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Management Of Seizure

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Management of seizures including new ILAE seizure classification, newer anti epileptics, management of refractory epilepsy, and Indian guidelines..

Management of seizures including new ILAE seizure classification, newer anti epileptics, management of refractory epilepsy, and Indian guidelines..

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  • The International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) work together to advance research and to improve the quality of life for those afflicted with epilepsy. The two organizations work in collaboration to raise awareness around the world and help to provide a broader understanding of the nature of epilepsy and the needs of persons with epilepsy.
  • A major contribution of the International League against Epilepsy was the establishment of standardized classifications and terminology for epileptic seizures and syndromes. This provided a universal vocabulary that not only facilitated communication among clinicians, but also established a taxonomic foundation for the performance of quantitative clinical and basic research on epilepsyThis abnormal paroxysmal activity is intermittent and usually self-limited, lasting seconds to a few minutes. A seizure (from the Latin sacire, "to take possession of") is a paroxysmal event due to abnormal excessive or synchronous neuronal activity in the brain. Depending on the distribution of discharges, this abnormal brain activity can have various manifestations, ranging from dramatic convulsive activity to experiential phenomena not readily discernible by an observer. Although a variety of factors influence the incidence and prevalence of seizures, 5–10% of the population will have at least one seizure, with the highest incidence occurring in early childhood and late adulthood.Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process. This definition implies that a person with a single seizure, or recurrent seizures due to correctable or avoidable circumstances, does not necessarily have epilepsy. Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes of epilepsy. However, among the many causes of epilepsy there are various epilepsy syndromes in which the clinical and pathologic characteristics are distinctive and suggest a specific underlying etiology. Using the definition of epilepsy as two or more unprovoked seizures, the incidence of epilepsy is 0.3–0.5% in different populations throughout the world, and the prevalence of epilepsy has been estimated at 5–10 persons per 1000.The definition of epilepsy includes patients with only one seizure in the presence of any factor that may predispose to future seizures. All patients with epilepsy have seizures, but not all patients with seizures have epilepsy. In general, there are two kinds of seizures - acute symptomatic or unprovoked. Acute symptomatic seizures occur in close temporal proximity with an insult to the brain or during a systemic insult. Unlike epilepsy, the proximate cause of these seizures is clearly identifiable and there is no necessary tendency for recurrence unless the acute causal factor continues. An unprovoked seizure is a seizure or a cluster of seizures occurring within 24 h, without precipitating factors and may be caused by a static injury (remote symptomatic seizures) or a progressing injury (progressive symptomatic injury). A single unprovoked seizure predisposes to epilepsy, although seizure recurrence occurs in only about half of the cases.
  • Epilepsy is a chronic disorder characterized by recurrent unprovoked seizures.Seizures occurring in setting of acute illness The definition of epilepsy includes patients with only one seizure in the presence of any factor that may predispose to future seizures. All patients with epilepsy have seizures, but not all patients with seizures have epilepsy. In general, there are two kinds of seizures - acute symptomatic or unprovoked. Acute symptomatic seizures occur in close temporal proximity with an insult to the brain or during a systemic insult. Unlike epilepsy, the proximate cause of these seizures is clearly identifiable and there is no necessary tendency for recurrence unless the acute causal factor continues. An unprovoked seizure is a seizure or a cluster of seizures occurring within 24 h, without precipitating factors and may be caused by a static injury (remote symptomatic seizures) or a progressing injury (progressive symptomatic injury). A single unprovoked seizure predisposes to epilepsy, although seizure recurrence occurs in only about half of the cases.or medical conditions like high fever or hypoglycemia etc.
  • The International League against Epilepsy (ILAE) Commission on Classification and Terminology, 2005–2009 has provided an updated approach to classification of seizures. This system is based on the clinical features of seizures and associated electroencephalographic findings. Other potentially distinctive features such as etiology or cellular substrate are not considered in this classification system, although this will undoubtedly change in the future as more is learned about the patho-physiologic mechanisms that underlie specific seizure types.
  • Focal SeizuresFocal seizures arise from a neuronal network either discretely localized within one cerebral hemisphere or more broadly distributed but still within the hemisphere. With the new classification system, the subcategories of "simple focal seizures" and "complex focal seizures" have been eliminated. Instead, depending on the presence of cognitive impairment, they can be described as focal seizures with or without dyscognitive features. Focal seizures can also evolve into generalized seizures. In the past this was referred to as focalseizures with secondary generalization, but the new system relies on specific descriptions of the type of generalized seizures that evolve from the focal seizure.Focal Seizures Without Dyscognitive FeaturesFocal seizures can cause motor, sensory, autonomic, or psychic symptoms without impairment of cognition. For example, a patient having a focal motor seizure arising from the right primary motor cortex near the area controlling hand movement will note the onset of involuntary movements of the contralateral, left hand. These movements are typically clonic (i.e., repetitive, flexion/extension movements) at a frequency of 2–3 Hz; pure tonic posturing may be seen as well. Since the cortical region controlling hand movement is immediately adjacent to the region for facial expression, the seizure may also cause abnormal movements of the face synchronous with the movements of the hand. The EEG recorded with scalp electrodes during the seizure (i.e., an ictal EEG) may show abnormal discharges in a very limited region over the appropriate area of cerebral cortex if the seizure focus involves the cerebral convexity. Seizure activity occurring within deeper brain structures is often not recorded by the standard EEG, however, and may require intracranial electrodes for its detection.Three additional features of focal motor seizures are worth noting. First, in some patients the abnormal motor movements may begin in a very restricted region such as the fingers and gradually progress (over seconds to minutes) to include a larger portion of the extremity. This phenomenon, described by Hughlings Jackson and known as a "Jacksonian march," represents the spread of seizure activity over a progressively larger region of motor cortex. Second, patients may experience a localized paresis (Todd's paralysis) for minutes to many hours in the involved region following the seizure. Third, in rare instances the seizure may continue for hours or days. This condition, termed epilepsia partialis continua, is often refractory to medical therapy.Focal seizures may also manifest as changes in somatic sensation (e.g., paresthesias), vision (flashing lights or formed hallucinations), equilibrium (sensation of falling or vertigo), or autonomic function (flushing, sweating, piloerection). Focal seizures arising from the temporal or frontal cortex may also cause alterations in hearing, olfaction, or higher cortical function (psychic symptoms). This includes the sensation of unusual, intense odors (e.g., burning rubber or kerosene) or sounds (crude or highly complex sounds), or an epigastric sensation that rises from the stomach or chest to the head. Some patients describe odd, internal feelings such as fear, a sense of impending change, detachment, depersonalization, déjá vu, or illusions that objects are growing smaller (micropsia) or larger (macropsia). These subjective, "internal" events that are not directly observable by someone else are referred to as auras.
  • Focal SeizuresFocal seizures arise from a neuronal network either discretely localized within one cerebral hemisphere or more broadly distributed but still within the hemisphere. With the new classification system, the subcategories of "simple focal seizures" and "complex focal seizures" have been eliminated. Instead, depending on the presence of cognitive impairment, they can be described as focal seizures with or without dyscognitive features. Focal seizures can also evolve into generalized seizures. In the past this was referred to as focalseizures with secondary generalization, but the new system relies on specific descriptions of the type of generalized seizures that evolve from the focal seizure.Focal Seizures Without Dyscognitive FeaturesFocal seizures can cause motor, sensory, autonomic, or psychic symptoms without impairment of cognition. For example, a patient having a focal motor seizure arising from the right primary motor cortex near the area controlling hand movement will note the onset of involuntary movements of the contralateral, left hand. These movements are typically clonic (i.e., repetitive, flexion/extension movements) at a frequency of 2–3 Hz; pure tonic posturing may be seen as well. Since the cortical region controlling hand movement is immediately adjacent to the region for facial expression, the seizure may also cause abnormal movements of the face synchronous with the movements of the hand. The EEG recorded with scalp electrodes during the seizure (i.e., an ictal EEG) may show abnormal discharges in a very limited region over the appropriate area of cerebral cortex if the seizure focus involves the cerebral convexity. Seizure activity occurring within deeper brain structures is often not recorded by the standard EEG, however, and may require intracranial electrodes for its detection.Three additional features of focal motor seizures are worth noting. First, in some patients the abnormal motor movements may begin in a very restricted region such as the fingers and gradually progress (over seconds to minutes) to include a larger portion of the extremity. This phenomenon, described by Hughlings Jackson and known as a "Jacksonian march," represents the spread of seizure activity over a progressively larger region of motor cortex. Second, patients may experience a localized paresis (Todd's paralysis) for minutes to many hours in the involved region following the seizure. Third, in rare instances the seizure may continue for hours or days. This condition, termed epilepsia partialis continua, is often refractory to medical therapy.Focal seizures may also manifest as changes in somatic sensation (e.g., paresthesias), vision (flashing lights or formed hallucinations), equilibrium (sensation of falling or vertigo), or autonomic function (flushing, sweating, piloerection). Focal seizures arising from the temporal or frontal cortex may also cause alterations in hearing, olfaction, or higher cortical function (psychic symptoms). This includes the sensation of unusual, intense odors (e.g., burning rubber or kerosene) or sounds (crude or highly complex sounds), or an epigastric sensation that rises from the stomach or chest to the head. Some patients describe odd, internal feelings such as fear, a sense of impending change, detachment, depersonalization, déjá vu, or illusions that objects are growing smaller (micropsia) or larger (macropsia). These subjective, "internal" events that are not directly observable by someone else are referred to as auras.
  • Here is a diagram that shows a conceptual network for generalized seizures involving the corticothalamic circuitry. Theoretically a generalized seizure could start at different points in the network and engage bilaterally distributed networks. Thus a seizure could start frontally or even parietally. The key point is that a generalized seizure can start from a focal point.
  • The wrong diagnosis of epilepsy is common; 20-30% of cases seen at epilepsy centers are misdiagnosedHistory: No test or finding can reliably differentiate unwitnessed seizures from other events (e.g., syncope).History from a reliable observer often is necessary to determine whether the event actually was a seizure.In as many as 50% of patients with a “first” seizure, thorough history will likely reveal previously unrecognized seizures. Although most epilepsy syndromes begin in childhood or adolescence, a significant number of patients will experience their first seizure in adulthood.A thorough neurologic examination should be performed. In a minority of cases, an exam will suggest a focal lesion. An impaired level of consciousness might represent a post-ictal state or delirium.Provoked seizure: One that reults from a recognizable cause20% of referral epilepsy are PNES Common causes of provoked seizure:1.Metabolic (Electrolite imbalance , hyo hyper glycemia, porphyria, hashimotothyroiditis, hyperthyroidism, RF)2.Hypoxia3.Medication withrawal4.Subtance abuse (Alcohol withdrawal, LSD, Cocaine, Amphetamine, Phencyclidine)
  • The diagnostic dilemma encountered most frequently is the distinction between a generalized seizure and syncope. Observations by the patient and bystanders that can help differentiate between the two are listed in Table. Characteristics of a seizure include the presence of an aura, cyanosis, unconsciousness, motor manifestations lasting >15 seconds, postictal disorientation, muscle soreness, and sleepiness. In contrast, a syncopal episode is more likely if the event was provoked by acute pain or anxiety or occurred immediately after arising from the lying or sitting position. Patients with syncope often describe a stereotyped transition from consciousness to unconsciousness that includes tiredness, sweating, nausea, and tunneling of vision, and they experience a relatively brief loss of consciousness. Headache or incontinence usually suggests a seizure but may on occasion also occur with syncope. A brief period (i.e., 1–10 seconds) of convulsive motor activity is frequently seen immediately at the onset of a syncopal episode, especially if the patient remains in an upright posture after fainting (e.g., in a dentist's chair) and therefore has a sustained decrease in cerebral perfusion. Rarely, a syncopal episode can induce a full tonic-clonic seizure. In such cases the evaluation must focus on both the cause of the syncopal event as well as the possibility that the patient has a propensity for recurrent seizures.
  • Psychogenic seizures are nonepileptic behaviors that resemble seizures. They are often part of a conversion reaction precipitated by underlying psychological distress. Certain behaviors such as side-to-side turning of the head, asymmetric and large-amplitude shaking movements of the limbs, twitching of all four extremities without loss of consciousness, and pelvic thrusting are more commonly associated with psychogenic rather than epileptic seizures. Psychogenic seizures often last longer than epileptic seizures and may wax and wane over minutes to hours. However, the distinction is sometimes difficult on clinical grounds alone, and there are many examples of diagnostic errors made by experienced epileptologists. This is especially true for psychogenic seizures that resemble focal seizures with dyscognitive features, since the behavioral manifestations of focal seizures (especially of frontal lobe origin) can be extremely unusual, and in both cases the routine surface EEG may be normal. Video-EEG monitoring is very useful when historic features are nondiagnostic. Generalized tonic-clonic seizures always produce marked EEG abnormalities during and after the seizure. For suspected focal seizures of temporal lobe origin, the use of additional electrodes beyond the standard scalp locations (e.g., sphenoidal electrodes) may be required to localize a seizure focus. Measurement of serum prolactin levels may also help to distinguish between organic and psychogenic seizures, since most generalized seizures and some focal seizures are accompanied by rises in serum prolactin (during the immediate 30-minute postictal period), whereas psychogenic seizures are not. The diagnosis of psychogenic seizures does not exclude a concurrent diagnosis of epilepsy, since the two often coexist.Nonepileptic seizures (NES), formerly called psychogenic seizures, may at times be indistinguishable from generalized convulsive SE. The risk in such cases is that the physician may immediately assume that a neurologic emergency was present and embark on an aggressive course of pharmacotherapy, neglecting physical examination and historical information. A brief period of observation for atypical features (see Physical Examination) may lead to the conclusion that the patient has nonepileptic seizures and does not need anticonvulsant therapy.Geotropic eye movements (a physical finding that indicates the eyes deviating toward the ground in a nonphysiologic manner whether the head is turned left or right)Behaviors such as pelvic thrusting, head turning from side to side, and bizarre vocalizations are usually not seen in epileptic seizures. The exception to this rule is seizure of frontal-lobe onset.
  • The first goal is to determine whether the event was truly a seizure. An in-depth history is essential, for in many cases the diagnosis of a seizure is based solely on clinical grounds—the examination and laboratory studies are often normal. Questions should focus on the symptoms before, during, and after the episode in order to differentiate a seizure from other paroxysmal events (see "Differential Diagnosis of Seizures" below). Seizures frequently occur out-of-hospital, and the patient may be unaware of the ictal and immediate postictal phases; thus, witnesses to the event should be interviewed carefully.Where in the body did the movements begin?
  • Routine blood studies are indicated to identify the more common metabolic causes of seizures such as abnormalities in electrolytes, glucose, calcium, or magnesium, and hepatic or renal disease. A screen for toxins in blood and urine should also be obtained from all patients in appropriate risk groups, especially when no clear precipitating factor has been identified. A lumbar puncture is indicated if there is any suspicion of meningitis or encephalitis, and it is mandatory in all patients infected with HIV, even in the absence of symptoms or signs suggesting infection.ECGElectrocardiography (ECG) should be considered in certain patients. Seizure activity can be precipitated by cerebral hypoperfusion from an arrhythmia. ECG may identify the following:Prolonged QTcWidened QRSProminent R in aVRHeart blockOther tests can be ordered at the physician’s discretion on the basis of the history and symptoms. For patients with known seizure disorder who are currently taking medications, blood levels of antiepileptic medications should be obtained. levels are often not available for newer agents. For patients with a history of malignancy, serum calcium levels should be obtained.No evidence suggests that toxicologic testing changes outcomes. Toxicologic testing may be beneficial for help with future medical and psychiatric management.An arterial blood gas (ABG) measurement has limited clinical utility for the patient in status epilepticus (SE) because it will likely reveal metabolic acidosis but should rapidly correct after the patient stops seizing.
  • Should include recordings during sleep, photic stimulation, and hyperventilationIn the evaluation of a patient with suspected epilepsy, the presence of electrographic seizure activity during the clinically evident event (i.e., abnormal, repetitive, rhythmic activity having a discrete onset and termination) clearly establishes the diagnosis. The absence of electrographic seizure activity does not exclude a seizure disorder, however, because focal seizures may originate from a region of the cortex that cannot be detected by standard scalp electrodes. The EEG is always abnormal during generalized tonic-clonic seizures. Since seizures are typically infrequent and unpredictable, it is often not possible to obtain the EEG during a clinical event. Continuous monitoring for prolonged periods in video-EEG telemetry units for hospitalized patients or the use of portable equipment to record the EEG continuously on cassettes for 24 hours in ambulatory patients has made it easier to capture the electrophysiologic accompaniments of clinical events. In particular, video-EEG telemetry is now a routine approach for the accurate diagnosis of epilepsy in patients with poorly characterized events or seizures that are difficult to control.The EEG may also be helpful in the interictal period by showing certain abnormalities that are highly supportive of the diagnosis of epilepsy. Such epileptiform activity consists of bursts of abnormal discharges containing spikes or sharp waves. The presence of epileptiform activity is not specific for epilepsy, but it has a much greater prevalence in patients with epilepsy than in normal individuals. However, even in an individual who is known to have epilepsy, the initial routine interictal EEG may be normal up to 60% of the time. Thus, the EEG cannot establish the diagnosis of epilepsy in many cases.The EEG is also used for classifying seizure disorders and aiding in the selection of anticonvulsant medications. For example, episodic generalized spike-wave activity is usually seen in patients with typical absence epilepsy and may be seen with other generalized epilepsy syndromes. Focal interictal epileptiform discharges would support the diagnosis of a focal seizure disorder such as temporal lobe epilepsy or frontal lobe seizures, depending on the location of the discharges.The routine scalp-recorded EEG may also be used to assess the prognosis of seizure disorders; in general, a normal EEG implies a better prognosis, whereas an abnormal background or profuse epileptiform activity suggests a poor outlook. Unfortunately, the EEG has not proved to be useful in predicting which patients with predisposing conditions such as head injury or brain tumor, will go on to develop epilepsy, because in such circumstances epileptiform activity is commonly encountered regardless of whether seizures occur.EEG significantly improves diagnostic accuracy in patients with a first seizure. Unfortunately, although EEG can be helpful, it is often harmful, because normal EEGs are frequently overread as epileptiform, leading to the misdiagnosis of seizures. The tendency to overread normal EEGs is common and has numerous causes. The most common reason for misdiagnosis is that the history is not suggestive of seizures, but the entire diagnosis is essentially based on the EEG.VEEG Continuous video & synchronized EEG recording for more than 24 hrs. Documentation of at least 3 or more events In case of diagnostic uncertainty (e.g. focal seizure of frontal lobe origin) & if surgical treatment is considered Differential diagnosis of type of seizure
  • Almost all patients with new-onset seizures should have a brain imaging study to determine whether there is an underlying structural abnormality that is responsible. The only potential exception to this rule is children who have an unambiguous history and examination suggestive of a benign, generalized seizure disorder such as absence epilepsy. MRI has been shown to be superior to CT for the detection of cerebral lesions associated with epilepsy. In some cases MRI will identify lesions such as tumors, vascular malformations, or other pathologies that need immediate therapy. The use of newer MRI methods such as 3-Tesla scanners, multichannel head coils, three-dimensional structural imaging at submillimeter resolution, and new pulse sequences including fluid-attenuated inversion recovery (FLAIR), has increased the sensitivity for detection of abnormalities of cortical architecture, including hippocampal atrophy associated with mesial temporal sclerosis, as well as abnormalities of cortical neuronal migration. In such cases the findings may not lead to immediate therapy, but they do provide an explanation for the patient's seizures and point to the need for chronic anticonvulsant therapy or possible surgical resection.In the patient with a suspected CNS infection or mass lesion, CT scanning should be performed emergently when MRI is not immediately available. Otherwise, it is usually appropriate to obtain an MRI study within a few days of the initial evaluation. CT scan is an appropriate initial investigation in acute settings if, MRI is not readily available Cannot be performed for technical reasons (e.g., a patient who has a cardiac pacemaker)For patients with new-onset seizures or those in status epilepticus (SE), noncontrast computed tomography (CT) of the head in the emergency department (ED) is the imaging procedure of choice because of its ready availability and ability to identify potential catastrophic pathologies.For the patient who presents for a first-time, generalized tonic-clonic seizure that has returned to baseline mental status, who has normal results on neurologic examination, and who has no comorbidities, CT may be completed as on outpatient basis, provided that follow-up is ensured. However, because of the availability and speed of CT scanning in the ED, routine CT scanning for first-time seizure is strongly recommended.For any partial seizure or suspected intracranial process (trauma, history of malignancy, immunocompromise, or anticoagulation, new focal neurologic examination, age >40 y), a head CT should be performed on an emergency basisApproximately 3-41% of patients with first-time seizures will have abnormal findings on head CT. The timing of CT scanning is still somewhat controversial.In patients with a known seizure disorder, consider head CT if any of the following are present: new focal deficits, trauma, persistent fever, new character or pattern to the seizures, suspicion of AIDS, infection, or anticoagulation.Magnetic resonance imaging (MRI) may be a better diagnostic test because of higher yield and ability to identify smaller lesions, but its availability in the ED may be a limiting factor. In addition, MRI is time-consuming and may interfere with adequate patient monitoring.
  • In the first 2 years of life, myelination is incomplete resulting in a poor contrastMRI scans may not reveal lesions and scans may have to be repeated again after 1-2 yearsThe American Academy of Neurology has published practice guidelines for neuroimaging studies in patients with epilepsy. MRI is the structural imaging modality of choice for investigating patients with epilepsyIf MRI has done <2yr age , scan to be repeated after 1-2 yearsFLAIRCertain lesions such as focal cortical dysplasiaFLAIRincreases conspicuity of lesionsShould be part of a standard MRI protocol
  • Identification of a possible epileptic focus, when structural imaging is unremarkableAssessment of suitability for epilepsy surgery99Tc as the radiotracerInterictal scans alone – unreliable Ictal SPECT can be used to identify epileptogenic regions Focal ictal hyperperfusion with surrounding hypoperfusion Followed by hypoperfusion in the focus Assessment of suitability for epilepsy surgerySISCOS – subtraction ictal SPECT co-registered with SPECTSISCOM – subtraction ictal SPECT co-registered with MRI
  • For practical purposes, uses have been superseded by fMRI PET imaging with FDG shows area of hypometabolism, the possible site of seizure onset
  • Neuroimaging should be performed, because discovery of an epileptogenic lesion can have an impact on the diagnosis, prognosis, and treatment of new-onset seizures. Electroencephalography (EEG) should be performed within 24 hours of the seizure, because this study is significantly more sensitive when obtained during that period 
  • W hen the first epileptic seizure occurs, it heralds a newlife for the patient, with tough decisions to be made.
  • First Seizure Trial (FIRST), a multi-centre study from Italy, reported that the recurrence risks after an untreated first unprovoked seizure were 18%, 28%, 41% and 51% at 3, 6, 12 and 24 months after the initial event. The Europe-based Multicenter Epilepsy and Single Seizure study (MESS) showed that the risks of recurrence were 26%, 39%, 51% and 52% at 6 months, 2, 5 and 8 years after randomisation. On the whole, observational studies provide a 2-year recurrence risk estimate in the region of 40%, concurring to a large extent with data from the randomised trials. Both randomised trials and almost all long-term observational studies of first seizures demonstrate that the recurrence is the highest during the period immediately after the first seizure. Several studies with long follow-up periods indicate that 80-90% of patients who recur do so within the first 2 years.A random effects meta-analysis performed because of significant heterogeneity among the studies gave an absolute reduction in the risk of seizure recurrence of 34% (95% CI: 15-52).In the largest randomised study (MESS), while immediate treatment increased the probability of 2-year remission at 2 years, this effect is lost by 4 years in patients with single seizures. Similarly, in the second largest randomised trial (FIRST), although the overall risk of seizure recurrence was 50% lower in the treated group compared with the untreated group at 2 years [relative risk 0.5 (95% CI: 0.3-0.6)], there was no significant difference between the groups in achieving a 2-year remission period [relative risk 1.2 (95% CI: 0.97-1.56)].Therefore, immediate treatment only appears to reduce seizure recurrences in the next 1 to 2 years after the first seizure.Only two trials examined long-term outcomes. In the MESS study, 2-year remission rates were identical at 92% for the immediate and deferred treatment groups at 5 years, and almost identical (95% immediate treatment group vs. 96% deferred treatment group) at 8 years. Similar results were obtained from the FIRST study, where the treated and untreated groups had a 64% risk of 5-year remission at 10 years. Therefore, long-term prognosis of epilepsy is unaffected with early intervention.
  • 80-90% of patients who recur do so within the first 2 years
  • Assess carefully the patient with a 1st seizure and identify predictors for recurrence and prognosisConclusionsThe decision to treat or not to treat a first unprovoked seizure is dependent on several medical and non-medical factors. From a medical perspective, treatment significantly reduces the risk of recurrence in the short term (1 to 2 years after the first seizure), but does not alter the long-term prognosis of epilepsy, suggesting that there is little to be lost in waiting to see if there is seizure recurrence. In addition, treatment is associated with adverse events, including teratogenecity and harmful drug interactions, which must be weighed-up against the benefits of treatment in the decision-making process. It is crucial to recognise that there are socioeconomic factors such as the impact on lifestyle, driving, employment, finance and relationships, which may be more important for the patient than the medical aspects, which influence an individual patient's preference in treatment decisions. Therefore, only a case-by-case approach, which balances the pros and cons on whether or not to treat a first unprovoked seizure and focuses the treatment decision to the individual patient, is recommended. It is of paramount importance to assess carefully the patient with a first seizure and identify predictors for recurrence and prognosis.
  • In 1857, Sir Charles Locock first used potassium bromide to treat patients with catamenial epilepsy [Krall et al. 1978; Copelman and Andreev, 1962], although who should receive the credit for its introduction as a true 'antiepileptic' agent is debatable [Friedlander, 2000]. Although clinical controlled trials were nonexistent, bromides were found to reduce seizure frequency and became more widely used. 
  • A wide range of antiepileptic drugs (AEDs) is available for the treatment of epilepsy. Since 1993, the US Food and Drug Administration (FDA) has approved 13 new AEDs, with more in the pipeline. As the number of therapeutic options has increased, choosing the best AED for a particular patient has become more challenging.With the exception of rufinamide, which is indicated uniquely for seizures associated with Lennox Gastaut syndrome, all of the new drugs are approved for the treatment of partial seizures.
  • It is important to understand the mechanisms of action and the pharmacokinetics of antiepileptic drugs (AEDs) so that these agents can be used effectively in clinical practice, especially in multidrug regimeMany structures and processes are involved in the development of a seizure, including neurons, ion channels, receptors, glia, and inhibitory and excitatory synapses. The AEDs are designed to modify these processes so as to favor inhibition over excitation and thereby stop or prevent seizure activity.Dynamic target of seizure control in management of epilepsy is achieving balance between factors that influence excitatory postsynaptic potential (EPSP) and those that influence inhibitory postsynaptic potential (IPSP).The AEDs can be grouped according to their main mechanism of action, although many of them have several actions and others have unknown mechanisms of action. The main groups include sodium channel blockers, calcium current inhibitors, gamma-aminobutyric acid (GABA) enhancers, glutamate blockers, carbonic anhydrase inhibitors, hormones, and drugs with unknown mechanisms of actionCarbonic anhydrase inhibitorsInhibition of the enzyme carbonic anhydrase increases the concentration of hydrogen ions intracellularly and decreases the pH. The potassium ions shift to the extracellular compartment to buffer the acid-base status. This event results in hyperpolarization and an increase in seizure threshold of the cells.
  • The firing of an action potential by an axon is accomplished through sodium channels. Each sodium channel dynamically exists in the following 3 states:A resting state, during which the channel allows passage of sodium into the cellAn active state, in which the channel allows increased influx of sodium into the cellAn inactive state, in which the channel does not allow passage of sodium into the cellDuring an action potential, these channels exist in the active state and allow influx of sodium ions. Once the activation or stimulus is terminated, a percentage of these sodium channels become inactive for a period known as the refractory period. With constant stimulus or rapid firing, many of these channels exist in the inactive state, rendering the axon incapable of propagating the action potential.AEDs that target the sodium channels prevent the return of these channels to the active state by stabilizing them in the inactive state. In doing so, they prevent repetitive firing of the axons 
  • Calcium channels function as the " pacemakers " of normal rhythmic brain activity. This is particularly true of the thalamus. T-calcium channels have been known to play a role in the 3 per second spike-and-wave discharges of absence seizures. AEDs that inhibit these T-calcium channels are particularly useful for controlling absence seizures.Calcium channels exist in 3 known forms in the human brain: L, N, and T. These channels are small and are inactivated quickly. The influx of calcium currents in the resting state produces a partial depolarization of the membrane, facilitating the development of an action potential after rapid depolarization of the cell.Low-voltage calcium (Ca2+) currents (T-type) are responsible for rhythmic thalamocortical spike and wave patterns of generalized absence seizures. Some antiepileptic drugs lock these channels, inhibiting underlying slow depolarizations necessary to generate spike-wave bursts.
  • Gamma-Aminobutyric acid (GABA) has 2 types of receptors, A and B. When GABA binds to a GABA-A receptor, the passage of chloride, a negatively charged ion, into the cell is facilitated via chloride channels. This influx of chloride increases the negativity of the cell (ie, a more negative resting membrane potential. This causes the cell to have greater difficulty reaching the action potential. The GABA-B receptor is linked to a potassium channel.The GABA system can be enhanced by binding directly to GABA-A receptors, by blocking presynaptic GABA uptake, by inhibiting the metabolism of GABA by GABA transaminase, and by increasing the synthesis of GABA.GABA is produced by decarboxylation of glutamate mediated by the enzyme glutamic acid decarboxylase (GAD). Some AEDs may act as modulators of this enzyme, enhancing the production of GABA and down-regulating glutamate. Some AEDs function as an agonist to chloride conductance, either by blocking the reuptake of GABA (eg, tiagabine [TGB]) or by inhibiting its metabolism as mediated by GABA transaminase (eg, vigabatrin [VGB]), resulting in increased accumulation of GABA at the postsynaptic receptors.Gamma-aminobutyric acid (GABA)-A receptor mediates chloride (Cl-) influx, leading to hyperpolarization of cell and inhibition. Antiepileptic drugs may act to enhance Cl- influx or decrease GABA metabolism.
  • Glutamate (main excitatory neurotransmitter in central nervous system) binds to multiple receptor sites that differ in activation and inactivation time courses, desensitization kinetics, conductance, and ion permeability. Three main glutamate receptor subtypes are N-methyl-D-aspartate (NMDA), metabotropic, and non-NMDA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA] and kainate receptors).Talampanel (GYKI 53405) is a drug which is being investigated for the treatment of epilepsy, malignant gliomas and amyotrophic lateral sclerosis (ALS).As of May 2010, results from the trial for ALS have been found negative.It is a noncompetitive antagonist of the AMPA receptor, a type of glutamate receptor in the central nervous system.
  • Carbonic anhydrase inhibitorsInhibition of the enzyme carbonic anhydrase increases the concentration of hydrogen ions intracellularly and decreases the pH. The potassium ions shift to the extracellular compartment to buffer the acid-base status. This event results in hyperpolarization and an increase in seizure threshold of the cells.Acetazolamide has been used as an adjunctive therapy in refractory seizures with catamenial pattern (ie, seizure clustering around menstrual period). Topiramate and zonisamide (ZNS) also are weak inhibitors of this enzyme; however, this is not believed to be an important mechanism for their antiseizure efficacy.Sex hormonesProgesterone is a natural anticonvulsant that acts by increasing chloride conductance at GABA-A receptors and attenuates glutamate excitatory response. It also alters messenger RNA for glutamic acid decarboxylase (GAD) and GABA-A receptor subunits. On the other hand, estrogen acts as a proconvulsant by reducing chloride conductance and acting as an agonist at NMDA receptors in the CA1 region of the hippocampus.SV2A-binding agentsSynaptic vesicle protein 2A (SV2A) is ubiquitously expressed in the brain, but its function has not been clearly defined. SV2A appears to be important for the availability of calcium-dependent neurotransmitter vesicles ready to release their content. The lack of SV2A results in decreased action potential-dependent neurotransmission, while action potential–independent neurotransmission remains normal. Ie can modify release of glutamate and GABA through an action on vescicular functionLevetiracetam binds the SV2A.No drug interaction..Both oral and i/v preparation availableRufinamide new triazole derivative with little similarity to other anti epileptic drugs. was approved by the US FDA on November 14, 2008 as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children 4 years and older and adults. Its official FDA-approved labeling does not mention use in the treatment of partial seizures inasmuch as clinical trials submitted to the FDA were marginal. The mechanism of action of rufinamide is unknown. However, it is presumed to involve stabilization of the sodium channelinactive state, effectively keeping these ion channels closed.LacosamideAmino acid related compound, FDAapproved in 2008,for treatment of partial seizures.Antiepileptic effects unknown, may slowly inactivate voltage-gated Na channelsBinds to Collapsin Response Mediator protein-2 (CRMP-2), a phosphoprotein which is mainly expressed in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth. Block the neurotrophic factors NT3 and BDNF.No drug interaction,100% bioavailability.There are several new AEDs that are either in the licensing phase or still undergoing clinical trials. These include eslicarbazepine acetate, brivaracetam, and retigabine.RetigabineEzogabine was approved by the US Food and Drug Administration (FDA) in June 2011. The FDA approved ezogabine as adjunctive therapy in partial-onset seizures uncontrolled by current medications.Retigabine works primarily as a potassium channel opener—that is, by activating a certain family of voltage-gated potassium channels in the brain.This mechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including migraine and neuropathic pain. A multicenter, randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of this agent.Carisbamate (YKP 509, proposed trade name Comfyde) is an experimental anticonvulsant drug under development byJohnson & Johnson Pharmaceutical Research and Development,  reduces glutamatergic transmission by an action potential-dependent presynaptic mechanism and consequently inhibits excitatory synaptic strength in the DG without affecting GABAergic transmission. This effect may contribute to the antiepileptic action observed clinically at therapeutic concentrations of CRS.Talampanel (GYKI 53405) is a drug which is being investigated for the treatment of epilepsy, malignant gliomas and amyotrophic lateral sclerosis (ALS).As of May 2010, results from the trial for ALS have been found negative.It is a noncompetitive antagonist of the AMPA receptor, a type of glutamate receptor in the central nervous system.Eslicarbazepine acetate is a prodrug for S(+)-licarbazepine, the major active metabolite of oxcarbazepine.Its mechanism of action is therefore identical to that of oxcarbazepine.  There may, however, be pharmacokinetic differences. Eslicarbazepine acetate may not produce as high peak levels of (S)-(+)-licarbazepine immediately after dosing as does oxcarbazepine which could theoretically improve tolerability. The U.S. Food and Drug Administration (FDA) announced on 2 June 2009 that the drug has been accepted for filing. Eslicarbazepine acetate, recently licensed as an adjunctive agent in partial epilepsy, is structurally linked to carbamazepine and oxcarbazepine. It is converted into the major active metabolite S-licarbazepine [Gazzola et al. 2011; Almeida and Soares-da-Silva, 2007]. The exact MOA is unknown, although S-licarbazepine stabilizes the inactive state of voltage-gated sodium channels [Gazzola et al. 2011; Almeida and Soares-da-Silva, 2007]. In phase III clinical trials (which used eslicarbazepine doses of 400, 800, and 1200 mg/day), eslicarbazepine was well tolerated, with the most common AEs reported to include dizziness, headache, and somnolence. [Elger et al. 2008a; Hufnagel et al.2008; Lopes-Lima et al. 2008]. Hyponatremia and rash were rare.Brivaracetamis a pyrrolidone derivative in the same class as levetiracetam that continues to undergo clinical trials. Like levetiracetam, brivaracetam binds to the synaptic vesicle protein 2A, but with higher affinity; brivaracetam also inhibits sodium channels [Gazzola et al. 2011; Zona et al. 2010]. An exploratory, phase IIb, double-blind, randomized, parallel-group, placebo-controlled study using brivaracetam doses of 5, 20, or 50 mg/day was performed; tolerability was good, with only 2.6% of patients discontinuing drug due to AEs, compared with 3.7% of patients in the placebo arm [French et al.2010]. The most common AEs were mild to moderate in intensity, and included headache, somnolence, influenza, dizziness, neutropenia, and fatigue [French et al. 2010]. No clinically significant changes were noted in laboratory values, vital signs, body weight, physical and neurologic examinations, and EKG measurements [French et al. 2010]. Phase III clinical trials are currently ongoing.
  • An advantage of carbamazepine (which is also available in an extended-release form) is that its metabolism follows first-order pharmacokinetics, and the relationship between drug dose, serum levels, and toxicity is linear. Carbamazepine can cause leukopenia, aplastic anemia, or hepatotoxicity and would therefore be contraindicated in patients with predispositions to these problems. Oxcarbazepine has the advantage of being metabolized in a way that avoids an intermediate metabolite associated with some of the side effects of carbamazepine. Oxcarbazepine also has fewer drug interactions than carbamazepine. Lamotrigine tends to be well tolerated in terms of side effects. However, patients need to be particularly vigilant about the possibility of a skin rash during the initiation of therapy. This can be extremely severe and lead to Stevens-Johnson syndrome if unrecognized and if the medication is not discontinued immediately. This risk can be reduced by slow introduction and titration. Lamotrigine must be started slowly when used as add-on therapy with valproic acid, since valproic acid inhibits lamotrigine metabolism, thereby substantially prolonging its half-life. Phenytoin has a relatively long half-life and offers the advantage of once or twice daily dosing compared to two or three times daily dosing for many of the other drugs. However, phenytoin shows properties of saturation kinetics, such that small increases in phenytoin doses above a standard maintenance dose can precipitate marked side effects. This is one of the main causes of acute phenytoin toxicity. Long-term use of phenytoin is associated with untoward cosmetic effects (e.g., hirsutism, coarsening of facial features, and gingival hypertrophy), and effects on bone metabolism, so it is often avoided in young patients who are likely to require the drug for many years.
  • Standard and New Antiepileptic Drugs (SANAD)The Standard and New Antiepileptic Drugs (SANAD) study reported that lamotrigine was significantly better in terms of time to treatment failure than the current standard treatment, carbamazepine, and the newer drugs Gabapentin and topiramate for treatment of partial seizures.[44] (The study compared carbamazepine, Gabapentin, lamotrigine, Oxcarbazepine, and Topiramate.) For time to 12-month remission from seizures, carbamazepine was not significantly advantageous compared with lamotrigine.Lamotrigine also has the lowest incidence of treatment failure and has better outcome than all drugs except Oxcarbazepine.SANAD study resultsThe Standard and New Antiepileptic Drugs (SANAD) study reported that lamotrigine was significantly better in terms of time to treatment failure than the current standard treatment, carbamazepine, and the newer drugs Gabapentin and topiramate for treatment of partial seizures.(The study compared carbamazepine, Gabapentin, lamotrigine, Oxcarbazepine, and topiramate.) For time to 12-month remission from seizures, carbamazepine was not significantly advantageous compared with lamotrigine.Lamotrigine also has the lowest incidence of treatment failure and has better outcome than all drugs except Oxcarbazepine.The same SANAD study compared valproate, lamotrigine, or topiramate for generalized and unclassifiable epilepsy seizures, and found that valproate is the drug of choice and is better tolerated than topiramate.An unblinded randomised controlled trial in hospital-based outpatient clinicsIn patients with generalised onset seizures or seizures that are difficult to classify, to compare the longer-term effects of ValproateLamotrigineTopiramate
  • Role of AED level monitoring•Routine monitoring of AED blood levels is not recommended and should be done only when clinically indicated.Indications for monitoring AED blood levels:•Detection of AED non-compliance in case of uncontrolled seizures.•Documenting suspected AED toxicity.•Adjustment of AED dose while managing drug interactions.•Specific clinical conditions (e.g. status epilepticus, liver or renal disease and pregnancy).Routine laboratory tests during AED therapyThe following tests may be carried out as necessary:•Complete blood count, liver enzymes and renal functions before starting AED.•Serum calcium, alkaline phosphatase and other tests of bone metabolism every year for adults taking enzyme-inducing drug.•Asymptomatic minor abnormalities in blood test results are not necessarily an indication for changes in medication.Role of newer AEDsThe newer AEDs (Gabapentin, Lamotrigine, Levetiracetam, Tiagabine, Topiramate, Vigabatrin and Zonisamide) are recommended for the management of epilepsy in people who have not benefited from treatment with theconventional AEDs or for whom the older AEDs are unsuitable because of intolerable adverse events. The new AEDS are almost as effective as the conventional drugs but do add significantly to the cost.The newer AEDS can also be used when:•There are contraindications to the first line drugs due to coexisting illnesses.•The first line drugs interact with other drugs the person is taking (notably oral contraceptives, anticoagulants, anti-retrovirals or immunosuppressants).•Always consider factors such as cost and continued availability of medicines before starting newer AEDs.Drug interactionsThere are many interactions between different AEDS and between AEDs and other drugs that the patient might be taking. A detailed knowledge of the pharmacokinetics of AEDS and other drugs is necessary to understand the drug interactions. The important points to remember are:•Certain AEDs (PHT, PB, CBZ and OXC ) induce hepatic enzymes and enhance the metabolism of lipid soluble drugs. Enzyme induction results in rapid clearance and reduced efficacy of other drugs requiring adjustment of the dose of other drugs to a slightly higher level. These interact with other AEDs (necessitating higher dose of concomitant AEDs)oral contraceptives and oral anticoagulants.•VPA inhibits hepatic enzymes and slows down the metabolism of concomitant AEDs and other drugs causing toxicity and requiring dose adjustments.•Drug interactions become important while using AEDs with theophylline group erythromycin, ciprofloxacin or ofloxacin; anti-tubercular drugs (like isoniazid and rifampicin are enzyme inducers and also hepatotoxic), anti-retroviral drugs and mefloquin.Frequency of follow-up•People with epilepsy should maintain a seizure diary and have regular follow-up to ensure that the prescribed medication is taken as advised and to detect any adverse effects of AED. This will also avoid a situation in which they continue to take treatment that is ineffective or poorly tolerated.•The first follow-up may be undertaken at anytime within 2-4 weeks of initiation of treatment. Subsequent follow-ups at every 3-6 months, depending on the control of seizures and side-effects.•The doctor should review the seizure diary ( Appendix III) to assess efficacy tolerability and ensure AED compliance. Lifestyle issues such as sleep, regular food intake, alcohol use, driving and pregnancy (if planned) should also be discussed.•PWE and their care givers should be provided information about the disease, maintaining seizure diary, counselling services, and timely and appropriate investigations.•In patients with poorly controlled seizures or unacceptable side effects due to AEDs, consider referral to tertiary services for appropriate diagnosis, investigations and advanced treatment including surgery for epilepsy.When to refer to a specialized ‘Epilepsy Centre’An individual should be referred to a specialized epilepsy centre:•Seizures controlled despite use of maximum tolerated dose of 2 AEDs•Seizures are controlled even after 2 years of starting AEDs•The diagnosis of seizure type and/or syndrome is not certain•The individual experiences unacceptable side effects of medication•Abnormal behaviour, progressive deterioration in the intellect, associated psychological and/or psychiatric co-morbidity•There is a remediable structural lesion that could be the cause of epilepsyWithdrawal of AEDs•Withdrawal in most cases after a seizure-free period of two to three years. The decision is mainly based on the type of epilepsy syndrome and cause of seizures. and should be taken after discussion of the risks and benefits of withdrawal with the PWE and family.•AED withdrawal should be avoided in certain epilepsy syndromes (e.g., juvenile myoclonic epilepsy) because of the higher risk of seizure relapse following AED withdrawal.How to withdraw AEDs•AEDs are usually withdrawn gradually over several months (at least 3-6 months or longer). There is possibility of seizure recurrence during and after withdrawal.•The tapering may be performed at a slower rate for benzodiazepines (6 months or longer).•Withdraw one drug at a time in those patients who are on multiple AEDs.•If seizure recurs during or after AED withdrawal, the person may be advised to revert to their AED dose before reduction and seek medical help.PRACTICE POINTS•Establish the diagnosis of epilepsy before starting treatment.•The choice of AED should be based on seizure type, epilepsy syndrome (appropriate drug), affordability and availability of AEDs.•Initiate treatment with monotherapy. Use polytherapy with caution when monotherapy is not successful.•The principle, “start low and go slow” should be followed for AED dosages.•Maintain seizure diary, ensure regular follow up and AED compliance.•Conventional AEDs are generally as effective as newer AEDs and should be the first line of treatment in most cases
  • Withdrawal of AEDs•Withdrawal in most cases after a seizure-free period of two to three years. The decision is mainly based on the type of epilepsy syndrome and cause of seizures. and should be taken after discussion of the risks and benefits of withdrawal with the PWE and family.•AED withdrawal should be avoided in certain epilepsy syndromes (e.g., juvenile myoclonic epilepsy) because of the higher risk of seizure relapse following AED withdrawal.How to withdraw AEDs•AEDs are usually withdrawn gradually over several months (at least 3-6 months or longer). There is possibility of seizure recurrence during and after withdrawal.•The tapering may be performed at a slower rate for benzodiazepines (6 months or longer).•Withdraw one drug at a time in those patients who are on multiple AEDs.•If seizure recurs during or after AED withdrawal, the person may be advised to revert to their AED dose before reduction and seek medical help.PRACTICE POINTS• Establish the diagnosis of epilepsy before starting treatment.•The choice of AED should be based on seizure type, epilepsy syndrome (appropriate drug), affordability and availability of AEDs.•Initiate treatment with monotherapy. Use polytherapy with caution when monotherapy is not successful.•The principle, “start low and go slow” should be followed for AED dosages.•Maintain seizure diary, ensure regular follow up and AED compliance.•Conventional AEDs are generally as effective as newer AEDs and should be the first line of treatment in most cases.
  • Strategies in case of failure of initial treatmentFailure of an initial AED should prompt the treating doctor to ascertain the accuracy of the diagnosis of epilepsy, the seizure type or syndrome; the appropriateness of the drug for the particular seizure type, the adequacy of dosage, compliance of the individual and whether there are any remediable structural or other causes for epilepsy.•All PWE should be asked to note down what happens before and during a seizure and to maintain a ‘seizure diary’. They should be encouraged to make a record seizure on a cell phone camera. This will help the treating doctor in arriving at a correct diagnosis.•Attempt should be made to optimize the AED therapy by using maximally tolerated doses, ensuring compliance and avoiding seizure precipitants.
  • Onset in infancyOrganic brain damage (mental retardation and neurological signs)Multiple seizure typesHigh seizure frequencyLong duration of uncontrolled seizuresFailure of past AED treatments An abnormal electroencephalogram (EEG)Not all medically refractory patients are suitable candidates for resective surgery. For example, some patients have seizures arising from more than one site, making the risk of ongoing seizures or potential harm from the surgery unacceptably high. Vagus nerve stimulation (VNS) may be useful in some of these cases, although the benefit for most patients seems to be very limited (i.e., the efficacy of VNS appears to be no greater than trying another drug, which rarely works if a patient has proved to be refractory to the first two to three drugs). The precise mechanism of action of VNS is unknown, although experimental studies have shown that stimulation of vagal nuclei leads to widespread activation of cortical and subcortical pathways and an associated increased seizure threshold. Adverse effects of the surgery are rare, and stimulation-induced side effects, including transient hoarseness, cough, and dyspnea, are usually mild.Two key hypotheses for explanationTarget hypothesis – alteration in drug targets leading to poor response to drug treatmentVoltage-gated sodium channelsGABAA receptorsMultidrug transporter hypothesisMultidrug transporters reduce antiepileptic drug concentration around neurons by active export away from neuronsVariation in the gene ABCB1 encoding P glycoprotein, is associated with a broad drug resistance
  • Intermittent programmed (e.g. 30 sec. on, 5 min. off) electrical stimulation of left vagus nerve
  • Status epilepticus has numerous subtypes, including generalized convulsive status epilepticus (GCSE) (e.g., persistent, generalized electrographic seizures, coma, and tonic-clonic movements), and nonconvulsive status epilepticus (e.g., persistent absence seizures or focal seizures, confusion or partially impaired consciousness, and minimal motor abnormalities). The duration of seizure activity sufficient to meet the definition of status epilepticus has traditionally been specified as 15–30 minutes. However, a more practical definition is to consider status epilepticus as a situation in which the duration of seizures prompts the acute use of anticonvulsant therapy. For GCSE, this is typically when seizures last beyond 5 minutes.In early studies, SE was defined by its duration—that is, as continuous seizures occurring for longer than 1 hour. Clinical and animal experiences later showed that pathologic changes and prognostic implications occurred when SE persisted for 30 minutes. Therefore, the time for the definition was shortened.Treiman classification is as follows:Generalized convulsive SESubtle SENonconvulsive SE (Absence SE & complex partial SE)Simple partial SEThe term status epilepticus may be used to describe continuing seizure of any type.The predominant type of seizure further refines the definition of SE, and several classification schemes have been proposed.Categorization of SE cases is no simple matter because they often exhibit characteristics of both focal and generalized processes. Considerable literature has been devoted to this question over the last 30 yearsGeneralized convulsive status epilepticusGeneralized convulsive SE is the most frequent and potentially dangerous type of SE. Generalized refers to the abnormal excessive cortical electrical activity, while convulsive refers to the motor activity of a seizure.Subtle status epilepticusSubtle SE consists of electrical seizure activity in the brain that endures when the associated motor responses are fragmentary or even absent.The terminology is confusing, since subtle SE is sometimes designated a type of nonconvulsive SE (NCSE). Although subtle SE is, by definition, nonconvulsive, it should be distinguished from other NCSE. Subtle SE is considered the most severe clinical stage of generalized convulsive SE and patients with subtle SE, in contrast to that of those with NCSE, have a dismal prognosis.Nonconvulsive status epilepticusNonconvulsive SE is divided into 2 categories: absence SE and complex partial SE. Differentiating these subtypes is important, since they indicate major differences in treatment, etiology, and prognosis.In one review, NCSE has been further subdivided according to the age of occurrence, as follows:Neonatal and infantileOnly in childhoodIn both childhood and adult lifeIn late adult lifeSeveral epileptic syndromes, such as electrical status epilepticus in slow-wave sleep (ESES), would be classified under the "NCSE only in childhood" category.Absence status epilepticusOn clinical presentation, a clear change in the level of consciousness is observed in patients with absence SE. Most patients are not comatose but are lethargic and confused, with decreased spontaneity and slow speech. Absence SE is also known as absence stupor because of the apparent state of low alertness.The ictal electroencephalograph (EEG) during typical absence SE demonstrates generalized spike and wave discharges. The frequency may be slower than 3 Hz, and the waveforms (though bilaterally synchronous) are often irregular, poorly formed, and discontinuous, especially in the late stages. In adults and in some children, the apparently bisynchronous EEG discharges may represent complex partial SE as opposed to true absence SE.About 2.6% of patients with absence seizures have had an episode of absence SE earlier in their lives. Approximately 10% of adults with childhood-onset absence seizures experience absence SE. About 75% of all cases of absence SE occur before the age of 20 years. When it occurs in adults, the patients are often elderly. The mean age of onset of absence SE in adults is 51 years.Typical absence SE that occurs in children or adolescents who have primary or idiopathic generalized epilepsy (which includes absence seizures) readily responds to treatment. In contrast, absence SE in the symptomatic, primary generalized epilepsies (eg, Lennox-Gastaut syndrome) is often more difficult to control.Four issues should be considered in the differential diagnoses of absence SE. First, complex partial SE usually manifests with recurring cycles of 2 separate phases: ictal and interictal. In contrast, absence SE usually occurs as 1 continuous episode of variable intensity.Second, stereotyped automatisms can be seen in both complex partial and absence SE, though they tend to be richer in complex partial SE than in absence SE. Anxiety, aggression, fear, and irritability may be most common in complex partial SE, but they can be seen in both types.Third, EEG is the best way to differentiate absence SE from complex partial SE.Fourth, other possibilities include a postictal state and encephalopathies from toxic-metabolic causes, drugs, trauma, or infection. Psychiatric causes should be considered.No deaths or long-term morbidity due to typical absence SE have been reported. Whether absence SE in children with developmental dementia and myoclonic/astatic epilepsy is injurious to the brain is controversial. Differentiating absence SE from other causes is important because many mimics of absence SE can lead to irreversible neuronal damage if they are not aggressively treated.Complex partial status epilepticusComplex partial SE is rare. Although many cases of prolonged complex partial SE without long-term neurologic sequelae have been described, negative outcomes can occur. No criteria for differentiating the cases associated with a poor outcome are known.Complex partial SE that arises in the limbic cortex (eg, mesial temporal lobe) causes signs and symptoms such as staring, unresponsiveness, automatisms, atypical anxiety, rising abdominal symptoms, déjà vu, or more profound stupor. Complex partial SE of frontal-lobe origin may produce clinical symptoms indistinguishable from cases of temporal-lobe origin.While isolated complex partial seizures usually originate in the temporal lobe, complex partial SE usually has an extratemporal focus. Shorvon believes that at least 15% of patients with complex partial epilepsy have a history of nonconvulsive SE.Simple partial status epilepticusBy definition, simple partial SE consists of seizures that are localized to a discrete area of cerebral cortex and produce no alteration in consciousness. Because this form of epilepsy is rare, no good studies have been done to determine its incidence.Focal SE can arise in any region of the cortex. When motor cortex is affected, the condition is termed epilepsia partialis continua (EPC), which characteristically involves repetitive, often rhythmic, unilateral focal twitching of the limbs and/or face, usually with preservation of consciousness. This sparing of consciousness subcategorizes EPC as a form of simple partial SE.Other regions of cortex similarly may generate focal SE. These cases are characterized by predictable phenotypes depending on the function of the particular region involved. For example, episodes of focal SE involving primary sensory cortex are expected to be associated with focal sensory symptoms, and occipital focal SE causes focal visual symptoms (eg, flashing spots of light, colorful visual hallucinations). Focal SE of language cortex typically causes aphasia, termed ictal aphasia.Diagnosis is primarily based on clinical findings. Because of the relatively small area of cerebral cortical involvement, results of conventional scalp EEG are frequently uncharacteristic of the clinical ictal activity, or they may be normal.In contrast to convulsive SE, simple partial SE is not associated with high rates of morbidity or mortality. Outcomes seem to be related to the underlying etiology, the duration of the SE, the age of the patient, and the medical complications, as in convulsive SE.Treatment involves the same drugs and general pharmacologic principles as those used for convulsive SE. However, the relatively low morbidity and mortality rates suggest that aggressive treatment might not be needed. For example, if first-line drugs are ineffective, the clinician may elect not to use a general anesthetic agent to stop simple partial SE.
  • Super-refractory status epilepticus is defined as status epilepticus that continues or recurs 24 h or more after the onset ofanaesthetic therapy, including those cases where status epilepticus recurs on the reduction or withdrawal of anaesthesia. It is anuncommon but important clinical problem with high mortality and morbidity rates. Super-refractory status epilepticus is a serious condition. The mor-tality rate is substantial, reported in various series between 30 and50%. Yet, despite the fact that it remains an important clinicalproblem in all neurology centres worldwide,Super-refractory status epilepticus is not uncommonly encountered in neurointensive care, but its exact frequency is not known.In the only prospective study, 22% of all the cases with statusepilepticus (29 of 108 cases) admitted to hospital failed to respondto first and second lines of therapy, and of these, 41% (12 cases)required coma induction (however, it should be noted that only 47of the 108 patients had convulsive status epilepticus and presum-ably it is mainly in these in whom coma induction was needed).Other retrospective studies have shown that 12–43% of the caseswith status epilepticus become refractory.The primary aim of treatment in the earlier phases of status epi-lepticus is to control seizures with the objective of preventing ini-tialexcitotoxicity. In super-refractory status epilepticus, this alsoremains an objective but it should be recognized that, after 24 h ofcontinuous or recurring seizures, the excitotoxic processes causingcerebral damage are very likely already to have been initiated—andto what extent further control of seizures can prevent the damagecaused by the direct processes of excitotoxicity is unknown.A second aim is neuroprotection—an attempt to block the pro-gression over time of the secondary processes triggered by initialexcitotoxicity.A third aim, as the episode of status epilepticus becomes pro-longed, is the need to avoid or treat the systemic complications ofprolonged unconsciousness and of prolonged anaesthesia.MAGNESIUMIntravenous magnesium sulphate has a unique place in the treatment of seizures. In a large well-conducted randomized controlledstudy, magnesium was shown to be the drug of choice in con-trolling seizures in eclampsia (Anon, 1995) and superior to pheny-toin in this role. It is lifesaving too in the very rare congenitalmagnesium deficiencies, and in status due to acquired hypomag-nesaemia. It was also frequently used to control status epilepticusin porphyria (especially acute intermittent porphyria). There is abody of experimental evidence demonstrating its anti-epilepticaction (Nowak et al., 1984), and its effect in blockading theN-methyl-D-aspartate receptor may be the basis of this action.
  •  Concerns during these pregnancies include the risk of fetal malformation, miscarriage, perinatal death, and increased seizure frequency. In women who are pregnant, the volume of distribution and the hepatic metabolism of AEDs are increased. This, along with decreased compliance with AEDs because of concerns about their effects on the fetus, leads to an increase in seizure frequency, which is observed in as many as 17-33% of pregnancies. A population-based study conducted in Norway found that pregnant women with epilepsy had a lower risk of complications but an increased risk of induction, cesarean delivery, and postpartum hemorrhage.However, whether this is a result of AEDs or severe epilepsy is unclear.Specific increases in congenital abnormalities observed in infants born to mothers with epilepsy include a 4-fold increase in cleft lip and palate and a 3- to 4-fold increase in cardiac anomalies. An increase in the rate of neural tube defects is also observed in the offspring of patients with epilepsy who are using carbamazepine or valproic acid. Long-term studies on neurodevelopment show higher rates of abnormal electroencephalogram (EEG) findings, higher rates of developmentally delayed children, and lower intelligence quotient (IQ) scores. During pregnancy, important considerations include; therapeutic drug monitoring, surveillance for obstetric complications and vigilance for seizures during the intrapartum and postpartum period.
  • They also found that over 50% of patients with HIV potentially require therapy with anti-epileptic drugs for the controls of seizures, psychiatric conditions or peripheral neuropathy. Anti-epilepsy drugs not only prevent seizures but are also used to treat neuropathy and psychiatric conditions such as bipolar mood disorder. Anemia is a well-described adverse effect of zidovudine therapy,occurring in 2% and 9.7%. Given the dose-dependentnature ofthis adverse effect, the concomitant administrationof medications that impair the glucuronidation of zidovudineto its inactive derivative, 5-glucuronyl zidovudine (GZDV),may inadvertently increase the risk of zidovudine-mediatedanemia. Because the enzyme responsible for the biotransformation of zidovudine has been identified as the UGT2B7 isoenzymeof the uridine diphosphate glucuronosyltransferase system, it may be possible to anticipate drug interactions betweenzidovudine and clinically significant inhibitors of this enzyme-Valproic acid.Clinicians should be aware of the potential for this interactionand monitor complete blood counts closely when valproic acidand zidovudine are coadministered. Alternatively, nucleosideanalogues that do not undergo glucuronidation and/or do notcause significant hematologic toxicity (e.g., stavudine, tenofovir,and abacavir) can be substituted for zidovudine in regimensfor patients receiving concomitant valproic acid.
  • Other sequences, such as T2, may reveal abnormalities such as small cavernous angiomas A fluid-attenuated inversion recovery sequence
  • N-acetyl aspartate (NAA) found primarily within neurons and precursor cells; reduction indicates loss or dysfunction of neurons.Creatinine and choline present in much higher concentrations in glia than in neurons
  • Care should be taken with the administration of parenteral phenytoin because the propylene glycol diluent may cause hypotension, cardiac arrhythmias, and death if given too quickly.Fosphenytoin is a phenytoin precursor that is considered to be safer than phenytoin by some authors because it does not contain a propylene glycol diluent.Other authors have disputed the idea that fosphenytoin has a safety advantage, and this agent is much more expensive than phenytoin. Fosphenytoin may be administered IM, and this is an advantage for patients without IV access.Valproic acid is effective in treating all forms of seizure. The recommended dose acid is 15-20 mg/kg. Valproic acid has an excellent safety profile.It is contraindicated in hepatic dysfunction because of the extremely rare occurrence of fatal idiosyncratic hepatotoxicity.
  • PHENOBARITATEBeware of respiratory and cardiac depression, prolonged sedation, allergy, and blood dyscrasia , contraindicated in severe liver dysfunctionMIDAZBeware of respiratory depression, sedation, and hypotensionPROPOFOL Beware of sedation, hypotension, bradycardia, allergic reaction, and “propofol infusion syndrome” at high doses (metabolic acidosis, cardiac failure with dysrhythmia, rhabdomyolysis, hyperkalemia, and lipemia)       Monitor acid base status       continuous infusion involves a large lipid and caloric load
  • There is universal agreement that general anaesthesia is requiredas the backbone of therapy for super-refractory status epilepticus,at least in the first weeks. However, there is no agreement aboutthe optimal choice of anaesthetic. The conventional choice is between three anaesthetic drugs—thiopental or pentobarbital,which is a main metabolite of thiopental), propofol and midazolam. Each has advantages and drawbacks and there are no con-trolled or randomized comparative data on which to base a choice.
  • Sodium valproate vs phenytoin in status epilepticus: a pilot study.Misra UK, Kalita J, Patel R.SourceDepartment of Neurology, Sanjay Gandhi PGIMS, Lucknow, IndiaSixty-eight patients with convulsive status epilepticus (SE) were randomly assigned to two groups to study the efficacy of sodium valproate(VPA) and phenytoin (PHT). Seizures were aborted in 66% in the VPA group and 42% in the PHT group. As a second choice in refractory patients, VPA was effective in 79% and PHT was effective in 25%. The side effects in the two groups did not differ. Sodium valproate may be preferred in convulsive SE because of its higher efficacy.Randomized study of intravenous valproate and phenytoin in status epilepticus.Agarwal P, Kumar N, Chandra R, Gupta G, Antony AR, Garg N.SourceNeurology Unit, KPS PG Institute of Medicine, GSVM Medical College, Kanpur 208002, India. pgpuneet@gmail.Hundred, age and sex matched, patients of benzodiazepine refractory SE were randomly divided into Group A (50 patients), treated with IV VA and Group B (50 patients) treated with IV phenytoin. Twelve patients, in whom SE was not controlled with a single drug, were switched over to the other group. Treatment was considered successful when all motor or EEG seizure activity ceased within 20 min after the beginning of the drug infusion and no return of seizure activity during the next 12h. Secondary study end points were adverse events to treatment, in-hospital complications and the neurological outcome at discharge.RESULTS:In this study, IV VA was successful in 88% and IV phenytoin in 84% (p>0.05) of patients of SE with a significantly better response in patients of SE <2h (p<0.05). The total number of adverse events did not differ significantly between the two groups (p>0.05). There were no differences among the treatments with respect to recurrence after 12-h study period or the outcome at 7 days.CONCLUSION:IV VA is as effective as IV phenytoin. It is easy to use, better tolerated and can be used as an alternative to IV phenytoin in patients of benzodiazepine refractory SE, especially in patients of cardio-respiratory disease. The better outcome in patients having shorter duration of SE (<2h) suggests need of immediate treatmentA comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, Gottwald MD, O'Neil N, Neuhaus JM, Segal MR, Lowenstein DH.SourceDepartment of Clinical Pharmacy, San Francisco General Hospital and the University of California, USA.Erratum inN Engl J Med 2001 Dec 20;345(25):1860.Of the 205 patients enrolled, 66 received lorazepam, 68 received diazepam, and 71 received placebo. Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (59.1 percent) or diazepam (42.6 percent) than patients given placebo (21.1 percent) (P=0.001). After adjustment for covariates, the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 4.8 (95 percent confidence interval, 1.9 to 13.0). The odds ratio was 1.9 (95 percent confidence interval, 0.8 to 4.4) in the lorazepam group as compared with the diazepam group and 2.3 (95 percent confidence interval, 1.0 to 5.9) in the diazepam group as compared with the placebo group. The rates of respiratory or circulatory complications (indicated by bag valve-mask ventilation or an attempt at intubation, hypotension, or cardiac dysrhythmia) after the study treatment was administered were 10.6 percent for the lorazepam group, 10.3 percent for the diazepam group, and 22.5 percent for the placebo group (P=0.08).A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, Handforth A, Faught E, Calabrese VP, Uthman BM, Ramsay RE, Mamdani MB.SourceNeurology Services of the Veterans Affairs Medical Center in West Los Angeles, Calif, USA.As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.
  • Here is a diagram that shows a conceptual network for generalized seizures involving the corticothalamic circuitry. Theoretically a generalized seizure could start at different points in the network and engage bilaterally distributed networks. Thus a seizure could start frontally or even parietally. Here the conceptual diagram of the network is superimposed on a functional MRI of generalized spike wave activity.
  • As the number of therapeutic options has increased, choosing the best AED for a particular patient has become more challenging.Many factors must be considered when prescribing an AED for a particular patient including the patient's seizure type, epilepsy syndrome, history of allergies, medical and psychiatric comorbidities, potential drug-drug interactions, renal function, hepatic function, protein binding, possibility of pregnancy, dosing schedule, availability of liquid, parenteral and extended release formulations, pharmacogenetics, and cost. When AEDs are similar in efficacy, differences in tolerability often guide medication selection.The growing science of pharmacogenetics has not yet provided new tools to predict drug efficacy in an individual patient.However, pharmacogenetics does enable identification of Asian patients more likely to suffer carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis.These adverse reactions may be avoided by prospectively testing patients for the human leukocyte antigen-B*1502 allele.Overall, only about 50% of patients with newly diagnosed seizures become seizure free with their first AED.[3] This sobering statistic emphasizes the importance of trying the drug most likely to succeed the first time around to prevent further seizures and their related medical and psychosocial morbidity. 
  • A myriad of other conditions may precipitate SE, including toxic or metabolic causes and anything that might produce cortical structural damage, as follows:Drugs (eg, cocaine, theophylline); isoniazid (INH) may cause seizures and is unique in having a specific antidote, pyridoxine (vitamin B-6)Electrolyte abnormalities (eg, hyponatremia, hypernatremia, hypercalcemia,hepatic encephalopathy)In more recent series of SE, HIV infection and use of illicit drugs were reported with increased frequency.Causes of SE vary significantly with age. DeLorenzo et al reported that in patients younger than 16 years, the most common cause was fever and/or infection (36%); in contrast, this accounted for only 5% of SE in adults. In adults, the most common precipitant was cerebrovascular disease (25%), whereas this factor caused only 3% of pediatric cases. In roughly one third of cases, status epilepticus is the initial presentation of a seizure disorder.The most common causes of GCSE are anticonvulsant withdrawal or noncompliance, metabolic disturbances, drug toxicity, CNS infection, CNS tumors, refractory epilepsy, and head trauma.Stroke (remote or acute)Hypoxic injuryTumorSubarachnoid hemorrhageHead traumaDrugs (eg, cocaine, theophylline,isoniazid)Alcohol withdrawalElectrolyte abnormalitiesNeoplasmsCNS infectionsToxins
  • Demographic pattern clearly show that the population of world is agingSeizures are more common in elderly compared to general population.Epilepsy is the most common serious neurological disorder in the elderly after stroke and dementia. Epilepsy in the elderly is potentially life threatening. Elderly people with epilepsy have a two- to three-times greater mortality than the general population Epilepsy in the elderly may present in many ways; distinguishing epilepsy from potentially more serious epilepsy mimics, including life-threatening conditions, such as cardiac arrhythmic syncope, adds an urgency to the diagnostic process.Epilepsy is the the most common serious chronic neurological disorder in the elderly after stroke and dementia. Obtaining an accurate seizure diagnosis in the elderly is challenging and relies much more upon an accurate clinical history and eye-witnessed accounts (which are often absent) than on diagnostic tests. Therefore, the true incidence and prevalence of epilepsy in the elderly, although undoubtedly greater than in younger people, is probably actually lower than commonly reported.Certain drugs commonly prescribed to elderly people, such as tramadol, also reduce seizure threshold, and are best avoided. Older people seem to be more susceptible to the epileptogenic effects of some other drugs, such as antipsychotics, antidepressants (particularly tricyclics), antibiotics, theophylline, levodopa, thiazide diuretics and even the herbal remedy, ginkgo biloba.In later life, the most common tumors causing seizures are gliomas, meningiomas and metastases. Seizures may be the first presentation of metastatic disease: in Lyman et al.'s study, 43% of those presenting with seizures from metastases had no previous systemic diagnosis of cancer.Cardiac arrhythmias are a relatively common and a potentially life threatening cause of sudden loss of consciousness in the elderly. Characteristically, they occur without warning, and may be brief and not associated with post-event fatigue. Elderly people with ischemic heart disease are at an increased risk of cardiac arrhythmias, including ventricular tachycardia (from ventricular scar tissue) or diseased conduction systems.Transient ischemic attacks (TIAs) are commonly (and usually incorrectly) diagnosed when patients present with transient loss of consciousness. TIAs rarely cause a true loss of consciousness unless there is focal involvement of the brainstem reticular activating system or medial thalamus. However, a 'limb-shaking TIA' caused by bilateral critical carotid stenosis is an important and potentially reversible cause of stereotyped events with focal features.FIRST MANIFESTATION OF ISOLATED ABSECNCE SEIZURE IN LDERLY MAY BE NCSE, AND MAY NOT HAVE CLINICAL SEIZURES AND PRESENT AS SUDDEN CHANGE IN MENTAL STATUSEEGA routine interictal electroencephalogram (EEG) is rarely helpful in the elderly since it is much less sensitive or specific to epilepsy than in younger people. With increasing age, up to 40% of individuals develop EEG abnormalities, but elderly people with seizures rarely have typical epileptiform activity on interictal EEGs: clearly, the absence of epileptiform discharges does not rule out epilepsy. Therefore, interpreting an EEG in an elderly patient requires caution. Nonconvulsive status is the one clinical situation in the elderly where the EEG is definitely indicated, showing continuous epileptiform activity in a patient who is confused or who has altered mental status.Pharmacokinetics and pharmacodynamicsof AEDs differ in old age from younger patients. These differences depend on the physical status of the patient, the presence or absence of comorbidities and the effects of other medications. fluroquinolones and macrolides can result in an increase in plasma concentrations of phenyotin and carbamazepine. Isoniazid can inhibit the metabolism of several AEDs.Plasma levels of antiarrhythmic drugs, such as amiodarone, can be decreased by enzyme-inducing AEDs and, therefore, may need to be increased accordingly.Digoxin-Plasma concentrations of digoxin can also be decreased due to concurrent administration of phenytoin. Given the narrow therapeutic index of digoxin, plasma concentrations of digoxin and phenytoin may require dose adjustments and careful monitoring. Owing to the incidence of psychiatric disorders, including depression, anxiety and psychosis, psychotropic and antidepressant drugs are commonly prescribed to elderly people. Enzyme-inducing AEDs can increase the metabolism of antidepressant drugs, such as amitriptyline, and antipsychotics, such as haloperidol, chlorpromazine and clozapine. The elderly are more susceptible than younger people to the hyponatremia associated with carbamazepine or oxcarbazepine, especially in those already taking a thiazide or another diuretic.Antiepileptic drug adherence may not be as good in elderly patients with epilepsy, a further factor increasing seizure likelihood and healthcare costs.Although some of the discussed interactions may be theoretical, clinicians should be aware of the potential for harm, and should prescribe AEDs and other drugs in an informed manner in order to minimize the risk. In certain situations, harmful interactions can easily be avoided by prescribing alternative medication or by using one of the new-generation AEDs. In other cases, a simple dose adjustment alongside monitoring the clinical response may be all that is required.Epilepsy in the elderly undoubtedly contributes to social isolation, withdrawal, anxiety and depression. Living alone may make the unpredictable nature of epilepsy more problematic. Epilepsy can substantially disrupt quality of life in the elderly, as at any age.  Therefore, it is clear that the treatment of epilepsy in the elderly is about far more than simply controlling seizures and must also focus upon quality of life.
  • The basic principles of emergency care (ie, attention to airway, breathing, and circulation [ABCs] apply to focal as well as to generalized SE. Although generalized convulsive SE frequently jeopardizes the ABCs, epilepsy partialis continua only infrequently does so. The first steps in the management of a patient in GCSE are to attend to any acute cardiorespiratory problems or hyperthermia, perform a brief medical and neurologic examination, establish venous access, and send samples for laboratory studies to identify metabolic abnormalities. Anticonvulsant therapy should then begin without Administer oxygen. For patients who are in SE or are cyanotic, endotracheal intubation using rapid sequence intubation (RSI) should be strongly considered. If RSI is employed, short-acting paralytics should be given to ensure that ongoing seizure activity is not masked. Consider EEG monitoring in the ED if the patient has been paralyzed because there is no other method to determine if seizure activity is still present.Establish large-bore IV access. Initiate rapid glucose determination, and treat appropriately. Consider antibiotics with or without antiviral agents, depending on the clinical situation.The goal of treatment is to control the seizure before neuronal injury occurs (theoretically between 20 min to 1 h). Central nervous system (CNS) infections and anoxic injury are the leading causes of mortality associated with SE.Stat blood work: basic metabolic panel, liver function tests, calcium, magnesium, phosphate, complete blood count, toxicology screens, troponin, arterial blood gas, and antiepileptic drug levels if appropriateBrief medical and neurological examination…focus on evidence ofinfection,head trauma, stroke and drug ingestion
  • Juvenile Myoclonic EpilepsyEpilepsy syndromes are disorders in which epilepsy is a predominant feature, and there is sufficient evidence (e.g., through clinical, EEG, radiologic, or genetic observations) to suggest a common underlying mechanismJuvenile myoclonic epilepsy (JME) is a generalized seizure disorder of unknown cause that appears in early adolescence and is usually characterized by bilateral myoclonic jerks that may be single or repetitive. The myoclonic seizures are most frequent in the morning after awakening and can be provoked by sleep deprivation. Consciousness is preserved unless the myoclonus is especially severe. Many patients also experience generalized tonic-clonic seizures, and up to one-third have absence seizures. Although complete remission is relatively uncommon, the seizures respond well to appropriate anticonvulsant medication. There is often a family history of epilepsy, and genetic linkage studies suggest a polygenic cause.Other keys to the diagnosis include normal intelligence, onset around adolescence, and a family history of the condition. GTCSs occur shortly after awakening or after precipitating factors such as sleep deprivation, alcohol use, or psychological stress. Patients usually require lifelong anticonvulsant therapy, but their overall prognosis is generally good.Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epileptic syndrome characterized by myoclonic jerks, generalized tonic-clonic seizures (GTCSs), and sometimes absence seizures. JME is relatively common and responds well to treatment with appropriate anticonvulsants.The US Food and Drug Administration (FDA) has not approved any anticonvulsant solely for the treatment of JME. In 2006, the FDA approved the adjunctive use of levetiracetam for the treatment of JME. Divalproex sodium has been approved as adjunctive therapy for patients with multiple seizure types that include absence seizures. However, many patients with JME do not have absence seizures.In most patients with JME, seizures are well controlled with monotherapy. Valproic acid has been considered the treatment of choice for JME for many years, but epileptologists are increasingly using other choices as first-line therapies. Approximately 80% of patients with JME become seizure free with valproate monotherapy. Several studies using lamotrigine, topiramate, levetiracetam, and zonisamide have shown similar efficacy to that achieved with divalproex sodium, and in some cases better tolerability.In general, excellent seizure control can be achieved in JME patients with relatively low doses of appropriate anticonvulsants (eg, valproic acid). The risk of recurrence is higher than 80% if anticonvulsants are withdrawn; hence, lifelong treatment is usually necessary.The severity of JME seizures appears to decrease in adulthood and senescence. Whether patients outgrow JME, as compared with other primary generalized epilepsies, at a late age (ie, >60 y) is unknown. However, in 1 author’s experience, older relatives of people with JME who have a history of seizures are often untreated and rarely have seizures.Lennox-Gastaut SyndromeLennox-Gastaut syndrome occurs in children and is defined by the following triad: (1) multiple seizure types (usually including generalized tonic-clonic, atonic, and atypical absence seizures); (2) an EEG showing slow (<3 Hz) spike-and-wave discharges and a variety of other abnormalities; and (3) impaired cognitive function in most but not all cases. Lennox-Gastaut syndrome is associated with CNS disease or dysfunction from a variety of causes, including developmental abnormalities, perinatal hypoxia/ischemia, trauma, infection, and other acquired lesions. The multifactorial nature of this syndrome suggests that it is a nonspecific response of the brain to diffuse neural injury. Unfortunately, many patients have a poor prognosis due to the underlying CNS disease and the physical and psychosocial consequences of severe, poorly controlled epilepsy. Long-term prognosis overall is unfavorable but variable in LGS.Unfortunately, no one AED gives satisfactory relief for all or even most patients with LGS. A combination of agents frequently is required. Patients with LGS experience frequent exacerbations of their seizures that may require inpatient adjustment of AEDs.Patients with LGS have a recognized high risk for status epilepticus. Because of the consequent risk of injury or death, a medication for emergency intervention (eg, rectal diazepam) should be prescribed.The ketogenic diet may be useful in patients with LGS refractory to medical treatment. Surgical options for LGS include corpus callostomy, vagus nerve stimulation, and focal cortical resectionMesial Temporal Lobe Epilepsy SyndromeMesial temporal lobe epilepsy (MTLE) is the most common syndrome associated with focal seizures with dyscognitive features and is an example of an epilepsy syndrome with distinctive clinical, electroencephalographic, and pathologic features (Table 369-3). High-resolution MRI can detect the characteristic hippocampal sclerosis that appears to be essential in the pathophysiology of MTLE for many patients (Fig. 369-1). Recognition of this syndrome is especially important because it tends to be refractory to treatment with anticonvulsants but responds extremely well to surgical intervention. Advances in the understanding of basic mechanisms of epilepsy have come through studies of experimental models of MTLE, discussed below.
  • Phenytoin loading dose should be given in severe traumatic head injuryPhenytoin prophylaxis reduces early post traumatic seizureNo additional benefit on continuing AED >7daysIn mild head injury no AED neededHeadache and vomiting not influence the occurrence of seizureEEG is not helpful in predicting seizureEpilepsy and seizures are more likely after hemorrhagic than ischemic strokes: 80% compared with 5% developing seizures within 2 weeks, respectivelyCortical and hemorrhagic lesions have higher incidenceA single seizure after stroke may not be treatedRoutine treatment with AED in all CVA patients is not recommendedPhenobarbitone is better avoidedLamotrigine & Gabapentin have been recommendedNeurocystic-ercosisSingle enhancing lesions on CT and MRIStart AED and give for at least 6 monthsRepeat scan after 6 monthTaper by 8-12 weeks if lesion disappearContinue AED if…Due to alcohol intoxication or a/c alcohol withdrawalEEG is indicated after 1st alcohol withdrawal seizurei/v Thiamine 200 mg to be given before starting Dextrose (25% 100ml)Long term AED (PHT,PB or CBZ preferred) should be continued for 6-12 months & tapered
  • Patients with two unprovoked seizures, and hence a diagnosis of epilepsy, are routinely treated with AEDsThe decision to treat a patient with a single unprovoked seizure is not as straightforward - several factors need considerationTreatment Effect on Risk of Seizure RecurrenceSix randomised trials have examined immediate vs. delayed treatment in patients with a single unprovoked seizure. Only one of these was double-blind placebo controlled. Two studies only looked at generalised seizures. Neonates were included in one trial, whereas another had only children. All the randomised trials demonstrated that immediate treatment with an AED reduced the subsequent risk of a seizure in the short term. The absolute risk reductions ranged from 8% to 51%, although follow-up periods were variable between the trials. A random effects meta-analysis performed because of significant heterogeneity among the studies gave an absolute reduction in the risk of seizure recurrence of 34% (95% CI: 15-52). In the largest randomised study (MESS), while immediate treatment increased the probability of 2-year remission at 2 years, this effect is lost by 4 years in patients with single seizures. Similarly, in the second largest randomised trial (FIRST), although the overall risk of seizure recurrence was 50% lower in the treated group compared with the untreated group at 2 years [relative risk 0.5 (95% CI: 0.3-0.6)], there was no significant difference between the groups in achieving a 2-year remission period [relative risk 1.2 (95% CI: 0.97-1.56)]. Therefore, immediate treatment only appears to reduce seizure recurrences in the next 1 to 2 years after the first seizure.Only two trials examined long-term outcomes. In the MESS study, 2-year remission rates were identical at 92% for the immediate and deferred treatment groups at 5 years, and almost identical (95% immediate treatment group vs. 96% deferred treatment group) at 8 years. Similar results were obtained from the FIRST study, where the treated and untreated groups had a 64% risk of 5-year remission at 10 years. Therefore, long-term prognosis of epilepsy is unaffected with early intervention.Adverse Events Associated With Antiepileptic DrugsThe adverse events caused by AEDs may potentially affect any body system. More than 50% of patients with epilepsy on AEDs may experience adverse events, which can result in treatment failure in up to 40% of patients. Adverse events may be life-threatening. A life-threatening adverse event is defined as an abnormal medical occurrence that may lead to death. It most commonly affects the skin, hematopoietic system, liver, pancreas and heart.Severe cutaneous reaction hypersensitivity syndrome resulting from AED use is estimated to have an incidence ranging from 1/1000 to 1/10 000. It is more common in aromatic AEDs such as carbamazepine, phenytoin and phenobarbitone. Aromatic AEDs are also more commonly associated with Stevens-Johnson syndrome and toxic epidermal necrolysis, with an incidence ranging from one to four per 10,000 patient years in this group of AEDs. One study investigating the frequency of serious blood dyscrasias in almost 30,000 patients taking AEDs showed a potential association between blood dyscrasias and AED use in only 0.06% of cases. The incidence of severe hepatotoxicity and pancreatitis resulting from AEDs is not known for most AEDs. However, severe liver damage has been extensively studied in sodium valproate, which is the AED most commonly associated with life-threatening liver failure. The incidence of fatal liver failure appears to have fallen to as low as 0.2 per 10,000 patients receiving sodium valproate, probably as a result of greater awareness of and the resultant closer monitoring for the development of this adverse event. Fatal cardiac adverse events have been rarely associated with carbamazepine and phenytoin, but the exact incidence remains unknown.It is also important to remember that potential teratogenicity and adverse drug interactions resulting from AEDs must also be discussed with a patient when deciding on treatment options after a first unprovoked seizure.The relevance of how potential adverse events may affect the decision to treat a patient with a single unprovoked seizure is well illustrated in the MESS study. In this study, patients in the immediate treatment arm were more likely to report at least one adverse event than those in the deferred treatment arm [difference 8.6% (95% CI: 3.6-11.6)]. In two recent large randomised pragmatic epilepsy trials comparing standard and new AEDs, with a follow-up of 6 years, the frequency of withdrawal for different AEDs because of adverse events was approximately between 15% and 30%, with the majority of withdrawals occurring by the end of the first year.Lifestyle ChangesInterference of the sleep-wake cycle, excessive alcohol intake, and possibly extraordinary physical or psychological stress, are thought to be common precipitating factors of a first seizure, particularly in idiopathic generalised epilepsy, which often presents in adolescence where these issues are most often relevant. Most of these factors can be managed by careful attention to lifestyle habits. A regular sleep pattern, avoidance of sleep deprivation or excessive alcohol intake can be useful in preventing seizure recurrence. Although excessive physical and psychological stresses may sometimes be beyond the control of patients, the recognition and awareness of these as possible triggers of seizures can help patients to learn how to cope and respond appropriately when these situations arise. Weighing these non-pharmacological vs. pharmacological measures is important to determine whether to start an AED after a first seizure.Driving and EmploymentThe importance of driving, especially in relation to one's occupation or employment, is also often a crucial factor to be taken into account when deciding on treatment, as a patient will have to refrain from driving for at least 12 months after a seizure. Certain occupations which may involve the use of machinery, or require solo supervision (e.g. childcare) may affect the choice of the patient to take treatment or not after a seizure. Furthermore, patients may feel that their position in a workplace is more vulnerable after a first seizure, therefore opting for treatment with the hope of reassuring the employers and themselves.Social RelationshipsMany societies stigmatise epilepsy, making it difficult for patients to integrate fully with other members of society. This is especially the case if the seizure occurred at work, school or in the midst of friends. This may influence the decision to take treatment and hence being 'labelled' as having epilepsy, or adopt a wait-and-see policy.Financial ConsiderationsConsistent supply of AEDs and access to healthcare may be variable in different parts of the world, even when treatment is affordable. In contrast, in other parts of the world, the financial burden of AEDs may affect the uptake and consistent use of AEDs.
  • Additional information that would help physicians select the best AED for a given patient are data from head-to-head trials.Newer AED often promoted as having advantages over old drugs..butEfficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, non inferiority parallel-group trial.  Pregabalin has similar tolerability but seems to have inferior efficacy to lamotrigine for the treatment of newly diagnosed partial seizures in adults. Inferior efficacy of pregabalin might have been attributable to limitations in the study design, as treatment doses might have not been optimised adequately or early enough.A prospective, multicenter, double-blind, parallel group trial compared an older drug (controlled release carbamazepine) with a newer drug (levetiracetam) in patients with newly diagnosed epilepsy and determined "noninferiority" of levetiracetam.[7] Both drugs produced similar seizure free rates and incidence of adverse reactions. Side effect profiles differed, with more back pain in patients treated with controlled-release carbamazepine and more depression and insomnia in patients taking levetiracetam. Randomised open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy.Epilepsy Res.  1996; 23(2):149-55 (ISSN: 0920-1211)New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine.The main limiting factor in patient retention was adverse drug reactions. Patients taking lamotrigine (LTG) or gabapentin (GBP) did better than those taking carbamazepine. Seizure control was similar among groups. LTG and GBP should be considered as initial therapy for older patients with newly diagnosed seizures.Choosing an AED for a patient with epilepsy is a complex decision that must be individualized for each patient based on numerous factors including seizure type, epilepsy syndrome, comorbidities, and many other variables. An increasing number of head-to-head trials, although imperfect, offer guidance for the practitioner. 
  • Status epilepticus refers to continuous seizures or repetitive, discrete seizures with impaired consciousness in the interictal period. Status epilepticus (SE) is a common, life-threatening neurologic disorder. It is essentially an acute, prolonged epileptic crisis. Recognition of SE may be easy or difficult. SE in the patient with sequential, generalized major motor convulsions is obvious; the patient with nonconvulsive or subtle SE presents a diagnostic dilemma.2nd most frequent neurological emergency,next to acute stroke.In fact, nearly one-third of older patients with new-onset epilepsy initially present in status epilepticus.4 Children often present in status epi-lepticus as a consequence of febrile illness, whereas the most common identifiable cause of seizures and status in the elderly include cerebrovascular disease, degen-erative disease, neoplasm, infection, and trauma.5
  • Transcript

    • 1. Management of Seizures with special emphasis onnewer Anti Epileptic Drugs Speaker Dr. Suneesh.K Dept. Of Medicine A.I.I.M.S New Delhi
    • 2. Overview• Definition and classification• Approach to seizure• Investigations• Treatment of seizure with details of AED• Refractory epilepsy• Status epilepticus• Special situations
    • 3. Definition Epileptic Seizure A transient occurrence of signs and or symptoms due to abnormal, excessive or synchronous neuronal activity in the brain Acute symptomatic seizures Occur in close temporal proximity with an insult to the brain or during a systemic insult Epileptic Seizures and Epilepsy: Definitions Proposed by ILAE and IBE, Epilepsia, 46(4):470–472, 2005
    • 4. Definition (Contd…) Epilepsy An enduring predisposition to generate epileptic seizures and the neurobiologic, cognitive, psychological, and social consequences of this condition Requires the occurrence of at least 2 epileptic seizure, 24 hr apart All people with epilepsy have seizures. But all those who have seizures do not have epilepsy
    • 5. 2005-2009 Commission ReportClassification 2010;51:676-685 Epilepsia Classification of epileptic seizures and syndromes is continually evolving Clinical & Etiology or Electro- Cellular encephalographi substrate c findings ILAE Commission on Classification and Terminology, 2005-2009 updated the classification,
    • 6. Principal types of seizures Originating within networks limited to one hemisphere. FOCAL GENARALISED beFOCAL, GENARA These may discretely LISED OR SEIZURES SEIZURES UNCLEAR localized or more widely distributed
    • 7. Types of Focal seizures Without Dyscognitive Motor, sensory, autonomic, psychic symptoms features Focal seizures With Dyscognitive features Evolving to bilateral convulsive seizure
    • 8. Originating at some point within, and rapidlyGeneralized Seizures engaging, bilaterally distributed networks
    • 9. Generalized Seizures Tonic ClonicGTCS Absence Atonic Myoclonic Typical Atypical
    • 10. Case scenario.. What are the• Mr. X. 24 year old gentleman was brought to the investigations to be casualty after a Should we start 3 hours back. reported seizure What is we will of done in the role How casualty? If we start According to hisShould we gofound the patient on brother, who for AED? lumbar puncture was throwing approach this AED, will it What imaging is the floor, unresponsive and What is the plan an EEG? preferred? Urgent convulsions lasting this epilepsy? a minute. The prevent patient? in for less than case? of management? CT or routine MRI patient regained consciousness quickly with slight drowsiness. He has no history of seizures in the past.
    • 11. Is it a seizure ?History.. Chance of Provoked recurrence or or not unprovokd Approach Is it a first Focal or episode or generalised epilepsy Clinical practice: Initial management of epilepsy. N Engl J Med. 2008;359:166-176
    • 12. Features Syncope SeizureSeizure mimicsOccurrence Awake, mostly when Awake/asleep uprightPremonition (Nausea, Common Uncommonsweating, Tunnel vision Stereotyped transitionlightheadedness) TIAOnset Less abrupt Abrupt Hypoglycemia SyncopeFacial appearance Pallor Panic attacks at Cyanosis, Frothing mouth Psychogenic-Jerking of limbs Occasional Delirium tremens Frequent seizures Breath holding-Duration of tonic or clonic Never >15 S 30-60 S spellsmovementPost ictal recovery Rapid SlowPost ictal confusion Uncommon Common Harrison’s Principles of internal medicine 18th edition, page 3260
    • 13. Features Psychogenic episode Seizure (NES)Age and gender Young, usually females Any agePrecipitating factors NES Emotional disturbances Lack of sleep, Poor drug complianceOccurrence in sleep Side-to-side turning of the head No YesMovements Asymmetric & large-amplitude or tonic-clonic Vocalization, pelvic Tonic thrusting, bizarre flinging of jerks shaking- movements of the limbs limbsEyes Can be forcibly closed, open Resistance thrusting Pelvic to openingInjuries including tongue bite Infrequent FrequentPost ictal confusion Unknown CommonEEG / Video EEG/Prolactin Normal Usually abnormal J Emerg Med. Jan-Feb 1995;13(1):31-5.
    • 14. History (Contd..)  Transient neurological  Exact description symptoms  Head or eye deviated? H/O Questions to  Awakening with a  Incontinence? Suspicious tongue bite or  Injury? incontinence Aura the witness events duration  Total in past Ictus  Lip masking  Postictal state? Post ictal  Hand automatism Neurology. 2007;69:1996-2007 Am Fam Physician. Sep 15 1997;56(4):1113-20
    • 15. History (Contd..) Epileptogenic factors Precipitating factors Prior head trauma Sleep deprivation Stroke Electrolyte or Metabolic Tumor derangements Acute infection Infection Drugs Family & Personal- Alcohol history Neurology. 2007;69:1996-2007.
    • 16. Physical and neurological examination Neuro cutaneous Focal neurological markers deficit Trauma Systemic illness Subcutaneous Optic fundus Infection nodules Neurology. 2007;69:1996-2007
    • 17. Back to Mr.X..• From the story , • Postictal? Was confused , Not able• With this history, did episode Did he experienced an aura? explain the exact Maybe..had blurry vision..and a sense this gentleman had events in past?? • Suspicious a Never of impending change 15-20 minutes prior to episode seizure? episodes in past that• Trigger? Not identifiable • Medical history: Not significant• Yes, he had •a seizure Not significant Impaired consciousness? Yes Family history:• Got a good description from witnesses Because… attack!! • Personal history: Smoker, no illicit about event, ..Had jerking movement of Focal seizure withdrug abuse the right UL lasted for less than a minute dyscognitive get any relevant finding • Couldn’t• Loss of continence? No. features. general physical and systemic from examination
    • 18. Laboratory studies Routine blood studies Immunocompromise Finger stick glucose Severe headache Persistent fever Lumbar puncture if .. Persistently altered ECG mental status Toxin screening if suspected Pregnancy test in women of childbearing age AED levels ??ABG American College of Emergency Physicians. Clinical policy: Critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures. Ann Emerg Med. May 2004;43(5):605-25
    • 19. Electroencephalogram Three types of information:  Confirmation of the presence of abnormal electrical activity  Type of seizureEEG is not a substitute disorder, and  Location of the seizuregood clinical for a focus Spikes or history, but can add to Sharp waves Interictal epileptic activity: discharges value of a diagnosis Ideal to be done within 24 hr Video EEG Lancet. Sep 26 1998;352(9133):1007-11.
    • 20. Brain Imaging Mandatory in new onset seizure MRI is superior to CT Any focal seizure FND Recent trauma Urgent CT mandatory if Immunocompromise Malignancy Persistently altered mental status On anticoagulation Am J Emerg Med. Jan 1995;13(1):1-5 Indian Epilepsy Society guidelines, (Oct, 2008)
    • 21. Epilepsy protocol MR imaging T1 & T2 sequences in a min of 2 orthogonal planes Contrast enhancement - not necessary in routine cases If focal seizure or FND, sequences should include  3 Dimensional sequence to allow reformatting in any orientation. FLAIR Epilepsia, 38(11):1255-1256, 1997
    • 22. Single photon emissioncomputed tomography (SPECT)
    • 23. FDG – PET If there is no good concordance b/w MRI, EEG & other data Shows area of hypometabolism -Possible site of seizure onset Useful for planning the sites of intracranial electrode
    • 24. Coming back to Mr. X..• Hemogram –Normal• Metabolic work up and electrolytes- Normal• ECG-NSRMr. X had first episode of an• unprovoked seizure (Focal) Urgent NCCT head-Normal• Toxin screening and AED level-Not required• LP-Not required What next?• EEG performed within 24hr – No epileptogenic discharges.
    • 25. SeizureAcute symptomatic Unprovoked or ProvokedTreat underlying cause Epilepsy First episode ?? Start AED ??
    • 26. Recurrence..In MESS Trial Immediate treatment will have a 35–39% chance Trial Chance of recurrence in untreated 1st unprovoked seizure (%)of recurrence at 3 and 5 yearsprovide a 36% relapse rateis 50–Population-based studies but with deferred treatment it at 3 Month 6 Month 1 Year 2 year 5 year 8 Year st unprovoked seizure decreases the56% risk. 1 year and 45% relapse rate at 2 years Treatment of a 1FIRST risk of relapse in the following 2 yrs, but it does notseizure 18 28 Epilepsia, 49(Suppl. 1):58–61, 2008 41 51trial affect the probability of long-term remission and will(Italy) not prevent epilepsyMESSIn FIRST Seizure trial the overall risk of seizure recurrence wasTrial 26 39 51 5250% lower(Musicco treated group et al.,2003; Marson et al.,2005)(Europe) in the et al.,1997; Hirtz compared with the untreated groupat 2 years [RR 0.5 Epilepsia, 49(Suppl. 1):58–61, 2008 (95% CI: 0.3-0.6)]. Immediate treatment onlyreduce seizure recurrences in the next 1-2 years after the 1stseizure
    • 27. Factors that predict seizure recurrence Epileptiform discharges on EEG Abnormal brain imaging Pre-existing neurological condition Abnormal neurological examination Mental retardation
    • 28. TreatFND or Todd’s palsy 1st Unprovoked Presenting as status epilepsy seizure if Mental Treatment significantly reduces the retardation risk of recurrence in the short term Positive family history But does not alter the long-term prognosis EEG or Imaging abnormality Only a case by case approach which balances the pros and cons High risk jobs Individual & family do not accept the expected risk of recurrence Indian Epilepsy Society guidelines, (Oct, 2008)
    • 29. Antiepileptic drugs Treatment modalities Non Pharmacological pharmacological
    • 30. Old drugs (Before 1993) New drugs (Since 1993) Felbamate Gabapentin Carbamazepine Lamotrigine Clonazepam Levetiracetam Lacosamide Ethosuximide Oxcarbazepine Phenobarbital Pregabalin Tiagabine Phenytoin Topiramate Primidone Vigabatrine Valproic acid Zonisamide Ezogabine Rufinamide Eslicarbazepine N Engl J Med 2008;359:166-76
    • 31. Mechanism of Action of AEDEPSPs IPSPs K+ EffluxNa+ Influx Cl- InfluxCa++ Currents PumpsParoxysmal Depolarization Low pHSeizure!!! Control
    • 32. Classification based onMechanism of Action Na Channel Ca2+ Current GABA Blockers inhibitors Enhancers Carbonic Glutamate Unknown anhydrase blockers mechanism inhibitors
    • 33. Enhanced Sodium channel inactivation Na Na + + Activation gate Zonisamide Topiramate Phenytoin Valproate Inactivation gate Carbamazepine Lamotrigine
    • 34. Reduced current through T type Calcium channelsEthosuximide Valproate Ca++ Ca++
    • 35. GABA EnhancersGabapentin Tiagabine ValproateVigabatrine BZD Barbiturate
    • 36. Glutamate blockersNMDA Blockers Felbamate LevetiracetamAMPA Blocker TopiramateMetabotrophic Under research
    • 37. AED (Contd..) of the Future!! A Glimpse Carbonic anhydrase + Prolong Na Channel inhibitors Rufinamide inactive AcetazolamideWaiting for FDA approval state Talampanel-AMPA Blocker SV2A-binding agents Carisbamate Retigabine (INN) K+ Channel Levetiracetam BrivaracetamEzogabine (USAN) opener Lacosamide CRMP-2 Eslicarbazepine Anal Bioanal Chem. 201016 2010;75(20):1817-24 Neurology. Nov Jun;397(4):1605-15
    • 38. Cerebellar Phenytoin Carbamazepine Valproic acid Lamotrigine Ethosuximide Gabapentin Lacosamide Adverse effects Rufinamide Psychomotor slowing Language problems Topiramate Tiagabine Mood changes Felbamate Levetiracetam ZonisamideHarrison’s Principles of internal medicine 18th edition, page 3263
    • 39. Skin rash Lamotrigine Phenytoin Phenytoin Gum hyperplasia Carbamazepine LNE Phenobarbitone Hirsutism Osteomalacia Cardiac conduction CBZLacosamide Rufinamide Hyponatremia Hepatotoxicity VPA Valproate Increase NH3 Benzodiapine Weight gain Felbamate Topiramate BM Suppression Renal stones Carbamazepine Weight loss Ethosuximide Glaucoma Levetiracitam Valproate FelbamateHarrison’s Principles of internal medicine 18th edition, page 3263
    • 40. Liver and renal disease Avoid VPA, PB and BZD OXC,LEV and GBP are safe Phenytoin, Lamotrigine and Valproate are safer Indian Epilepsy Society guidelines, (Oct, 2008)
    • 41. Drug Interactions Enzyme Inducers decrease All AED level except Gabapentin and Levetiracetam Valproate increase blood level of LEV and PB INH increase PHT and CBZ INH and Rifampicin increase Carbamazepine level Rifampicin reduces Phenytoin and valproate level Harrison’s Principles of internal medicine 18th edition, page 3263
    • 42. AED selection-First line AtypicalGeneralised Typical absence onset Focal absence MyoclonicTonic-Clonic AtonicValproate CBZ Valproate ValproateLamotrigine Ox-CBZ Lamotrigine Ethosuximide Topramate Phenytoin Topramate Lamotrigine Harrison’s Principles of internal medicine 18th edition, page 3262
    • 43.  Valproate -more effective than used as 1st line and topiramate Older drugs are still lamotrigine therapy No evidence that new drugs are more effective Lamotrigine had twice the failure rate because of inadequate Newer AEDs:seizure control But side effect and drug interactions low Comparative trials are not necessarily the last word How good?? Topiramate -similar in efficacy but had a each patient Decision must be individualized for higher failure rate thanvalproate due to side effects Valproate should remain the drug of 1st choice for generalisedand unclassified epilepsies Lancet 2007; 369: 1016–26
    • 44. Follow-up and monitoring Routine AED level Follow-up laboratory tests monitoring Routine Monitoring not First follow-up CBC, LFT & RFT Therapeutic range recommended within 2-4 weeks before Starting (In micro gm/mL) Suspected AED toxicity treatment and every Subsequent Managing drug Phenytoin 10-20 follow-ups every 3-6 month interactions CBZ 6-12 3-6 months Ca2+,ALP and VPA 50-125 Vit-D every year Liver or renal disease and Seizure diary Phenobarbital 10-40 pregnancy Indian Epilepsy Society guidelines, (Oct, 2008)
    • 45. When to stop AED?  Withdraw AED if seizure-free period of 2-3 yr Prolonged AED RX after 2 years, without seizures, does not guarantee lifelong  Should discuss the risk and benefitsseizure freedom  Withdraw gradually over 3-6 months Using life-table analysis, the cumulative probability of remaining seizure-freeafter RX discontinuation is 39–74% at 1st year and 35–57% at 2nd year  Withdraw one drug at a time The relapse rate is highest in the Indianmonths (Mainly 6guidelines, (Oct, 2008) 1st 12 Epilepsy Society months) J Neural Transm (2011) 118:187–191
    • 46. Accuracy A of DiagnosisTreatment failure B Best drug C Compliance D Dose Indian Epilepsy Society guidelines, (Oct, 2008)
    • 47. Refractory Epilepsy  Epilepsy not controlled by 2 or more appropriate AEDs used in their optimal dosage or  Adults (16 years or above) who continue to have seizures even after 2 years of treatment  20–30% of patients with epilepsy  Surgery should be considered early; not as last resort Indian Epilepsy Society guidelines, (Oct, 2008)
    • 48. Medically intractable epilepsyNo lesion seen on epilepsy protocol MRI: Lesion seen on epilepsy protocol MRI: Substrate negative Substrate positive Standard investigations: EEG, MRI, VEEGPatient not a suitable candidate -ve +vefor curative/palliative surgery -ve Advance investigations: SPECT, PET, fMRI Evaluate for Vagal nerve stimulation (VNS) EPILEPSY SURGERY
    • 49. Non-pharmacological options Vagal nerve stimulation Lifestyle Modifications Ketogenic diet• Adequate sleep Approved in 1997 by FDA • for Intermittent programmed electricallow protein, high fat Indicated Low carbohydrate, stimulation of left Vagus nerve• Avoidance of alcohol, after fasting to initiate ketosis Refractory partial onset seizures Either not of• seizures can stimulants, etc. 50% reduction good candidates orbe of ketosis, acidosis Anti-seizure effect expected in up •to 30–40% of release ? Role of leptin patients unwilling for surgery• Stress reduction — specific • Main experience with children, especially with multiple seizure types techniques • Long-term effects unknown• Adequate diet
    • 50. Back to Mr. X..• What are the future plans? – Advise to stop driving Start with lowest – But he is the only earning member in family !!! possible dose!! – Start AED (After discussing with relatives-adverse Monotherapy is effects…) CBZ 100 mg BD Phenytoin 300 mg OD – Phenytoin ,Carbamazepine or Lamotrigine?? Consider the rule!! Lamotrigine 25 mg OD cost also!! Valproate 200 mg BD – Repeat EEG after 2 weeks → Then after 2 month Levetiracetam 250 mg BD – MRI brain with epilepsy protocol – Ensure adequate follow-up, compliance & avoid triggers of seizure
    • 51. Status epilepticus Convulsive status epilepticus (CSE) Continuous convulsive seizures lasting more than 5 minutes or 2 or more seizures during which patient does not return to baseline consciousness Nonconvulsive status epilepticus (NCSE) Change in mental status from baseline for at least 30 minutes a/w ictal changes on EEG Indian Epilepsy Society guidelines, (Oct, 2008)
    • 52. Management of Status Epilepticus Lancet Neurol 2011; 10: 922–30
    • 53. SuperRefractory SE Non-pharmacological options Resective surgery Ketogenic diet Vagal nerve stimulation Repetitive transcranial magnetic stimulation ECT Mild hypothermia
    • 54. Special situations..
    • 55. Seizure disorders in pregnancy Monotherapy and lowest possibleStudy The NEAD dose Seizure frequency unchanged in 50%, Increase Supplement with folate at & Decrease ingenetic counseling in 30% 4 mg/d & 20% Seizure Disorders in Check AED level 5-6% congenital defects in babies monthly Pregnancy Valproate-Maximum! Maternal sAFP levels and USG at 19-20 wks Risk to Valproate, as compared with otherIn utero exposure increases with number of medications Oral Vitamin K (20 mg/day) in last 2 weekscommonly used Monotherapy as far as possibleincreased risk of AED, is associated with an Give 1mg of vitamin K (i/m) for the infant Newer drugs??impaired cognitive function at 3 yr of age. This finding supports a Rule out eclampsia in status epilepticusrecommendation that valproate not be used as a 1st drug inwomen of childbearing potential. epilepsy in pregnancy. BJOG 116:758, 2009 The management of
    • 56. ↑With Phenytoin-- Dose of Ritonavir & Lopinavir AEDs and ART With Valproate-- ↓ Dose of Zidovudine ↑With Ritonavir / Atazanavir-- Dose of Lamotrigine Avoid enzyme inducing AED with PI/NNRTI Epilepsia, 53(1):207–214, 2012
    • 57. Take home message… Establish the diagnosis of epilepsy before starting treatment The choice of AED should be based on seizure type, affordability and availability of AEDs Initiate treatment with monotherapy. Use polytherapy with caution when monotherapy is not successful The principle, “start low and go slow” should be followed for AED dosages
    • 58. Take home message… Maintain seizure diary, ensure regular follow up and AED compliance Conventional AEDs are generally as effective as newer AEDs and should be the first line of treatment in most cases Consider AED withdrawal after 2 years of seizure-free interval
    • 59. Thank you..
    • 60. Video EEG (VEEG) Continuous video & synchronized EEG recording for more than 24 hrs. Documentation of at least 3 or more events In case of diagnostic uncertainty (e.g. focal seizure of frontal lobe origin) & if surgical treatment is considered Differential diagnosis of type of seizure
    • 61. FLAIR Certain lesions such as focal cortical dysplasia FLAIR increases conspicuity of lesions Should be part of a standard MRI protocol
    • 62. Magnetic Resonance Spectroscopy Reductions in NAA/(Cho + Cr) ratio in Temporal lobe epilepsy Correlate with presence of hippocampal sclerosis and correctly lateralize side of seizure onset in 97% of patients
    • 63. Diffusion tensor imaging -tractography Visualise white-mattertracts includingconnections of eloquentareas Reduce the risks ofsurgery
    • 64. SPECT (Contd..) Identification of a possible epileptic focus, when structural imaging is unremarkable Assessment of suitability for epilepsy surgery SISCOS – subtraction ictal SPECT co-registered with SPECT SISCOM – subtraction ictal SPECT co-registered with MRI
    • 65. Treatment modalities Non- Pharmacological Pharmacological Lifestyle Ketogenic Vagal nerveSurgery modification diet stimulation
    • 66. 100 mg thiamine IV and Beware of sedation, 50 mL of 50% dextrose iv if hypoglycemic, respiratory depression, and 0.1 mg/kg IV Lorazepam (<2 mg/min) hypotension If seizures persist, may repeat initial dose of Lorazepam once mg/kg)!!! Dose (in If no IV access,0.1 Lorazepam consider rectal Diazepam 106-10 to 20 mg Diazepam 0.15Min If Midazolam 0.2 may repeat initial dose of seizures persist, Diazepam once 0.015 Clonazepam Lancet Neurol 2011; 10: 922–30
    • 67.  Phenytoin iv 20 mg/kg by slow push (50 mg/min) or fosphenytoinValproate PE/min) (150 mg Not Established 20-30 mg/kg FDA SE If seizures persist, Levetiracetam give additional iv approvd 20-30 mg/kg for SE fosphenytoin or phenytoin to a maximum Rate 500 mg/min total dose of 30 mg/kg  Try to correct cardiac depression Beware of metabolic abnormalities if11-30 and arrhythmia, hypotension, any parasthesias, and pruritis Min  Alternatives to phenytoin are Valproate, Or Levetiracetam Lancet Neurol 2011; 10: 922–30
    • 68. Early  Midazolam Refractory SE  Propofol  Barbiturates  Intubate the patient31-60  Shift to ICUMin Lancet Neurol 2011; 10: 922–30
    • 69. Late Try other general anesthetics Refractory SE Isoflurane Desflurane Ketamine Stillseizure Lidocainepersists Verapamil Lancet Neurol 2011; 10: 922–30
    • 70. What the literature says..?
    • 71. ChoosingAssessAntiepileptic Drug  an airway, apply o & pulse oximetry 2  Cardiac and hemodynamic monitoring  High oral efficacy withoutwith  Venipuncture seizure2aggravation large-gauge Which intravenous catheters Drugs Antiepileptic  Good tolerability Work Best?? work:  Stat blood  No or minimal drug interactions  ABG, and antiepileptic drug levels if  Once or appropriate dosing twice daily  Treat hypothermia  Low cost and high cost effectiveness  Check finger-stick glucose  Pharmacogenetics??  Begin normal saline drip
    • 72. Etiology Exacerbation of a pre-existing seizure disorder Change in medication Initial manifestation of a seizure disorder Toxic , Metabolic or Structural cortical damage Insult other than a seizure disorder
    • 73. Functional Operations Division of pathways of spread • Corpus callosotomyDivision of epileptogenic neuronal aggregate • Multiple subpial transections
    • 74. Seizures in elderly  Clinical history and examination Adherence Seizures in the  Cardiac evaluation is mandatory Frailty and medicalslow ‘Start low and go comorbidities Elderly  1st episode of unprovoked Social isolation & Withdrawal seizure: Better to treat (First Depression Seizure Trial)  Potential drug interactions!! Epilepsia 43(4), 365–385 (2002)Lancet Neurol. 2(8), 473–481 (2003) Indian Epilepsy Society guidelines, (Oct, 2008)
    • 75. Management of Status Epilepticus Brief medical and xamination neurological examination0-5Min 2011; 10: 922–30
    • 76. Epilepsy Syndromes Juvenile Lennox-Gastautx Mesial Temporal Lobe Myoclonic Syndrome Epilepsy Syndrome Epilepsy Gabapentin Valproate History of febrile seizures Topiramate Multiple seizure types Family history of epilepsy Lamotrigine Lamotrigine, Temporal lobectomy Generalized Lamotrigine EEG showing slow Early onset seizure disorder Topiramate Levetiracetam,Sodium valproate (<3 Hz) spike-and- AuraEarly adolescence Felbamate Vagus nerve stimulation Oxcarbazepine Topiramate wave discharges Behavioral arrest Bilateral Zonisamide (VNS) Pregabalin Impaired cognitive Unilateral or bilateral myoclonic jerks Levetiracetam Rufinamide Lacosamide function anterior temporal spikes on Vigabatrine EEG Ezogabine
    • 77. Common provoked seizures Stroke AlcoholHead injury CVST Cortical and Neurocystic- relatedPhenytoin hemorrhagic AED is ercosis seizures 7 days A single recommende AED at least AED should seizure may 6 months Only in d for 1year not be st be continued Repeat after 1 for 6-12 m severe treated imaging at episode EEG trauma Lamotrigine on 6th m advised Gabapentin Indian Epilepsy Society guidelines, (Oct, 2008)
    • 78. AEDs and ATT INH and Rifampicin increase Carbamazepine level AEDs and ATT Rifampicin reduces Phenytoin and valproate level Avoid Phenytoin with ATT
    • 79. AED selection-Alternatives AtypicalGeneralised Typical absence onset Focal absence MyoclonicTonic-Clonic Atonic Topiramate Lamotrigine Zonisamide Zonisamide Valproate Phenytoin CBZ Valproic acid Clonazepam ValproateLamotrigine Ox-CBZ Tiagabine Lamotrigine ValproateCarbamazepine Felbamate Lamotrigine Topramate Phenytoin Gabapentin Ethosuximide Clonazepam Felbamate Lacosamide Levetiracetam Topramate Phenobarbital Topiramate Felbamate Harrison’s Principles of internal medicine 18th edition, page 3262
    • 80. Definition Structural 7days Seizure occur due an acute brain insult Metabolic (24 hr) Indian Epilepsy Society guidelines, (Oct, 2008)
    • 81. Management ofCommon provoked seizures
    • 82. Other special issues in women Natural progestins or Catamenial epilepsy i/m medroxy progesterone Enzyme inducers decrease Contraception efficacy of OCP Breast feeding No evidence of long term harm on child
    • 83. Factors to consider when deciding whetheror not to treat a first unprovoked seizure Medical Non-medical Treatment effect on risk of seizure recurrence  Driving and employment Medical  Financial considerations Non Medical Adverse events A/W AED  Social relationships
    • 84. Newer AEDs – how good? Levetiracetam and carbamazepine produced equivalent seizure freedom rates in newly diagnosed epilepsy Neurology. 2007;68:402-408. Headdrugs are still usedtrials..  Older to head as 1 line therapyst Lamotrigine and carbamazepine were equally effective, but  No evidence that new drugs lamotrigine was better tolerated. are more effective  Comparative trials are not necessarily the last word Epilepsy Res. 1996;23:149-155  Decision must be individualized for each patient New onset geriatric epilepsy-Carbamazepine had the highest seizure-free rates, comparing Gabapentin or Lamotrigine Neurology. 2005;64:1868-1873
    • 85. "If an epilepsy demon falls many times upon him on agiven day, he seven times punishes him and possesseshim, his life will be spared. If he falls upon him eighttimes, his life may not be spared." Babylonian treatise on epilepsy: Med Hist. Apr 1990;34(2):185-98.