the causative agent from serology or CSF. Most patients are started on acyclovir, as this has broad spectrum activity against the commoner infecting organisms. The risk of subsequently developing unprovoked seizures is significantly increased following viral encephalitis, particularly if accompanied by acute symptomatic seizures, with epilepsy rates of over 20%.10
A minority of patients with infective endocarditis develop seizures. These may result from infective emboli causing infarction, abscess or meningitis or may be due to the systemic consequences of infection (electrolyte derangement, renal failure and septicaemia).
Abscesses are more common in the developing world and may be a consequence of local invasion or distant haematogenous spread (figure 4). Risk factors include ear, nose and throat infections, penetrating injuries from head trauma or neurosurgical procedures, diabetes mellitus, immunocompromise and congenital heart disease. Cerebral abscess commonly presents with headache, focal neurology, fever and signs of raised intracranial pressure. A recent large retrospective study found a lower rate of seizures than previously thought, with 17% developing acute symptomatic seizures.11 Generally, prophylactic AEDs were not used. Of the patients with seizures, 27% were continued on AEDs after resolution of the acute event and had no further seizures, whilst 19% developed epilepsy.
Neurocysticercosis is among the most common causes of epilepsy in the developing world, but may also present with acute symptomatic seizures in the context of the brain's inflammatory response to infection. The tapeworm parasite Taenia solium crosses into the bloodstream from the gastrointestinal tract and may seed in the CNS (figure 5). There is mixed evidence for clinical improvement following treatment with praziquantel and corticosteroids.12 Schistosomiasis can cause an encephalopathic presentation with generalised seizures or seeding of ova in the brain may lead to partial-onset seizures.
Malaria is extremely common in the developing world. The cerebral form predominantly affects children and young adults. The infected erythrocytes occlude cerebral capillaries and may trigger a vasculitic reaction. The primary presentation is with acute encephalitis, leading to generalised seizures in 40% of adults. Focal neurological signs may develop but tend not to persist. Treatment takes account of the international guidelines from the WHO and is adapted for local resistance patterns.
Early studies, before widespread use of highly active antiretroviral therapy, gave a seizure prevalence of 11%–17%.13 Later studies showed a disparity in prevalence between treatment naïve (19.8%)14 and those with access to antiviral therapy (6%).15 These figures refer to both epilepsy and acute symptomatic seizures, which may occur in the context of direct HIV cerebral infection, protozoal infections, (for example, Toxoplasma gondii causing mass lesions), cryptococcal meningitis, cerebral tuberculosis or other atypical infections.
The risk of seizures increases after head injury, and depends upon the injury severity and the intracranial sequelae (figure 6). Head injury is categorised as mild (<30 min amnesia and no skull fracture), moderate (>30 min amnesia and/or skull fracture) or severe (amnesia >24 h, cerebral contusion or intracranial haematoma). Early seizures (within 24 h) carry a worse prognosis overall, but do not increase the risk of subsequent epilepsy. Up to 50% of patients with penetrating head injury subsequently develop epilepsy.16 During the first week after mild head injury, 2% develop seizures.17 The risk of subsequent unprovoked seizures after traumatic brain injury is significantly higher following severe head injury than following moderate or mild head injury.18 Prophylactic AEDs reduce immediate and early seizures, but do not influence subsequent epilepsy, death or neurological disability.19
Multiple sclerosis and acute disseminated encephalomyelitis
Demyelinating disorders lead to a slightly increased risk of seizures. Seizures were thought more likely with large lesions, especially those involving the subcortical–cortical junction; subsequent studies have not confirmed this.20 Acute symptomatic seizures at presentation are rare in multiple sclerosis, although epilepsy may develop later.21 Conversely, seizures are a common presenting feature of acute disseminated encephalomyelitis, ranging from 10%–20% in smaller series from the developed world to 30%–50% in larger studies in non-Western populations.22
Neurosarcoidosis occurs in 5% of patients with sarcoidosis. Acute symptomatic seizures may occur in the context of a meningitis or hydrocephalus. With systemic immunosuppression, the granulomas may regress; however, the residual gliosis and scarring can lead to a long term epilepsy.23
Connective tissue diseases and systemic vasculitides
Estimates of neurological involvement in systemic lupus erythematosus vary depending on the criteria used and population studied. In a UK population, using the American College of Rheumatology criteria, systemic lupus erythematosus involved the nervous system in 57%.24 Seizures occur in 10%–20% but rarely at presentation. The pathogenesis involves vaso-occlusive events and/or systemic antibodies to cerebral tissue. Sjögren's syndrome affects the CNS in 20% of cases, sometimes with seizures. Polyarteritis nodosa may present with an encephalopathy including seizures. Seizures occur in <5% of Wegener's granulomatosis and Behçet's disease and are uncommon in rheumatoid arthritis and systemic sclerosis.
Vasculitis can occur as a primary CNS phenomenon or as part of a systemic inflammatory disease. Neurological symptoms may be acute, subacute or chronic, and there may or may not be systemic symptoms. Headaches, seizures, stroke-like episodes and encephalopathy are well-recognised presentations, sometimes with progressive cognitive decline, movement disorders, optic and other cranial neuropathies.25
Anti-N-methyl-D-aspartate (NMDA) receptor antibody encephalitis causes rapidly progressive encephalopathy, neuropsychiatric features, dyskinesias and autonomic disturbance. Seizures occur in about 75%.26 It is more common in women and is associated with underlying malignancy, usually ovarian teratoma, and is treatable with intravenous immunoglobulin. Limbic encephalitis occurs in association with anti-voltage-gated potassium channel antibodies and presents with a more indolent cognitive decline, neuropsychiatric features and partial-onset seizures that may secondarily generalise (figure 7).Treatment is with immunosuppression.27 Both NMDA receptor and limbic encephalitis can be associated with underlying malignancy. Hashimoto's encephalopathy (steroid-responsive encephalopathy with antithyroid antibodies (SREAT)) is characterised by subacute encephalopathy, with seizures, tremor, myoclonus and stroke-like episodes.
Electrolyte abnormalities may destabilise membrane action potentials or cause local oedema, leading to seizures. The CNS effects are determined by the speed of onset of the abnormality. The contributions of sodium, magnesium and calcium to seizures are more significant than potassium disturbances (though these cause serious cardiac effects).
Hypoglycaemia most commonly develops with treatment of diabetes mellitus, but other conditions may lower glucose levels, for example, alcohol intoxication, liver failure, insulinoma, disseminated malignancy, Addison's disease and hypothyroidism. Untreated hypoglycaemia leads to loss of consciousness, seizures and status epilepticus, but also focal neurological deficits. Treatment is with 10% dextrose intravenously (50% dextrose causes severe reactions after extravasation). Recurrent hypoglycaemia in a patient not taking insulin or sulphonylureas should prompt further investigations, perhaps including short Synacthen test, thyroid function, observed fast and imaging.
Partial-onset seizures and epilepsia partialis continua are a recognised presentation of hyperosmolar non-ketotic hyperglycaemia, particularly in older people, where they may be the first manifestation of diabetes mellitus. Seizures associated with hyperglycaemia are resistant to AEDs and respond best to correction of the hyperglycaemia with insulin and rehydration.
Delirium is the most common feature of hyponatraemia. Seizures occur in 5%–15%, usually in those with more severe hyponatraemia, and are reversed by correcting the underlying cause in most cases.
Clinical features commonly involve disturbances in consciousness. Seizures are uncommon but may result from either venous sinus thrombosis from dehydration or cerebral oedema from rapid correction of the abnormality. Hypernatraemia must be corrected slowly to prevent cerebral oedema from a large intracellular influx of water.
Magnesium is predominantly intracellular, and so low serum magnesium may lag behind the intracellular depletion. Magnesium is important for potassium, phosphate and calcium homeostasis. Magnesium deficiency may result from dietary deficiency, malabsorption or excess renal loss. Common clinical features are tetany, fasciculations, cardiac arrhythmia, confusion and seizures. Correction of low magnesium levels during seizures is with 4 g of magnesium sulphate over 20 min, and further 4 g infusions every 6 h as needed. This may not be sufficient to terminate the seizures and additional intravenous AEDs may be required.28 Hypermagnesiaemia does not generally cause seizures.
Calcium stabilises cell membranes and hypocalcaemia triggers synchronised neuronal firing in the hippocampus. The major features are tetany and carpopedal spasm, and later confusion, loss of consciousness and seizures. Important causes include renal failure, acute pancreatitis and endocrine aetiologies – hypo – and pseudohypo-parathyroidism and vitamin D deficiency. Treatment is with calcium replacement.
Hypercalcaemia most commonly causes stupor and coma; seizures are unusual. Causes include acute renal failure, hyperparathyroidism, malignancy (paraneoplastic phenomena and bone invasion), bone metabolism disorders, immobility and drug toxicity. The pathogenesis of seizures is unclear. Seizures are rapidly corrected by correcting the hypercalcaemia with intravenous normal saline, loop diuretics and bisphosphonates.
Hepatic encephalopathy presents with subtle cognitive and behavioural changes, progressing to disorientation, worsening somnolence, tremor and asterixis. Seizures are rare and mainly occur in advanced disease.
Some toxins and medications cause seizures directly, and others through acute withdrawal. Alcohol-related seizures are probably the commonest cause of acute symptomatic seizures in the UK (box 2).
Amphetamines, 3,4-methylenedioxy methamphetamine (MDMA) and cocaine each cause seizures in overdose. Seizures are more common in heroin users than in the general population and most likely within 24 h of acute intoxication. Benzodiazepines and barbiturates may cause seizures during withdrawal owing to GABA receptor downregulation. Cannabis probably does not provoke seizures and likewise other hallucinogenic agents, except at high doses.30
Animal toxins may cause seizures, including tetrodotoxin (from pufferfish), saxitoxin (from microorganisms consumed by clams and other shellfish) and ciguatera poisoning (reef fish). Fungal toxins such as from amanita mushroom species (usually inadvertently consumed by young children) can produce seizures. Several plant toxins, for example, water hemlock, jimsonweed, Atropa belladonna, squill plant, azalea, bleeding hearts and Christmas rose can also produce seizures. Other toxic causes are carbon monoxide, heavy metals (lead and tin) and organic solvents, in severe intoxication.31
Pregnancy and eclampsia
Pre-eclampsia and eclampsia comprise a pathological continuum caused by impaired placental formation. Eclampsia is defined as seizures and/or coma in the context of hypertension (systolic >140 mmHg, diastolic >90 mmHg), and proteinuria (0.3 g/24 h) with onset after the 20th week of pregnancy. It may present with neurological symptoms and can occur several days postpartum.32 Neurological symptoms include reduced attention, memory and orientation, psychosis, visual disturbance, seizures, headache, cortical and retinal blindness, as well as focal neurological deficits. Definitive treatment is delivery of the infant; interim management relies on antihypertensives, for example, methyldopa, labetalol, diuretics and nifedipine.33 Magnesium is effective in preventing pre-eclampsia progressing to eclampsia and in treating eclamptic seizures. Diazepam and phenytoin are less effective in seizure control.34
Not all seizures in the perinatal period are due to eclampsia; other conditions, such as posterior reversible encephalopathy syndrome and venous sinus thrombosis, may mimic eclampsia, and thrombotic thrombocytopenic purpura (microangipathic haemolytic anaemia, low platelets, renal failure, fever and neurological features, including seizures) is also more common in pregnancy.
The management priority is treatment of the underlying aetiology. Temporary use of AEDs may help suppress seizures while the underlying aetiology is still active; however, there is little evidence that this reduces the risks of subsequent epilepsy. Prophylactic AEDs reduce the risk of post-traumatic seizures in the first week following head trauma, but do not change the risk of epilepsy, or overall outcome following traumatic brain injury.35 Using prophylactic AEDs in this context therefore remains controversial. However, many experts recommend treatment for 1 week following severe head injury or subarachnoid haemorrhage to prevent a seizure-related exacerbation of raised intracranial pressure. In the acute setting, a single self-limiting seizure as part of a reversible problem usually does not warrant therapy. Recurrent seizures or status epilepticus (which may be non-convulsive) require intervention. Most authorities also recommend giving thiamine and intravenous glucose to patients presenting with recurrent seizures or status epilepticus.
Decisions about choosing and continuing AED treatment following an acute symptomatic seizure are not straightforward, with no clear guidelines available. In general, long term AED treatment is reserved for those with residual structural abnormalities on MRI. Rates of epilepsy are highest following severe head injury,18 36 and following viral encephalitis with acute symptomatic seizures,10 justifying a more cautious approach to AED withdrawal in these contexts. There is a strong argument for long term AED treatment following an acute symptomatic seizure in HIV patients, although enzyme-inducing drugs are best avoided. We have attempted to summarise some of these points, and offer suggestions for the treatment of acute symptomatic seizures, in the online supplementary appendix 1. This summary of our current practice is based on the evidence available and our own experience, with the caveat that these are certainly not black and white decisions, and that the specific details of each case (including the number and timing of seizures, and location of pathology) will vary. In all cases, the decision to start treatment, and how long to continue treatment, must be individualised, taking into account potential medication side-effects, employment status and, often of most relevance, driving status. AED selection in the acute situation is governed by efficacy, speed of onset of seizure control, side effect profile and comorbidities (table 1).
The overall risk of seizure recurrence following an acute symptomatic seizure is significantly lower than that following a single unprovoked seizure.40 In a study of acute symptomatic seizures (within 1 week) following stroke, traumatic brain injury or CNS infection, the 10-year risk of a subsequent unprovoked seizure was 18.7%. This compared with a 64.8% rate of seizure recurrence (after at least 1 week) following an unprovoked seizure.41 Despite this, the 30-day mortality rate was higher following acute symptomatic seizures compared with ‘unprovoked’ seizures, reflecting the associated CNS pathology. These differences support the notion that acute symptomatic seizures are separate from epilepsy, and that, in general, these patients do not have an underlying predisposition to epilepsy.
The underlying aetiology broadly dictates prognosis following acute symptomatic seizures. For example, acute seizures from metabolic derangement do not usually carry an increased risk of subsequent epilepsy. For most other aetiologies, for example, trauma, infection, and vascular causes, patients with acute symptomatic seizures are at higher risk for subsequent epilepsy than patients without.10 18 35 Perhaps research into the cellular and molecular mechanisms underlying epileptogenesis will identify interventions, possibly before seizure onset, to prevent subsequent epilepsy.42
■ Acute symptomatic seizures differ from epilepsy in terms of the common causes (although there is some overlap), treatment and prognosis and should be regarded as separate from epilepsy.
■ The most common causes are cerebrovascular disease (including venous sinus thrombosis), intracerebral infection, head injury and toxins, particularly alcohol.
■ Investigations should be guided by the history but imaging is essential for all first seizures; we suggest a low threshold for lumbar puncture in patients with acute symptomatic seizures.
■ The management priority is treatment of the underlying cause; there is little evidence that early treatment with AEDs reduces the risk of subsequent epilepsy.
■ Long term AED treatment is reserved for individuals at high risk of developing epilepsy, generally those with structural abnormalities on brain imaging.
■ Compared with unprovoked seizures, acute symptomatic seizures are associated with higher mortality but a significantly lower risk of seizure recurrence; in general, these patients are not predisposed to epilepsy.
The authors thank Dr Peter Bergin, New Zealand, for reviewing this paper and Dr Inder Sawhney, Swansea, for his helpful comments.
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Competing interests DM has no competing interests. RP has received travel grants from UCB Pharma and Eisai.
Provenance and peer review Not commissioned; externally peer reviewed.
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