Epilepsy and seizure disorders

I am professor Yasser Metwally, porofessor of neurology, Ain Shams university, Cairo, Egypt, Visit my web site at: http://yassermetwally.com

This post contains simple medical information to neurological patients (vist my site at http://patients.yassermetwally.com)

Download the patients neurological manual at: http://patients.yassermetwally.com/patients.zip

INTRODUCTION

A seizure is an abnormal, unregulated electrical discharge that occurs within the brain’s cortical gray matter and transiently interrupts normal brain function. A seizure typically produces altered awareness, abnormal sensations, involuntary movements, or convulsions.

An isolated seizure can be provoked in a normal brain by reversible stressors (eg, hypoxia, hypoglycemia; in children, fever). A seizure disorder (epilepsy) is diagnosed when a patient has = 2 seizures not related to reversible stressors.

  • Etiology and Classification

Seizure disorders are considered symptomatic or idiopathic (no known cause). Idiopathic seizure disorders probably have some genetic basis.

Seizures are classified as generalized or partial. In generalized seizures, the aberrant electrical discharge diffusely involves the entire cortex of both hemispheres from the onset, and consciousness is usually lost. Generalized seizures result most often from metabolic disorders and sometimes from genetic disorders. Generalized seizures include infantile spasms and absence, tonic-clonic, atonic, and myoclonic seizures.

Partial seizures (those of focal onset) are often due to structural abnormalities. The excess neuronal discharge begins in one cerebral cortex. Partial seizures may be simple (no impairment of consciousness) or complex (reduced but not complete loss of consciousness). Partial seizures may spread and activate the entire cerebrum bilaterally, manifesting as a generalized seizure. Activation may occur so rapidly that the initial partial seizure is not clinically apparent, or a generalized seizure may follow a brief partial seizure (called secondary generalization).

Idiopathic seizure disorders generally begin between ages 2 and 14. Incidence of symptomatic seizures is highest at birth and among the elderly. Seizures before age 2 are usually caused by developmental defects, birth injuries, or metabolic disorders. Many seizures that begin in adults are secondary to cerebral trauma, alcohol withdrawal, tumors, or cerebrovascular disease; for 50% of seizures, cause is unknown. Seizure disorders in the elderly are often due to tumors or strokes. Posttraumatic seizures occur after 25 to 75% of head injuries that cause skull fractures, intracranial hemorrhages, or focal neurologic deficits.

Sometimes patients with psychiatric disorders simulate seizures (called nonepileptic seizures or pseudoseizures).

  • Symptoms and Signs

Seizures may be preceded by an aura of sensory or psychic manifestations (eg, smell of rotting flesh, stomach butterflies). Most seizures end spontaneously in 1 to 2 min. A postictal state may follow a seizure (most commonly, generalized) and is characterized by deep sleep, headache, confusion, and muscle soreness; this state lasts from minutes to hours. Sometimes the postictal state includes Todd’s paralysis, a transient neurologic deficit on the side contralateral to the seizure focus.

Most patients appear neurologically normal between seizures, although high doses of anticonvulsants can reduce alertness. Any progressive mental deterioration is usually related to the neurologic disorder that caused the seizures rather than seizures themselves. Rarely, seizures are unremitting.

  • Simple partial seizures:

Motor, sensory, or psychomotor symptoms occur without loss of consciousness. Specific symptoms reflect the affected area of the brain. In jacksonian seizures, focal motor symptoms begin in one hand, then march up the arm. Other focal seizures affect the face first, then spread to an arm and sometimes a leg. Some partial motor seizures begin with an arm raising and the head turning toward the moving arm. Some proceed to generalized convulsions.

  • Complex partial seizures:

An aura often precedes the seizure. During the seizure, patients may stare, perform automatic purposeless movements, utter unintelligible sounds without understanding what is said, and resist assistance. Consciousness is impaired, but patients have some awareness of the environment (eg, they purposefully withdraw from noxious stimuli). Motor symptoms subside after 1 to 2 min, but confusion and disorientation may continue for another 1 or 2 min.

Patients may lash out if restrained during the seizure or while recovering consciousness after a generalized seizure. However, unprovoked aggressive behavior is unusual.

Left temporal lobe seizures may cause verbal memory abnormalities; right temporal lobe seizures may cause visual spatial memory abnormalities. Incidence of psychiatric disorders is higher in patients with a temporal lobe seizure than in the general population: 33% have psychologic difficulties, and 10% have schizophreniform or depressive psychoses.

Between seizures, many patients develop new behaviors, such as religiosity, hypergraphia (compulsion to write copiously), extreme dependence on other people, and altered sexuality.

  • Epilepsia partialis continua:

This rare form of focal motor seizures usually involves the hand or one side of the face; seizures recur every few seconds or minutes for days to years at a time. In adults, the cause is usually a structural lesion (eg, stroke). In children, it is usually a focal cerebral cortical inflammatory process (eg, Rasmussen encephalitis), possibly caused by a chronic viral infection or autoimmune processes.

  • Generalized seizures:

Consciousness is usually lost, and motor function is abnormal from the onset.

Infantile spasms are characterized by sudden flexion of the arms, forward flexion of the trunk, and extension of the legs. Seizures last a few seconds and recur many times a day. They occur only in the 1st 5 yr of life, then are replaced by other types of seizures. Developmental defects are usually present.

Absence seizures (formerly called petit mal) consist of 10- to 30-sec loss of consciousness with eyelid fluttering; axial muscle tone may or may not be lost. Patients do not fall or convulse; they abruptly stop activity, then just as abruptly resume it, with no postictal symptoms or knowledge that a seizure has occurred. Absence seizures are genetic and occur predominantly in children. Without treatment, such seizures are likely to occur many times a day. Seizures often occur when patients are sitting quietly, can be precipitated by hyperventilation, and rarely occur during exercise. Atypical absence seizures last longer, are accompanied by more pronounced jerking or automatic movements, and cause less complete loss of awareness. Many patients have a history of damage to the nervous system, developmental delay, and other types of seizures. Atypical absence seizures usually continue into adulthood.

Atonic seizures occur in children. They are characterized by brief, complete loss of muscle tone and consciousness. Children fall or pitch to the ground, risking trauma, particularly head injury.

Generalized tonic-clonic (sometimes called primarily generalized) seizures typically begin with an outcry; they continue with loss of consciousness and falling, followed by tonic, then clonic contractions of muscles of the extremities, trunk, and head. Urinary and fecal incontinence and frothing at the mouth sometimes occur. Seizures usually last 1 to 2 min. Secondarily generalized tonic-clonic seizures begin with a simple partial or complex partial seizure.

Myoclonic seizures are brief, lightning-like jerks of a limb, several limbs, or the trunk. They may be repetitive, leading to a tonic-clonic seizure. Unlike other seizures with bilateral motor movements, consciousness is not lost unless a generalized seizure occurs.

Juvenile myoclonic epilepsy appears during childhood or adolescence. Seizures begin with a few bilateral, synchronous myoclonic jerks, followed in 90% by generalized tonic-clonic seizures. They often occur on awakening in the morning, especially after sleep deprivation or alcohol use.

Febrile seizures occur with fever and in the absence of intracranial infection; they should be considered a type of provoked seizure. They affect about 4% of children aged 3 mo to 5 yr. Benign febrile seizures are brief, solitary, and generalized tonic-clonic in appearance. Complicated febrile seizures are focal, last > 15 min, or recur = 2 times in 5 to 10 min or = 2 seizures between which patients do not fully regain consciousness. The previous definition of > 30 min duration was revised to encourage more prompt identification and treatment. Untreated generalized seizures lasting > 60 min may result in permanent brain damage; longer-lasting seizures may be fatal. There are many causes, including rapid withdrawal of anticonvulsants. Complex partial and absence status epilepticus often manifest as prolonged confusion.

  • Diagnosis

Evaluation must determine whether a seizure (vs, eg, syncope, cardiac arrhythmia, or drug overdose) occurred, then identify possible causes or precipitants. Patients with new-onset seizures are evaluated in an emergency department; they can sometimes be discharged after thorough assessment. Those with a known seizure disorder may be evaluated in a physician’s office.

  • History:

Classic seizure activity, bitten tongue, incontinence, prolonged loss of consciousness followed by confusion, or presence of aura suggests a seizure. History should include information about the 1st and subsequent seizures (eg, duration, frequency, sequential evolution, longest and shortest interval between seizures, aura, postictal state, precipitating factors). Risk factors for seizures (eg, prior head trauma or CNS infection, known neurologic disorders, drug use or withdrawal, anticonvulsant noncompliance, family history of seizures or neurologic disorders) should be identified.

  • Physical examination:

Physical examination is almost always normal when seizures are idiopathic but may provide significant findings when seizures are symptomatic. Fever and stiff neck suggest meningitis, subarachnoid hemorrhage, or encephalitis. Papilledema suggests increased intracranial pressure. Focal neurologic defects (eg, asymmetry of reflexes or muscle strength) may indicate a structural abnormality (eg, tumor). Skin lesions may indicate a neurocutaneous disorder (eg, axillary freckling or café-au-lait spots in neurofibromatosis, hypomelanotic skin macules or shagreen patches in tuberous sclerosis).

  • Testing:

For patients with a known seizure disorder and a normal or unchanged neurologic examination, little testing is required except for blood anticonvulsant levels, unless symptoms or signs of trauma or a metabolic disorder are present.

For patients with new-onset seizures or with a newly abnormal neurologic examination, head CT is required immediately to exclude a mass or hemorrhage. Follow-up MRI is recommended when CT is negative; it provides better resolution for brain tumors and abscesses and can detect cerebral venous thrombosis and herpes encephalitis. Laboratory tests for metabolic disorders should be done, including CBC; serum glucose, BUN, creatinine, Na, Ca, Mg, and P; and liver function tests. If meningitis or CNS infection is suspected in any patient, head CT is done, and if it is normal, a lumbar puncture is required. EEG is done; it may be needed to diagnose complex partial or absence status epilepticus. Alert and oriented patients with normal imaging and laboratory tests can undergo EEG as outpatients.

In complex partial seizures of temporal lobe origin, temporal lobe foci (spikes or slow waves) occur between seizures (interictal). In generalized-at-onset tonic-clonic seizures, interictal EEG abnormalities may manifest as symmetric bursts of sharp and slow, 4- to 7-Hz activity. In secondarily generalized seizures, the EEG may show focal electrical discharges. In absence seizures, spikes and slow-wave discharges appear at a rate of 3/sec. In juvenile myoclonic epilepsy, a 4- to 6-Hz polyspike and wave abnormality is characteristic.

However, diagnosis is clinical and cannot be excluded by a normal EEG. EEG is less likely to detect abnormalities if seizures are infrequent. Of patients ultimately confirmed to have a seizure disorder, 30% have a normal 1st EEG; a 2nd EEG done after sleep deprivation detects abnormalities in 1/2. Some patients never have an abnormal EEG.

Inpatient combined video-EEG monitoring for 1 to 5 days may help determine type and frequency of seizures (eg, frontal lobe seizure vs a pseudoseizure) and guide treatment.

  • Prognosis and Treatment

With treatment, seizures are eliminated in 1/3 of patients, and frequency of seizures is reduced by > 50% in another 1/3. About 60% of patients whose seizures are well-controlled by anticonvulsants can eventually stop the drugs and remain seizure-free.

Optimal treatment is to eliminate the causes whenever possible. If the cause cannot be corrected or identified, anticonvulsants are often required, particularly after a 2nd seizure; usefulness of anticonvulsants after a single seizure is controversial, and risks and benefits should be discussed with the patient.

During a seizure, injury should be prevented by loosening clothing around the neck and placing a pillow under the head. Attempting to protect the tongue is futile and likely to damage the patient’s teeth or the rescuer’s fingers. Patients should be rolled onto their side to prevent aspiration.These measures should be taught to the patient’s family members and coworkers.

Until seizures are controlled, patients should refrain from activities in which loss of consciousness could be life threatening (eg, driving, swimming, climbing, bathing in a bathtub). After seizures are completely controlled (typically for > 6 mo), many such activities can be done if appropriate safeguards (eg, lifeguards) are used, and patients should be encouraged to lead a normal life, including exercise and social activities. In a few states, physicians must report patients with seizures to the Department of Motor Vehicles. However, most states allow automobile driving after seizures have been absent for 6 mo to 1 yr.

Cocaine and some other illicit drugs (eg, phencyclidine, amphetamines) can trigger seizures and should be avoided. Alcohol intake should be minimized. Some drugs (eg, haloperidol, phenothiazines) may lower seizure threshold and should be avoided if possible.

Family members must be taught a commonsense approach toward the patient. Overprotection should be replaced with sympathetic support that lessens negative feelings (eg, of inferiority or self-consciousness); invalidism should be prevented. Institutional care is rarely advisable and should be reserved for severely retarded patients and for patients with seizures so frequent and violent despite drug treatment that they cannot be cared for elsewhere.

  • Acute seizures and status epilepticus:

Most seizures remit spontaneously in several minutes and do not require emergency drug treatment. Status epilepticus and most seizures lasting > 5 min require drugs to terminate the seizures, with monitoring of respiratory status. Intubation is necessary if there is any indication of airway compromise. IV access should be quickly obtained, and lorazepam 0.05 to 0.1 mg/kg IV is given at a rate of 2 mg/min. Large doses are sometimes required. However, if seizures continue after about 8 mg is given, fosphenytoin 10 to 20 PE (phenytoin equivalents)/kg IV is given at a rate of 100 to 150 PE/min; phenytoin 15 to 20 mg/kg IV at a rate of 50 mg/min is a 2nd choice.

Additional seizures require an additional 5 to 10 PE/kg of fosphenytoin or 5 to 10 mg/kg of phenytoin . Persistent seizures after lorazepam and phenytoin defines refractory status epilepticus. Recommendations for a 3rd anticonvulsant vary and include phenobarbital, propofol, midazolam, and valproate. Phenobarbital 15 to 20 mg/kg IV at 100 mg/min (3 mg/kg/min in children) is given; continued seizures require another 5 to 10 mg/kg. A loading dose of valproate 10 to 15 mg/kg IV is an alternative. At this point, if status epilepticus has not abated, intubation and general anesthesia are necessary. The optimal anesthetic to use is controversial, but many physicians use propofol 15 to 20 mg/kg at 100 mg/min or pentobarbital 5 to 8 mg/kg (loading dose) followed by infusion of 2 to 4 mg/kg/h until EEG manifestations of seizure activity have been suppressed. Inhalational anesthetics are rarely used. After initial treatment, the cause for status epilepticus must be identified and treated.

  • Posttraumatic seizures:

Prophylactic anticonvulsants are given if head injury causes skull fracture, intracranial hemorrhage, or focal neurologic deficits. These drugs reduce risk of seizures during the 1st week after injury but do not prevent permanent posttraumatic epilepsy months or years later. They should be stopped after 1 wk unless seizures occur.

  • Long-term treatment:

No single anticonvulsant controls all types of seizures, and different patients require different drugs. Patients occasionally require multiple drugs.

The drug of choice for the particular seizure disorder is started at a relatively low dose, which is gradually increased over 1 to 2 wk to the standard therapeutic dose, based on the patient’s lean body mass. Dose should be tailored to the patient’s tolerance of the drug. After the target dose range is reached, trough blood drug levels are measured. If seizures continue or the blood level is subtherapeutic, the daily dose is increased by small increments. If toxicity develops before seizures are controlled, the dose is reduced to the pretoxicity dose. Then, another anticonvulsant is gradually added until seizures are controlled. Patients should be closely monitored because drug interactions can interfere with either drug’s rate of metabolic degradation. The initial, ineffective anticonvulsant is then slowly tapered and eventually withdrawn completely. Use of multiple anticonvulsants should be avoided because incidence of adverse effects and drug interactions increases significantly; adding a 2nd drug helps about 10% of patients, but incidence of adverse effects more than doubles. Many drugs alter the blood level of anticonvulsants and vice versa. Physicians should be aware of all potential drug-drug interactions before prescribing a new drug.

Once seizures are controlled, the drug should be continued without interruption until patients have been seizure-free for at least 1 to 2 yr. At that time, stopping the drug should be considered. Most anticonvulsants can be tapered by 10% q 2 wk. Relapse is more likely in patients who have had a seizure disorder since childhood, require more than one anticonvulsant to be seizure-free, had seizures while taking an anticonvulsant, have partial or myoclonic seizures, have an underlying static encephalopathy, or have had an abnormal EEG within the last year. Of those who relapse, about 60% do so within 1 yr, and 80% within 2 yr. Patients who have a relapse when they are not taking anticonvulsants and those who have important social reasons for avoiding seizures should be treated indefinitely.

Once drug response is known, blood levels are less useful to follow than is the clinical course. Some patients have toxic symptoms at low levels; others tolerate high levels without symptoms. Blood drug levels are only guidelines. The appropriate dose of any anticonvulsant is the lowest dose that stops all seizures with the fewest adverse effects regardless of blood drug level.

For generalized tonic-clonic seizures, phenytoin, carbamazepine, and valproate are preferred. For adults, phenytoin can be given in divided doses or in a single dose at bedtime. If seizures continue, the total daily dose can be increased cautiously to 600 mg while trough blood levels are monitored. At a higher dose, dividing the daily dose may reduce toxic symptoms.

For partial seizures, treatment begins with carbamazepine , carbamazepine derivatives (eg, oxcarbazepine), or phenytoin. Valproate is generally less effective but may be considered. Newer drugs (eg, gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, zonisamide) appear effective, but their efficacy vs that of standard anticonvulsants has not been established.

For pure absence seizures, ethosuximide is preferred. For atypical absence seizures or absence seizures associated with other seizure types, valproate is preferred. Although clonazepam is effective, tolerance to this drug often develops. Acetazolamide is reserved for refractory cases.

Infantile spasms, atonic seizures, and myoclonic seizures are difficult to treat. Valproate is preferred, followed by clonazepam . Ethosuximide is sometimes effective, as is acetazolamide (same dosages as for absence seizures). Lamotrigine may have some benefit; it is often used with other anticonvulsants, which affect the dosage of lamotrigine. Phenytoin has limited effectiveness. For infantile spasms, corticosteroids for 8 to 10 wk are often effective. The optimal regimen is controversial. ACTH 20 to 60 units IM once/day may be used. A ketogenic diet may help but is difficult to maintain. Carbamazepine may make certain patients with primary generalized epilepsies and multiple seizure types worse.

Juvenile myoclonic epilepsy responds only to certain anticonvulsants (eg, valproate) and can be exacerbated by others (eg, carbamazepine); lifetime treatment is usually recommended.

Anticonvulsants are not recommended for febrile seizures unless a child has a subsequent seizure in the absence of febrile illness. Previously, many physicians gave anticonvulsants to children with complicated febrile seizures to prevent development of nonfebrile seizures, but this treatment does not appear effective, and long-term phenobarbital use reduces learning capacity.

  • Adverse effects:

All anticonvulsants may cause an allergic scarlatiniform or morbilliform rash, and none is completely safe during pregnancy.

For patients taking carbamazepine, CBC should be monitored routinely for the 1st year of therapy. If the WBC count decreases significantly, the drug should be stopped. Dose-dependent neutropenia (ie, neutrophil count 2 times the upper limit of normal), the drug should be stopped. An increase in ammonia up to 1.5 times the upper limit of normal can be tolerated safely.

Fetal antiepileptic drug syndrome (cleft lip, cleft palate, cardiac defects, microcephaly, growth retardation, developmental delay, abnormal facies, digital hypoplasia) occurs in 4% of the children of women who take anticonvulsants during pregnancy. Among commonly used anticonvulsants, carbamazepine appears to be the least teratogenic, but only slightly so; valproate may be the most teratogenic. Yet, because uncontrolled generalized seizures during pregnancy can lead to fetal injury and death, continued treatment with anticonvulsants is generally advisable. The risk should be put in perspective: Ethyl alcohol is more toxic to the developing fetus than any anticonvulsant. Folate supplements help reduce risk of neural tube defects and should be used.

  • Surgery:

About 10 to 20% of patients have seizures that are refractory to medical treatment. For most patients whose seizures originate from a local area of abnormal brain, function improves markedly when the epileptic focus is resected. Some patients remain seizure-free, but most still require anticonvulsants.Because surgery requires extensive testing and monitoring, these patients are best treated in specialized seizure disorder centers.

  • Vagus nerve stimulation:

Intermittent electrical stimulation of the left vagus nerve with an implanted pacemaker-like device reduces the number of partial seizures by 1/3. After the device is programmed, patients can activate it with a magnet when they sense a seizure is imminent. Vagus nerve stimulation is used as an adjunct to an anticonvulsant. Adverse effects include deepening of the voice during stimulation, cough, and hoarseness. Complications are minimal. Duration of effectiveness is unclear.

The author,

Professor Yasser Metwally

2 Comments »

  1. Yasser Metwally said

    February 26, 2008 @ 4:15 pm

    I am professor Yasser Metwally, porofessor of neurology, Ain Shams university, Cairo, Egypt, Visit my web site at: http://www.yassermetwally.com

    This post contains simple medical information to neurological patients (vist my site at http://patients.yassermetwally.com)

    Download the patients neurological manual at: http://patients.yassermetwally.com/patients.zip

    STATUS EPILEPTICUS

    INTRODUCTION

    Refractory status epilepticus (RSE) is a common problem in intensive care units and emergency departments. The important risk factor predisposing patients with SE to RSE is delay in receiving treatment. Self-sustaining SE is associated with progressive, time-dependent development of pharmacoresistance. Early termination of convulsive SE by aggressive treatment is the best way to prevent RSE. RSE once develop, requires more aggressive treatment as it is associated with higher mortality and morbidity. To date, no randomized controlled trials have been done for RSE. The most experience exists with coma inducing agents like pentobarbital, midazolam and propofol. New evidence suggests for the possible role of newer AEDs.
    Status epilepticus (SE) is a frequent neurological emergency associated with an annual incidence between 3.86-38 per 100,000 individuals. The incidence of SE has a bimodal distribution with peaks in children aged less than a year and the elderly.[1] Although conventional antiepileptic drugs (AED) can terminate SE in most cases, a substantial minority of patients develop medically refractory SE (RSE). In Veteran Administrative (VA) Cooperative study[2] first treatment regimen was successful in 55.5% of patients with “overt” SE, but in only 14.9% of those with “subtle” SE. Subsequent treatments of patients, who did not respond to first-line agent, indicates that the aggregate response rate was 7% to second-line agents and 2.3% to third-line agents. Only 5% of patients with SE who did not respond to lorazepam and phenytoin therapy, responded to phenobarbital administration.[2,3]

    Definition

    Although the entity of RSE is widely recognized and discussed, a standard definition has not yet been evolved and is usually defined as seizure activity that continues after first- and second-line therapy has failed.[4] However the proposed criteria vary in the number of AEDs (e.g., 2[5,6,7,8,9] or 3[10,11,12,13]) failed and in the duration of seizure activity (e.g., ranging from <1[5,9,11,13] at least 1[7] or 2[6,8] hours).
    Recently Holtkamp and colleagues[14] have coined the term “malignant” SE for the most severe variant of SE with persistent epileptic activity even after high dose anesthetics.

    Epidemiology

    RSE is a common problem in intensive care units and emergency departments. Estimates of the frequency of RSE in patients with SE have ranged from 31 to 44%.[15,16] The proportion of patients with RSE in the cohort reported by Rossetti et al[17] was 38% when considering all episodes and was 44% when considering only incidence cases. In the VA Cooperative Study, 38% of patients with “overt” SE and 82% of patients with “subtle” SE continued to have seizures after receiving 2 AEDs.[2]

    RSE is associated with high mortality and a significant morbidity; only about a third of patients return to their pre-morbid state.[18] In the VA Cooperative study[2] outcomes 30 days after treatment were significantly worse for patients with “subtle” SE. At 30 days, only 8.8% of patients had been discharged from the hospital and 26.5% were still in the hospital and the mortality was 64.7%. In the recent studies the reported mortality rates varied between 16 to 23%.[15,16,17] In a retrospective study the outcome was independent of specific coma inducing agents used and the extent of EEG burst suppression, suggesting that the underlying cause represents its main determinant.[17]

    Risk factors

    RSE is more prevalent in incident than in recurrent SE.[17] Risk factors predisposing patients to RSE include delay in receiving treatment, infections of central nervous system (CNS), metabolic encephalopathy and hypoxia.[15,19] Encephalitis is a predictor for RSE, which is associated with markedly poor outcome, in particular, the development of post-SE symptomatic epilepsy.[16] The patient at risk for malignant SE is typically young and suffers from encephalitis.[16]

    Pathophysiology

    SE refers to a condition in which there is a failure of the “normal” factors that serve to terminate a typical seizure. y-Aminobutyric acid (GABA) receptor-mediated inhibition may be responsible for the normal termination of a seizure. In addition, the activation of the N-methyl-D aspartate (NMDA) receptor by the excitatory neurotransmitter glutamate may be required for the propagation of seizure activity.[20] SE that is refractory to treatment may be the result of several processes [Table - 1] and has been attributed to a mechanistic shift from inadequate GABAergic inhibitory receptor-mediated transmission to excessive NMDA excitatory receptor-mediated transmission.[21,22,23,24,25,26] In experimental models, resistance to both benzodiazepines and barbiturates develops during prolonged seizures and it has been hypothesized that prolonged seizure activity alters the structure and/or function of GABAA receptors.[27]

    SE induced neuronal death is morphologically necrotic and is initiated by excessive glutamate release, which activates postsynaptic NMDA receptors and triggers receptor-mediated calcium influx (excitotoxicity). This results in a cascade of events and cell death.[28]

    The alterations in inhibitory and excitatory pathways have important implications for the pharmacological management of SE. Another important aspect of self-sustaining SE is the progressive, time-dependent development of pharmacoresistance. Currently recommended agents acts primarily through the GABAA receptor and have been shown to become less effective in SE of longer duration. Drugs shown to be effective in RSE act at different receptor sites other than benzodiazepine receptor site, propofol acts at a site distinct from the benzodiazepine and barbiturate binding sites, isoflurane acts by potentiation of inhibitory postsynaptic GABAA receptor-mediated currents, although effects on thalamo-cortical pathways also have been implicated.[27,28,29,30,31]

    Continuous EEG Monitoring

    Though continuous EEG monitoring (cEEG) has a definite place in the diagnosis and management of nonconvulsive status epilepticus (NCSE), its place in the management of convulsive SE is still unclear.[32] However EEG is useful in determining whether seizures have completely stopped, as well as in diagnosing electrographic seizures or nonconvulsive status epilepticus (NCSE) in patients who do not regain consciousness after clinical seizure stops. Electrographic seizures may persist in patients after convulsive SE. In one study cEEG demonstrated electrographic seizures in 48% of patients and 14% manifested NCSE.[33] In the VA study, 20% of clinically controlled convulsive
    SE patients were still seizing on EEG.[2] Mortality in patients in whom cEEG demonstrates electrographic seizures and NCSE is high.
    cEEG monitoring is required in patients with RSE during continuous intravenous therapy to monitor seizure activity and to titrate the drug dosage to achieve burst suppression pattern and during the withdrawal of anesthetic therapy. However the major limiting factor may be lack cEEG monitoring facility in many intensive care units.

    Management – General Measures

    RSE requires more aggressive treatment and however, the optimal treatment has not been defined. Patients should be treated in intensive care unit, as artificial ventilation and hemodynamic support is required. These patients generally require intravenous fluids and vasopressors to treat hypotension associated with high dose intravenous use of anesthetic agents. In a third of adults in SE, arterial pH falls below 7;[34] the main contribution to this change is lactic acidosis from skeletal muscle,[35] which responds well to oxygen and control of convulsive activity. Mild acidosis might be an anticonvulsant[36] and neuroprotective.[37] The usual practice is to treat with bicarbonate if the patient is hypotensive and arterial pH if it is < 7 due to metabolic acidosis. Control of hypothermia is neuroprotective.[38,39]

    Pharmacological treatment

    To date, no randomized controlled trials have been done for SE refractory to first- and second-line therapy. The most experience exists with continuous infusion (cIV) of pentobarbital, midazolam and propofol[18,40,41] [Table - 2]. The best comparative information comes from the systematic review by Claassen and colleagues.[18] No difference was found in mortality among the groups treated with cIV propofol, cIV midazolam and cIV pentobarbital. Mortality was related to patient’s age and duration of SE rather than AED choice. A recent retrospective study investigated the effect on RSE prognosis of various coma-inducing pharmacologic options.[17] Mortality and likelihood of the patient’s condition returning to clinical baseline at discharge did not differ significantly among the three arms, barbiturates (pentobarbital and phenobarbital), propofol and midazolam. This study did not find any evidence for mortality related to propofol infusion syndrome.

    Traditionally, barbiturates such as pentobarbital or thiopental have been used to terminate RSE, inducing coma and EEG suppression.[11,42,43,44] However their effectiveness has not been studied systematically. In a systematic review of 109 adult patients with RSE who were treated with pentobarbital 8% experienced acute failure; 12%, breakthrough seizures; 43%, withdrawal seizures within 48 hours; and 8%, refractory hypotension during the therapy.[17] EEG burst suppression or complete suppression has been achieved more frequently in episodes treated with barbiturates.[17,18] Pentobarbital use is also often accompanied by prolonged sedation and life threatening infections.[45] Episodes treated with barbiturates were associated with significantly longer hospital stay for surviving patients compared with episodes in which barbiturates were not used.[17]
    Superior pharmacokinetics and favorable adverse effect profile makes propofol the drug of choice. The two main advantages of propofol are a rapid onset and short duration of action. Propofol is a GABAA agonist that suppresses seizure activity via GABA-mediated inhibition of neuronal firing.

    Other mechanisms of action include inhibition of N-methyl-D aspartate receptor and modulation of calcium influx through slow calcium ion channels. The safety of propofol was further supported in recent retrospective series both in adults[40] and children.[41] A prospective study has also shown its efficacy in RSE.[46] In a retrospective series by Rossetti et al[40] in which 27 patients who failed to intravenous clonazepam and phenytoin therapy were induced into burst suppression pattern on cEEG with cIV propofol at a dose of 2.1 to 13 mg/kg/h for 1 to 9 days while continuing clonazepam infusion. RSE was successfully treated with propofol in 21 (67%) episodes. Seven deaths (23%) wee reported and none were attributable directly to propofol use and no patient experienced propofol infusion syndrome. In pediatric RSE also propofol has been shown to be a safe and effective drug, 14 (64%) of the 22 episodes could be adequately controlled. Two patients who were successfully treated with propofol died and the death was related to the underlying etiology and not to the use of propofol.[41] However propofol may cause metabolic acidosis and cardiovascular collapse with prolonged use in children and deaths have been reported,[47,48] the propofol infusion syndrome.[49] Propofol should therefore be used with caution in children, ideally for short time only and the infusion rate should not exceed 67 ug/kg/min.[50] In a prospective study the quality of burst suppression was unsatisfactory in most patients. The maintenance of continuous burst suppression is difficult and vigilant titrating of dosage of propofol is necessary under cEEG monitoring.[46]

    Midazolam is an effective, short acting benzodiazepine that when given as an infusion has an efficacy in RSE, including at sub-anesthetic doses. It has the advantages of rapid onset of activity and greater water solubility, avoiding the problem of metabolic acidosis from the propylene glycol vehicle of other benzodiazepines and barbiturates. Midazolam binds to GABAA receptors and augments GABAergic transmission, there by imparting anticonvulsant and sedative-hypnotic properties.[51] Duration of antiepileptic effects is minutes to hours. The elimination half-life is 1.5 to 3.5 hours initially. With prolonged use, there may be tolerance, tachyphylaxis and significant prolongation of half-life, up to days.[52] After 24-48 h, the dose of the drug must often be increased severalfold to maintain seizure control. Clinical experience with midazolam for RSE is limited. The reported failed treatment with midazolam ranges between 14 to 18%.[52,53,54,55,56,57] In the series of Claassen and colleagues[57] acute treatment failure occurred in 18% of episodes, breakthrough seizures in 56%, post treatment seizures in 68% and ultimate treatment failure in 18%. The authors suggest that titrating continuous intravenous midazolam to burst suppression, more aggressive treatment with concurrent AED or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after midazolam is discontinued. In this series only 24% had an immediate and sustained response.

    Other Pharmacological treatment

    High dose phenobarbital

    High dose of phenobarbital with serum levels of 100 to 200 ug/ml, has been found effective and safe in the treatment of RSE in children.[58] In another study a very high dose phenobarbital at accumulated daily doses up to 80 mg/kg, with a resulting serum level of more than 1000 mumol/l has been shown to effective in achieving seizure control in children with RSE. In this study the adverse effects were milder compared with thiopental infusion.[59]

    Ketamine

    Ketamine, a NMDA antagonist, has been proved useful in RSE[60] and it is also a neuroprotective.[61] However, because ketamine can raise intracranial pressure, the absence of intracranial mass lesion should be confirmed by neuroimaging. The experience with this agent in RSE is very limited.

    Inhalational Anesthetics

    Inhalational anesthesia (IA) is an alternative approach to the treatment of RSE. Its attractive feature include efficacy, rapid onset of action and the ability to titrate the doses according to the effects demonstrated on the EEG.[62,63] Of the various agents, isoflurane and desflurane are the two agents that have been administrated for RSE because of their safety associated with long-term administration.[64] In a recent retrospective study, seven patients with RSE were initiated to IAs (all patients to isoflurane and one patient in addition to desfluratne) after 1 to 103 (mean,19) days. They received multiple AEDs (mean 10, range 7 -15) in addition to IAs. Regardless of seizure type, isoflurane and desflurane consistently stopped epileptic discharges with adequate, sustained electrographic burst suppression within minutes of initiating IA therapy. Four patients had good outcomes. Prolonged use of IAs is well tolerated.[64]

    Newer AEDs

    The use of newer AEDS in the treatment of RSE has not been studied systematically. In 6 patients with RSE unresponsive to sequential trials of multiple agents, a suspension of topiramate administered via nasogastric tube was effective in aborting RSE. Effective dosages ranged from 300 to 1,600 mg/d.[65] RSE was terminated in three children with topiramate loading, 5 mg/kg/day.[66] Seizure control has been achieved in patients with RSE by administration of levetiracetam (500-3000 mg/day) by nasogastric route.[67] Injectable levetiracetam formulation is available and the pharmacokinetics of levetiracetam administered by IV infusion was comparable across all dose groups and infusion rates and the pharmacokinetic profile was consistent with that for levetiracetam administered orally.[68] Well designed studies are needed to determine the place of newer AEDs as the use of drugs can avoid pharmacologic coma.

    Target of treatment-burst suppression

    Experimental studies demonstrated maximal depression of cerebral metabolism with barbiturates with burst suppression intervals of 30 seconds.[69] Burst suppression and isoelectric background EEG have been shown to be accompanied by fewer recurrent seizures than simply stopping seizures.[18] There is uncertainty about the optimal extent of EEG suppression in RSE. Several authors used different burst suppression intervals. Kofke et al[70] used 15 to 30 seconds as burst suppression interval. Van Ness[71] used 3 to 9 bursts per minute during pentobarbital treatment. Mirsattari and colleagues[64] considered the maintenance of burst suppression for burst duration of less than 1 second and suppression duration longer than 10 seconds as the goal of therapy. Where as Bleck[10] advocates a more aggressive approach using isoelectric EEGs. In a recent retrospective study the outcome was independent of the extent of EEG burst suppression and probably related to the underlying cause of RSE.[17]

    Maintenance therapy

    In parallel with emergency treatment attention must be given to maintenance AED therapy to prevent recurrence of seizures. In patients known to have epilepsy, their usual AEDs should be maintained and dose adjustments may be required depending on AED levels. In patients presenting denovo the AEDs, phenytoin/fosphenytoin or valproate, used to control the status can in principle be continued as oral maintenance therapy. In others, unless relatively short-lived treatment is anticipated, the preference is to initiate oral maintenance therapy, valproate or carbamazepine, starting immediately at standard doses.[72] If additional medication is needed, the most appropriate AEDs are topiramate and levetiracetam as these drugs can be started at high doses with a low risk of idiosyncratic reactions.[73]

    SUMMARY

    The important risk factor predisposing patients with SE to RSE is delay in receiving treatment. Self-sustaining SE is associated with progressive, time-dependent development of pharmacoresistance. Early termination of convulsive SE by aggressive treatment is the best way to prevent RSE. RSE once develop, requires more aggressive treatment as it is associated with higher mortality and morbidity. To date, no randomized controlled trials have been done for RSE. The most experience exists with coma inducing agents like pentobarbital, midazolam and propofol. New evidence suggests for the possible role of newer AEDs.
    ============================================

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  2. Yasser Metwally said

    February 29, 2008 @ 12:35 pm

    Seizures – Medication Treatment Offers Hope For a Normal LIfestyle

    Seizures are the manifestation of uncontrolled electrical activity in the brain. Affected individuals show clinical symptoms of seizures with twitching or jerking of one side or their entire body. With this they can make gasping noises, turn blue in the face, bite their tongue or lose control of their bladder. These symptoms are charateristic of a grand mal seizure. During an epileptic attacks, the person is not responsive or aware of what is going on around them. Fortunately there is excellent treatment available to control seizures and in many cases, keep patients seizure free.

    It is estimated that there are 2-3 million individuals in the United States who suffer from recurrent seizures (epilepsy.) Many of these people are neurologically intact with the cause of their seizures being unknown. It is estimated that up to 10 percent of the population will suffer a single seizure in their life time. This does not mean that they will go on to have recurrent seizures or epilepsy. The average lifetime risk of having recurrent seizures is 3 percent.

    Risk of developing seizures include prior head injuries, alcohol or drug abuse, stroke, meningitis or other brain infections. Brain damage from trauma, surgery or tumors can also predispose to seizures. For anyone who has even a single seizure, they should see a neurologist for a complete evaluation. A minimum of screening lab work, an EEG (electroencephalogram) and MRI brain scan should be done. Of course a complete history and physical (neurological) exam is also required. One important point to remember is that a normal EEG does not exclude the possibility that a patient suffers from seizures. In fact, approximately 70 percent of patients with recurrent seizures will have a normal EEG at all times other than during the time when they are having a seizure.

    Fortunately there are several excellent seizure preventing medications (anticonvulsants) available. For decades, Dilantin, Tegretol and Depakote were the mainstay in seizure treatment. In the 1990s, several new anticonvulsants received FDA approval. These included Felbatol, Topamax, Lamictal, Neurontin, Keppra and Zonegran. In 2005, the FDA approved Lyrica for treatment of seizures. Although highly effective in controlling and stopping seizures, the newer anticonvulsants are overall no more effective than the older agents. One benefit of the newer agents is that they do not require as much lab monitoring as the older agents. Some anticonvulsants, such as Lamictal, Neurontin and Lyrica require no lab monitoring.

    In summary, patient with recurrent seizures (epilepsy) or for those that have had a single seizure but are at high risk for further seizures, there are a number of therapeutic options available to control their seizures and improve their quality of life. Many patients can have complete control of their seizures, meaning seizure free, with appropriate evaluation and treatment. Most neurologically intact individuals can lead normal lives with specific seizure care by a neurologist. This fact has been shown through many studies on seizures and is the foundation of evidence based medicine for seizure control. It is critical that they see a neurologist as soon as possible, after their first attack, so that proper evaluation and treatment can be started.

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