And Etiological Profile in Developing Countries

Acute symptomatic seizures are those caused or provoked by an acute medical or neurological insult1 and, in the aggregate are almost as common as febrile seizures or epilepsy.2 They make up ~ 40% of all the newly diagnosed seizure disorders.3 Acute symptomatic seizures show clearly differentiated characteristics with regard to true epileptic seizures; (1) a clearly identified causal association, (2) generally tend not to recur, (3) usually long-term antiepileptic drug (AED) treatment is not necessary.

Incidence

The incidence of acute symptomatic seizures has been reported in a few epide-miological studies. In Rochester, Minnesota, U.S.A, the age-adjusted incidence rate for 1955-1984 was 39.0/100,000 person-years. The incidence was considerably higher in men, 52.0 as compared with 29.5 in women. And the cumulative incidence in patients up to 80 years of age was 3.7%.2 In Gironde, Bordeaux, France, the incidence was 28/100.000 person-years.3 The only incidence study from developing country is from Taiwan in young children and reported an incidence of 46.0/ 100,000.4 In a hospital-based study in south India, acute symptomatic seizures accounted for 22.5% of total population studied.5 A similar incidence, 21%, was reported in the British community-based study of newly diagnosed epilepsy.6 In a hospital-based prospective study of 1,000 consecutive patients with seizure disorder in Saudi Arabia, acute symptomatic accounted only for 3%.7

Acute symptomatic status epilepticus can be the presenting feature of acute medical or neurological illness. The incidence of acute symptomatic status epilepticus in French-speaking Switzerland was 62/100,000.8 In a hospital-based study from south India of the 527 patients with acute symptomatic seizures, 3% of patients presented with status epilepticus.5 Of the etiology of status epilepticus, acute symptomatic status epilepticus formed 54% in both the series from Argentina9 and south India.10

In Rochester, Minnesota study age-specific incidence was highest during the first year of life.2 In the Taiwan study age-specific incidence was highest in the group aged 1-12 months.4 The highest incidence in young children is probably because of high incidence of seizures due to encephalopathies, metabolic disorders, and infections.

Classification

Provoked or acute symptomatic seizures are those caused by an acute medical or central nervous system insult.1 There are distinct differences between the two provoking factors. Provoked seizures caused by acute medical illness are self-limited and there is no underlying permanent brain damage. The primary consideration in such patients should be the identification and treatment of underlying disorder. If AEDs are used to suppress acute seizures, generally they do not need to be continued after the patient has recovered from the primary illness. The prognosis is excellent and the risk of later epilepsy is virtually none,4 whereas in patients with acute central nervous system (CNS) insult, each etiological factor is a significant risk factor for both acute symptomatic seizures and epilepsy. Although AEDs are effective in treating acute seizures, none have yet been shown to delay or reduce the development of later epilepsy. However, the prognosis is substantially different when compared to remote symptomatic epilepsy.11

In the syndromic classification proposed by International League Against Epilepsy (ILAE)12 seizures related to acute metabolic or toxic factors and eclampsia fall into category 4.1, situation-related seizures. Epileptogenic zone in patients with acute symptomatic seizures caused by acute CNS insult is likely to be structural and as such may be categorized under symptomatic localization-related epilepsies (2.2) of syndromic classification.5

Etiology

The relative frequency of different etiologies may vary according to geographic location. Much of the acute symptomatic seizures in the developing world are from preventable causes, CNS infections.2,5,13

Infections of Central Nervous System

About 5% of people with CNS infections can be expected to experience an acute symptomatic seizure(s).14 In a hospital-based study from south India, CNS infections were the provoking factors in 71% of patients with acute symptomatic seizures,5 whereas in the Rochester, Minnesota study they accounted for only 15%.2 The pattern of infections differs according to geographic regions. Neurocysticercosis and neurotuberculosis are the common infections in developing countries.2,5

Neurocysticercosis

Neurocysticercosis is the most common cause of provoked seizure(s) in developing countries (see Chapter 10). All the evolutive stages of parenchymal brain cys-ticerci, from viable cysts to calcifications, may be associated with seizures. Seizures in patients with degenerating cyst are a consequence of inflammation around a cyst(s) and these seizures as such may be categorized under acute symptomatic seizures.15 In our study of acute symptomatic seizures, neurocysticercosis was the etiological factor in 66% of the patients.5 Nearly 100% of patients with solitary cysticercus granuloma, present with seizures.16,17 Seizures are either the presenting feature or occur during the course in 92% of patients with intraparenchymal lesions, and in 74% of patients with mixed intra- and extraparenchymal involvement.18 Multiple cysts, parenchymal and extraparenchymal, are more common in Latin American countries,15 whereas there is an over abundance of reports of solitary cysticercal lesions from India.17

Japanese Encephalitis

Japanese encephalitis is the most common cause of encephalitis, worldwide with an estimated 50,000 cases and 15,000 deaths annually.19 Most of China, Southeast Asia, and the Indian subcontinent are affected by the virus.20 Seizures have been reported in up to 85% of children and in 10% of adults in acute phase of the illness.

In some children a single seizure is followed by a rapid recovery. Multiple or prolonged seizures and status epilepticus are associated with a poor outcome.20

Central Nervous System Tuberculosis

The incidence of tuberculosis has increased drastically in recent years both in areas that were traditionally endemic and in areas where the incidence of tuberculosis is declining. About 2000 million people in the world today are infected with tuberculosis but only 10% develop clinical disease.20 Coinfection with HIV increases the lifetime risk of developing clinical tuberculosis 1 to 3 times.22 It has been estimated that about 10% of the immunocompetent patients who have tuberculosis will develop central nervous system disease.23 HIV also predisposes to the development of extra pulmonary tuberculosis, and in particular tuberculous meningitis.24 In our study of acute symptomatic seizures, 16% of provoked seizures were related to neurotuberculosis.5

In tuberculous meningitis seizures can occur at any stage of the illness and about 10% of adults and 55% of children develop seizures in the acute phase of illness.25 Seizures can be the presenting feature in about 10% of patients with tuberculous meningitis.26 The cause of seizures is attributed to associated, inflammatory response of the brain, tuberculomas, vasculitis and associated infarcts, and metabolic disturbances.

Intracranial tuberculomas account for less than 0.2% of intracranial mass lesions in developed countries, while it still represents a major neurosurgical finding in developing countries.27 In the earlier studies in India tuberculomas accounted for 30% of pathologically verified intracranial mass lesions in adults and 50% of those of children.28 Seizures occur in more than 60% of patients with intracranial tuberculoma, almost always with signs of focal CNS involvement.29

Malaria

Malaria is still one of the world's major killing disease and most of the malaria endemic area is confined to tropics. There may be as many as 300-500 million infections per year, 90% in Africa, with 1.5-3 million fatal cases most of which are African children.30 Vivax malaria is a frequent cause of typical febrile seizures in children in tropical endemic region. Rarely children may have status epilepticus and it may be difficult to differentiate from malignant cerebral falciparum malaria.13,18 Seizures commonly complicate cerebral falciform malaria. Majority of children and 40% of adults with cerebral malaria develop seizures. Possible causes of seizures include cerebral hypoxia associated with cerebral malaria, hyperpyrexia, hypoglyce-mia and other metabolic disturbances, and antimalarial drugs.31 Seizures are associated with an increased risk of death and neurological sequelae.

Cerebrovascular Diseases

Early seizure(s) has been reported to occur with a frequency of 2.5 to 5.7% within 14 days after stroke and is a predictor of recurrent seizures.5 and status epilepticus. Lesion location and stroke subtype are strong determinants of early sei-zure.32 In one study initial stroke severity has been shown as a predictor of early seizure.33 However in The Northern Manhattan Stroke Study (NOMSS) NIH stroke scale score was not an independent predictor of early seizure in multivariate analy-sis.32 The incidence of acute symptomatic seizures with stroke increases rapidly with increasing age.2 Like in developed countries, in developing countries also, stroke is

the leading cause for provoked seizures in the elderly.5 In developing countries cortical sino-venous thrombosis is an important cause of acute symptomatic seizures among young patients with cerebrovascular diseases. And early seizure(s) has been reported in 46 -79% of patients.34 In our series 14% of acute symptomatic seizures were related to stroke and cortical sino-venous thrombosis accounted for 37% of strokes.5

Seizures Associated with Fever in Children

There is a probability of a child with fever and seizures having primary CNS infection and in developing countries this probability is high. This is much more so in infants under 12 months.35-37 In a study in Nigeria, of the 522 children, aged one month to 6 years, who presented with convulsions and fever of acute onset at the emergency department of a university hospital, bacterial meningitis was diagnosed in 22 (4.2%) children on bacteriological and/or biochemical evidence. The prevalence declined sharply after six months of age. Six (27%) of the children with meningitis lacked meningeal signs.35

Clinical Features

Acute symptomatic seizures may be single or repetitive. Single seizure may be brief or prolonged. Repetitive seizures may be serial, clustered, or crescendo. Status epilepticus may be the presenting feature. In our study, of the 572 patients, 7% had single seizure, 90% had two or more seizures and 3% developed status epilepticus. Repetitive seizures included seizure clusters.5 Seizure type can be simple partial, complex partial (CPS) with or without secondary generalization, or generalized tonic-clonic seizures (GTCS). The most common seizure type is GTCS (including secondary generalization). In particular, alcohol or drug withdrawal, drug toxicity, or systemic metabolic disorders typically present as GTCS. Whereas patients with acute primary CNS insult may trigger simple or complex partial seizures depending on the site of pathology.

Nonconvulsive seizures and status are common in patients with acute neurological or systemic illness admitted to intensive care units. In one series of neurological ICU patients in coma, the incidence of nonconvulsive seizures (NCSzs) was 34%.38 In a university hospital-based study the incidence of NCSzs in patients with CNS infections was 26% and two-thirds of them had nonconvulsive status epilepticus.39 Clinical descriptions of nonconvulsive seizures cover a broad range. By definition there must be impairment of consciousness. This can vary from mild clouding of consciousness to unresponsive obtundation. Impairment of consciousness is accompanied by automatisms, agitated unresponsiveness with bizarre, almost psychotic activity, aphasia, amnesia, and twitching or myoclonic face or limb movements. Clinical seizure manifestations may be minimal and the diagnosis may be easily missed. Diagnosis of nonconvulsive seizures is critically dependent on EEG.

Diagnostic Evaluation

The primary consideration in patients with acute symptomatic seizures is identification of underlying cause. Laboratory screening should be ordered based on individual clinical circumstances to make diagnostic workup more cost-effective. Such an approach is of much relevance for developing countries.

Laboratory workup should include complete blood picture, serum electrolytes, blood urea nitrogen, creatinine, glucose, calcium, magnesium, arterial blood gas

(ABG), and toxicology screening. There are no studies that systematically evaluated the yield from doing routine laboratory screening in children and adults with acute symptomatic seizures.

Lumbar puncture is frequently performed in children in the presence of fever and seizures to rule out CNS infections. However, clinical features should guide decision on the need for lumbar puncture. Diagnostic lumbar puncture is indicated when the diagnosis of infectious meningitis or encephalitis is considered. In children with fever and acute seizures, age less than 6 months, complex febrile seizures, unarousable coma, and presence of extracranial focus of infection should warrant a lumbar puncture.36

Routine use of electroencephalogram is of limited value in the evaluation of acute symptomatic seizures. However, continuous EEG monitoring is of help in the evaluation of nonconvulsive seizures or status epilepticus. In patients with nonconvulsive seizures when the EEG demonstrates typical ictal patterns, the diagnosis is usually straightforward. However, in many circumstances the EEG has to be differentiated from encephalopathic patterns, and this differentiation can prove troublesome, although the clinical and electrographic response to treatment can prove helpful.

Commission on Neuroimaging of ILAE recommends, in acute circumstances, computed tomography (CT) scan as an appropriate initial investigation if magnetic resonance imaging (MRI) facility is not available.40 Abnormal neurologic examination is the most important criterion available to select patients for emergency cranial CT in patients with acute seizures.41,42 In developing countries CNS infections account for a significant proportion of acute symptomatic seizures and the pathology related to CNS infections can easily be demonstrated by a contrast CT scan. Contrast CT scan demonstrates most of the pathology of neurocysticercosis. Partial seizures with no obvious cause may be the presenting feature of neurocysticercosis and other CNS infections.43 In developing countries endemic to neurocysticercosis it will be prudent to get contrast CT scan in patients with acute onset seizure(s) or cluster seizures.

Treatment

Acute seizure(s), seizure clusters, and acute symptomatic SE, are neurological emergencies that are typically first encountered in the prehospital environment. Management of acute symptomatic seizures should proceed on three fronts: (1) termination of acute seizure(s), (2) prevention of recurrence, and (3) identification, and management of underlying disorder.

Termination of Seizure Single Seizure

Most acute single seizures (perhaps excluding febrile seizures) last about two minutes. A seizure lasting less than five minutes may not be treated. The chance in adults and older children, that a seizure lasting 5 minutes will self-terminate before 30 minutes is very small.44 However, there is minimal evidence to support that immediate treatment of prolonged seizure prevents progression to status epilepticus. Nevertheless, it is generally accepted that prolonged seizure episodes should be treated, and that such treatment may prevent progression to status epilepticus.44

Seizure Clusters

Seizure clusters include repetitive series or clusters of seizures that occur within a short period of time but that do not meet the criteria for a diagnosis of status epilepticus. Patient recovers to the baseline between the seizures. Temporary treatment to terminate the cluster is often necessary, even though the evidence that such treatment prevents progression to status epilepticus is lacking.46

Status Epilepticus

Status epilepticus is defined as more than 30 minutes of: a) continuous seizure activity, or b) two or more sequential seizures without full recovery of consciousness. Recently proposed operational definition of generalized convulsive SE in adults and older children (> 5 years old) refers to > 5 minute of (a) continuous seizures or (b) two or more discrete seizures between which there is incomplete recovery of consciousness.44 Acute symptomatic status epilepticus is associated with higher mortality, almost a 100 fold increased risk of dying compared to that expected in the general population.47 Treatment protocols are similar to any status epilepticus.48

Treatment Options

Clusters and Prolonged Seizures

Various types of benzodiazepine delivered via diverse routes have been reported to be efficacious in treating seizure clusters and prolonged seizure. Commonly used benzodiazepines include diazepam, midazolam, or lorazepam. For patients who have a single seizure, it is important to identify and deal with possible provocative factors. In patients with acute seizure clusters, intermittent therapy is never enough. An acute loading dose of phenytoin/fosphenytoin or valproic acid can provide temporary additional protection while provocative factors are corrected or while the natural history of the patient's cluster pattern runs its course, The plan in such a patient would be to continue maintenance treatment with whatever AED is deemed best. If antiepileptic drugs are used to suppress recurrence of seizures, they generally do not need to be continued after the patient has recovered from the primary illness.46

Intramuscular midazolam is very effective in stopping seizure activity within 5 to 10 minutes and is more than 90% bioavailable after intravenous and intramuscular administration. In a prospective randomized study (intramuscular midazolam versus intravenous diazepam) of children requiring acute treatment for seizures, there was approximately a 4-minute difference in both the times for drug administration and seizure cessation in favor of intramuscular midazolam.49 In patients in whom prolonged sedation may seriously confound neurological management, initial treatment of seizure(s) may be instituted with midazolam.

Status Epilepticus

Acute symptomatic status epilepticus is a neurological emergency and treatment protocols are similar to status epilepticus. Randomized double-blinded studies in adults50 and nonrandomized studies in children.51,52 supports the use of lorazepam as monotherapy. If status epilepticus persists this should be followed by phenytoin or fosphenytoin is effective. In case of refractory status epilepticus one of the anesthetic agents, midazolam, propofol, or pentobarbital, are the drugs of choice.53

Eclampsia of Pregnancy

Preeclampsia-eclampsia is a major problem in developing countries. Magnesium sulphate is clearly superior to phenytoin as an anticonvulsant in preeclampsia-eclampsia and it is preferred agent for this purpose. Clinical trails comparing magnesium sulphate with placebo or no anti-convulsant for women with preeclampsia provide promising evidence that magnesium sulphate reduces the risk of elcampsia.54-57

Prehospital Treatment

Recent studies have shown that the administration of benzodiazepines by paramedics is an effective and safe means of treating status epilepticus in adults58 and children.5960 In the prehospital setting. These studies also suggest prehospital therapy shortens the duration of status epilepticus and simplifies subsequent management in the emergency department. It is reasonable to extend these conclusions to the treatment of acute symptomatic clusters and prolonged seizures since rapid, maximal control is desired. In developing countries poor health care delivery systems and logistic difficulties in transporting patients to a center with adequate facilities, make prehospital administration of benzodiazepines by paramedics a viable option. The potential benefits of such approach include the prevention of systemic and neurologic sequelae of prolonged convulsive seizures.

Rectal diazepam is effective in aborting seizures and preventing febrile seizures.61 Prehospital intravenous and rectal diazepam therapy were initially effective in terminating SE in 100% and 81% of children, respectively. However, seizure recurred in 60% of the children treated with intravenous diazepam, as opposed to 30.8% of children treated with rectal diazepam.60 In a retrospective case-control study design of prehospital treatment of SE in children rectal or intravenous diazepam was associated with SE of shorter duration (32 minutes — diazepam group versus 60 minutes — standard emergency department (ED) AED therapy group) and a reduced likelihood of recurrent seizures in the ED (58% versus 85%).59 Prehospital administration of lorazepam for adult patients in SE by paramedics was found to be safe and effective.58 Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (59.1%) or diazepam (42.6%) than patients given placebo (20.1%). The rates of respiratory and circulatory complications after the study treatment was administered were 10.6% for the lorazepam group, 10.3% for the diazepam group, and 22.5% for the placebo group (P < 0.05). Results of both the studies suggest lorazepam is likely to be a better therapy for acute seizures than diazepam.

CNS Infections: Antimicrobials, Provoked Seizures, and AEDs

While prescribing antimicrobials in patients with CNS infections and provoked seizures the issues that need to be considered include: (a) proconvulsant activity of the antibiotics, (b) adverse effect of the antimicrobials on the safety and efficacy of the concurrent AED therapy, and (c) the effect of concurrent AED therapy on the safety and efficacy of the antimicrobials.62

The antimicrobials associated with proconvulsant properties include pencillins, cephalosporins, carbapenems, quinolones, and antimalarial drugs.62 Renal failure and hypoalbuminaemia when present will increase the risk for antimicrobial induced seizures.63-65

Fluconazole and iniconazole inhibit cytochrome P2C9 isoenzyme and may increase the plasma levels of phenytoin, which is a substrate of this isoenzyme. Isoniazide

is a broad ranging metabolic inhibitor and increases the plasma levels of phenytoin, carbamazepine, and valproic acid.66 Risk of phenytoin toxicity will be high when given in combination with isoniazide than when given alone.67 Rifampicin reduces the concentration of valproic acid, phenytoin, and carbamazepine.66

Carbamazepine, phenytoin, and barbiturates by hepatic enzyme induction may decrease the plasma levels of praziquantel and albendazole resulting in therapeutic failure if dosage is not adjusted appropriately.66

Conclusion

Acute symptomatic seizures in the aggregate are almost as common as febrile seizures or epilepsy and make up ~ 40% of all the newly diagnosed seizure disorders. Much of acute symptomatic seizures in the developing world result from preventable causes, CNS infections. Neurocysticercosis is the most common cause of provoked seizure(s) in developing countries.

Recent studies have shown that the administration of benzodiazepines by paramedics is an effective and safe means of treating status epilepticus. It is reasonable to extend these conclusions to the treatment of acute symptomatic seizure clusters and prolonged acute seizures. In developing countries poor health care delivery systems and logistic difficulties in transporting patients to a center with adequate facilities, make prehospital administration of benzodiazepines by paramedics a viable option. The potential benefits of such an approach include the prevention of systemic and neurologic sequelae associated with prolonged convulsive seizures or seizure clusters and may prevent progression to status epilepticus.

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