تشنج و صرع
348
تشنج و صرع
Seizures and Epilepsy
A seizure تشنج :(from the Latin sacire, “to take possession of”) is a paroxysmal event due to abnormal, excessive, hypersynchronous discharges from an aggregate of central nervous system (CNS) neurons. ~5 to 10% of the population will have at least one seizure,
with the highest incidence occurring in early childhood and late adulthood.
Epilepsyصرع : a condition in which a person has recurrent seizures due to a chronic, underlying process.
Using the definition of epilepsy as 2 or more unprovoked seizures,
incidence of epilepsy: ~0.3 to 0.5%, prevalence : 5 to 10 persons per 1000.
CLASSIFICATION OF SEIZURES
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TABLE 348-1 Classification of Seizures | |||
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Partial seizures à seizure activity is restricted to discrete areas of the cerebral cortex. Associated with structural abnormalities of the brain.
Generalized seizures à diffuse regions of the brain simultaneously. Result from cellular, biochemical, or structural abnormalities that have a more widespread distribution
تشنجهای پارشیال
PARTIAL SEIZURES
Partial seizures occur within discrete regions of the brain.
تشنج پارشیال ساده: هوشیاری طی حمله به طور کامل حفظ می شود.
تشنج پارشیال کمپلکس: هوشیاری طی حمله مختل می شود.
If consciousness is fully preserved during the seizure : simple partial seizure.
If consciousness is impaired, the symptomatology is more complex:complex partial seizure.
seizures that begin as partial seizures and then spread diffusely throughout the cortex, i.e., partial seizures with secondary generalization.
تشنج های پارشیال ساده:
Simple Partial Seizures
motor, sensory, autonomic, or psychic symptoms without an obvious alteration in consciousness.
تشنج پارشیال حرکتی برخاسته از کورتکس حرکتی اولیه سمت راست --› حرکات غیر ارادی دست چپ (سمت مقابل) به صورت کلونیک (تکراری فلکسیون/اکستانسیون) با فرکانس 2-3 هرتز + ممکن است با حرکات غیر طبیعی صورت.
اگر تشنج پارشیال ساده، تحدب مغز را درگبر کند ممکن است در EEG در یک ناحیه محدود کورتیکال مشخص شود ولی در صورتی که ساختارهای عمیقتر مغز را درگیر کرده باشد، ممکن است در EEG معمول مشخص نباشدو نیاز به الکترودهای اینتراکرانیال باشد.
سه تابلوی دیگر تشنجهای حرکتی پارشیال:
1- 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. described by Hughlings
2- Localized paresis (Todd's paralysis) for minutes to many hours in the involved region following the seizure.
3- In rare instances the seizure may continue for hours or daysàepilepsia partialis continua, often refractory to medical therapy.
Simple partial seizures à 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).
temporal or frontal cortex à alterations in hearing, olfaction, or higher cortical function (psychic symptoms).like 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, déjà vu, or illusions that objects are growing smaller (micropsia) or larger (macropsia).
When such symptoms precede a complex partial or secondarily generalized seizure, these simple partial seizures serve as a warning, or aura.
تشنجهای پارشیال کمپلکس:
Complex Partial Seizures
characterized by: focal seizure activity accompanied by a transient impairment of the patient's ability to maintain normal contact with the environment.
The patient is unable to respond appropriately to visual or verbal commands during the seizure and has impaired recollection or awareness of the ictal phase.
The seizures frequently begin with an aura (i.e., a simple partial seizure) that is stereotypic for the patient.
The start of the ictal phase is often a sudden behavioral arrest or motionless stare, which marks the onset of the period of amnesia.
The behavioral arrest is usually accompanied by automatisms, which are involuntary, automatic behaviors that have a wide range of manifestations.
Automatisms may consist of very basic behaviors such as chewing, lip smacking, swallowing, or “picking” movements of the hands, or more elaborate behaviors such as a display of emotion or running.
The patient is typically confused following the seizure, and the transition to full recovery of consciousness may range from seconds up to an hour.
Examination immediately following the seizure may show an anterograde amnesia or, in cases involving the dominant hemisphere, a postictal aphasia.
The routine, interictal (i.e., between seizures) EEG in patients with complex partial seizures is often normal or may show brief discharges termed epileptiform spikes, or sharp waves.
Since complex partial seizures can arise from the medial temporal lobe or inferior frontal lobe, i.e., regions distant from the scalp, the EEG recorded during the seizure may be nonlocalizing. However, the seizure focus is often detected using sphenoidal or surgically placed intracranial electrodes.
In cases of stereotypic episodes of bizarre or atypical behavior, detailed EEG studies may be helpful.
Partial Seizures with Secondary Generalization
Partial seizures can spread to involve both cerebral hemispheres and produce a generalized seizure, usually of the tonic-clonic variety.
ژنرالیزه شدن ثانویه به خصوص در مورد تشنج پارشیال ساده در لوب فرونتال رخ می دهد.
Secondary generalization is observed frequently following simple partial seizures, especially those with a focus in the frontal lobe, but may also be associated with partial seizures occurring elsewhere in the brain.
In some cases, the focal onset of the seizure becomes apparent only when a careful history identifies a preceding aura (i.e., simple partial seizure). Often, however, the focal onset is not clinically evident and may be established only through careful EEG analysis.
تشنجهای ژنرالیزه:
GENERALIZED SEIZURES
generalized seizures may be practically defined as bilateral clinical and electrographic events without any detectable focal onset.
تشنجهای ابسانس-بدون از دست رفتن کنترل وضعیتی- بدون کنفوزیون پست ایکتال- رویاهای روزانه – افت تحصیلی-تحریک با هیپرونتیلاسیون
Absence Seizures (Petit Mal)
Absence seizures are characterized by sudden, brief lapses of consciousness without loss of postural control.
The seizure typically lasts for only seconds, consciousness returns as suddenly as it was lost, and there is no postictal confusion.
Although the brief loss of consciousness may be clinically inapparent or the sole manifestation of the seizure discharge, absence seizures are usually accompanied by subtle, bilateral motor signs such as rapid blinking of the eyelids, chewing movements, or small-amplitude, clonic movements of the hands.
Absence seizures usually begin in childhood (ages
The seizures can occur hundreds of times per day, but the child may be unaware of or unable to convey their existence.
The first clue to absence epilepsy à unexplained “daydreaming” and a decline in school performance recognized by a teacher.
The electrophysiologic hallmark of typical absence seizures is a generalized, symmetric, 3-Hz spike-and-wave discharge that begins and ends suddenly, superimposed on a normal EEG background.
Periods of spike-and-wave discharges lasting more than a few seconds usually correlate with clinical signs, but the EEG often shows many more brief bursts of abnormal cortical activity than were suspected clinically.
Hyperventilation tends to provoke these electrographic discharges and even the seizures themselves and is routinely used when recording the EEG.
Typical absence seizures are often associated with generalized, tonic-clonic seizures, but patients usually have no other neurologic problems and respond well to treatment with specific anticonvulsants.
~60 to 70% of such patients will have a spontaneous remission during adolescence.
تشنجهای ابسانس آتیپیک: وقفه هوشیاری طولانی تر-شروع و توقف آن تدریجی تر- نشانه های حرکتی واضحتر مثل فوکال یا یکطرفه-با اختلالات ساختمانی منتشر یا چندکانونی مغز مرتبط- همراهی با منتال رتارداسیون- پاسخ به درمان کمتر
Atypical Absence Seizures
Lapse of consciousness is usually of longer duration and less abrupt in onset and cessation, and the seizure is accompanied by more obvious motor signs that may include focal or lateralizing features.
The EEG : generalized, slow spike-and-wave pattern with a frequency of ≤2.5/s, as well as other abnormal activity.
Usually associated with diffuse or multifocal structural abnormalities of the brain à signs of neurologic dysfunction such as mental retardation.
less responsive to anticonvulsants compared to typical.
تشنج های تونیک-کلونیک ژنرالیزه (گراندمال): در اختلالات متابولیک شایع- بدون هشدار و ناگهانی شروع
Generalized, Tonic-Clonic Seizures (Grand Mal)
main seizure type in ~10% of all persons with epilepsy.
They are also the most common seizure type resulting from metabolic derangements.
The seizure usually begins abruptly without warning.
This prodrome is distinct from the stereotypic auras associated with focal seizures that secondarily generalize.
فاز تونیک:
The initial phase à tonic contraction of muscles throughout the body, accounting for a number of the classic features of the event.
Tonic contraction of the muscles of expiration and the larynx at the onset will produce a loud moan or “ictal cry.” Respirations are impaired, secretions pool in the oropharynx, and cyanosis develops. Contraction of the jaw muscles may cause biting of the tongue.
A marked enhancement of sympathetic tone leads to increases in heart rate, blood pressure, and pupillary size.
فاز کلونیک:
After 10 to 20 s, the tonic phase à clonic phase, produced by the superimposition of periods of muscle relaxation on the tonic muscle contraction. The periods of relaxation progressively increase until the end of the ictal phase, which usually lasts no more than 1 min.
فاز پست ایکتال:
The postictal phase is characterized by unresponsiveness, muscular flaccidity, and excessive salivation that can cause stridorous breathing and partial airway obstruction. Bladder or bowel incontinence may occur at this point.
Patients gradually regain consciousness over minutes to hours, and during this transition there is typically a period of postictal confusion.
Patients subsequently complain of headache, fatigue, and muscle ache that can last for many hours.
بی اختیاری ادرار یا روده در فاز پست ایکتال رخ می دهد.
طولانی شدن فاز پست ایکتال در موارد: تشنج طولانی، بیماری زمینه ای CNS مثل آتروفی مغزی در اثر الکل
The duration of impaired consciousness in the postictal phase can be extremely long, i.e., many hours in:à1- prolonged seizures ,2- underlying CNS diseases such as alcoholic cerebral atrophy.
The EEG
during the tonic phase of the seizure shows a progressive increase in generalized low-voltage fast activity, followed by generalized high-amplitude, polyspike discharges.
In the clonic phase, the high-amplitude activity is typically interrupted by slow waves to create a spike-and-wave pattern.
The postictal EEG shows diffuse slowing that gradually recovers as the patient awakens.
variants :
1-pure tonic
2-pure clonic seizures.
3-Brief tonic seizures lasting only a few seconds are associated Lennox-Gastaut syndrome.
تشنجهای آتونیک:
Atonic Seizures
characterized by sudden loss of postural muscle tone lasting 1 to 2 s.
Consciousness is briefly impaired, but there is usually no postictal confusion.
A very brief seizure may cause only a quick head drop or nodding movement, while a longer seizure will cause the patient to collapse.
The EEG shows brief, generalized spike-and-wave discharges followed immediately by diffuse slow waves that correlate with the loss of muscle tone.
Similar to pure tonic seizures, usually seen in association with known epileptic syndromes.
تشنجهای میوکلونیک:
Myoclonic Seizures
Myoclonus is a sudden and brief muscle contraction that may involve one part of the body or the entire body.
A normal, common physiologic form of myoclonus is the sudden jerking movement observed while falling asleep.
Pathologic myoclonus is most commonly seen in association with metabolic disorders, degenerative CNS diseases, or anoxic brain injury.
They are caused by cortical (versus subcortical or spinal) dysfunction.
The EEG may show bilaterally synchronous spike-and-wave discharges synchronized with the myoclonus, although these can be obscured by movement artifact.
Are the predominant feature of juvenile myoclonic epilepsy.
سندرمهای صرعی:
EPILEPSY SYNDROMES
Epilepsy is a predominant feature, and there is sufficient evidence to suggest a common underlying mechanism.
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TABLE 348-2 Examples of Genes Associated with Epilepsy Syndromesa | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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صرع میوکلونیک جوانان:
JUVENILE 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.
The condition is otherwise benign, and although complete remission is 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.
سندرم لنوکس گاستاو:
LENNOX-GASTAUT SYNDROME
Lennox-Gastaut syndrome occurs in children.
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.
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.
many patients have a poor prognosis.
MESIAL TEMPORAL LOBE EPILEPSY SYNDROME
MTLE is the most common syndrome associated with complex partial seizures and is an example of a symptomatic, partial epilepsy with distinctive clinical, electroencephalographic, and pathologic features (Table 348-3).
High-resolution MRI can detect the characteristic hippocampal sclerosis that appears to be essential in the pathophysiology of MTLE for many patients (Fig. 348-1).
Recognition of this syndrome is especially important because it tends to be refractory to treatment with anticonvulsants but responds extremely well to surgical intervention.
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TABLE 348-3 Characteristics of the Mesial Temporal Lobe Epilepsy Syndrome | |||||||||||||||||||
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THE CAUSES OF SEIZURES AND EPILEPSY
- The normal brain is capable of having a seizure under the appropriate circumstances, and there are differences between individuals in the susceptibility or threshold for seizures. This implies there are various underlying, endogenous factors that influence the threshold for having a seizure: 1-genetic, as it has been shown that a family history of epilepsy will influence the likelihood of seizures occurring in otherwise normal individuals. 2-Normal development : brain appears to have different seizure thresholds at different maturational stages.
- There are a variety of conditions that have an extremely high likelihood of resulting in a chronic seizure disorder. One of the best examples of this is severe, penetrating head trauma, which is associated with up to a 50% risk of subsequent epilepsy. The high propensity for severe traumatic brain injury to lead to epilepsy suggests that the injury results in a long-lasting, pathologic change in the CNS that transforms a presumably normal neural network into one that is abnormally hyperexcitable. This process is known as epileptogenesis, and the specific changes that result in a lowered seizure threshold can be considered epileptogenic factors. Other processes associated with epileptogenesis include stroke, infections, and abnormalities of CNS development. Likewise, the genetic abnormalities associated with epilepsy likely involve processes that trigger the appearance of specific sets of epileptogenic factors.
- Seizures are episodic. Patients with epilepsy have seizures intermittently and, depending on the underlying cause, many patients are completely normal for months or even years between seizures. This implies there are important provocative or precipitating factors that induce seizures in patients with epilepsy. Similarly, precipitating factors are responsible for causing the single seizure in someone without epilepsy. Precipitants include those due to intrinsic physiologic processes, such as psychological or physical stress, sleep deprivation, or hormonal changes associated with the menstrual cycle. They also include exogenous factors such as exposure to toxic substances and certain medications.
Removal or modification of a precipitating factor may be an effective and safer method for preventing further seizures than the prophylactic use of anticonvulsant drugs.
علل تشنج بر اساس سن:
CAUSES ACCORDING TO AGE
age is one of the most important factors determining both the incidence and likely causes of seizures or epilepsy (Table 348-4).
علل تشنج طی دوره نوزادی و اوایل شیرخوارگی:
During the neonatal period and early infancy, potential causes include:
hypoxic-ischemic encephalopathy,
trauma,
CNS infection,
congenital CNS abnormalities, and
metabolic disorders.
Babies born to mothers using neurotoxic drugs such as cocaine, heroin, or ethanol are susceptible to drug-withdrawal seizures in the first few days after delivery.
Hypoglycemia and hypocalcemia, which can occur as secondary complications of perinatal injury, are also causes of seizures early after delivery.
Seizures due to inborn errors of metabolism usually present once regular feeding begins, typically 2 to 3 days after birth.
Pyridoxine (vitamin B6) deficiency, an important cause of neonatal seizures, can be effectively treated with pyridoxine replacement.
The idiopathic or inherited forms of benign neonatal convulsions are also seen during this time period.
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TABLE 348-4 Causes of Seizures | ||||||||||||||||
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علل تشنج طی اواخر شیرخوارگی و اوایل کودکی:
The most common seizures arising in late infancy and early childhood are:
Febrile seizuresà
Seizures associated with fevers but without evidence of CNS infection or other defined causes.
Prevalence: 3 to 5%.
Often Family history (+) of febrile seizures or epilepsy.
Between 3 months and 5 years of age
Peak incidence between 18 and 24 months.
The typical scenario is a child who has a generalized, tonic-clonic seizure during a febrile illness in the setting of a common childhood infection such as otitis media, respiratory infection, or gastroenteritis.
The seizure is likely to occur during the rising phase of the temperature curve (i.e., during the first day) rather than well into the course of the illness.
simple febrile seizure is a single, isolated event, brief, and symmetric in appearance.
Complex febrile seizures are characterized by repeated seizure activity, duration >15 min, or have focal features.
Approximately one-third of patients with febrile seizures will have a recurrence,
but <10% have three or more episodes.
Recurrences are much more likely when the febrile seizure occurs in the first year of life.
Simple febrile seizures are not associated with an increase in the risk of developing epilepsy.
Increased risk of developing epilepsy after febrile seizure:
1-complex febrile seizures have a risk of 2 to 5%;
2- presence of preexisting neurologic deficits
3- family history of nonfebrile seizures.
علل تشنج در دوران کودکی:
Childhood à many of the well-defined epilepsy syndromes present.
Someà idiopathic, generalized tonic-clonic seizures without other features that fit into specific syndromes.
Temporal lobe epilepsy àusually in childhood - may be related to mesial temporal lobe sclerosis or other focal abnormalities such as cortical dysgenesis.
Other types of partial seizures, including those with secondary generalization, may be:
the relatively late manifestation of a developmental disorder,
an acquired lesion such as head trauma,
CNS infection (especially viral encephalitis), or
very rarely a CNS tumor.
علل تشنج در نوجوانی و اوایل بلوغ:
Adolescence and early adulthoodà The period of transition during which the idiopathic or genetically based epilepsy syndromes, including JME and juvenile absence epilepsy, become less common, while epilepsies secondary to acquired CNS lesions begin to predominate.
Seizures associated with:
head trauma,
CNS infections (including parasitic infections such as cysticercosis),
brain tumors,
congenital CNS abnormalities,
illicit drug use, or
Head trauma is a common cause of epilepsy in adolescents and adults.
Likelihood of developing epilepsy is strongly correlated with the severity of the injury.
A patient with a:
1-Penetrating head wound,
2-Depressed skull fracture,
3-Intracranial hemorrhage, or
4-Prolonged posttraumatic coma or amnesia
Has a 40 to 50% risk of developing epilepsy!!!
While a patient with a closed head injury and cerebral contusion has a 5 to 25% risk.
Recurrent seizures usually develop within 1 year after head trauma, although intervals of ≥10 years are well known.
In controlled studies, mild head injury, defined as a concussion with amnesia or loss of consciousness of <30 min, was found to be associated with only a slightly increased likelihood of epilepsy. Nonetheless, most epileptologists know of patients who have partial seizures within hours or days of a mild head injury and subsequently develop chronic seizures of the same type; such cases may represent rare examples of chronic epilepsy resulting from mild head injury.
علل تشنج در بالغین مسن:
The causes of seizures in older adults include:
cerebrovascular disease,
trauma (including subdural hematoma),
CNS tumors, and
degenerative diseases.
Cerebrovascular disease may account for ~50% of new cases of epilepsy in patients older than 65.
Acute seizures (i.e., occurring at the time of the stroke) are seen more often with embolic rather than hemorrhagic or thrombotic stroke.
Chronic seizures typically appear months to years after the initial event and are associated with all forms of stroke.
Metabolic disturbances such as electrolyte imbalance, hypo- or hyperglycemia, renal failure, and hepatic failure may cause seizures at any age.
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TABLE 348-5 Drugs and Other Substances That Can Cause Seizures | ||||||||
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BASIC MECHANISMS
MECHANISMS OF SEIZURE INITIATION AND PROPAGATION
Partial seizure activity can begin in a very discrete region of cortex and then spread to neighboring regions, i.e., there is a seizure initiation phase and a seizure propagation phase.
The initiation phase is characterized by two concurrent events in an aggregate of neurons:
(1) high-frequency bursts of action potentials, and
(2) hypersynchronization.
The bursting activity is caused by a relatively long-lasting depolarization of the neuronal membrane due to influx of extracellular calcium (Ca2+), which leads to the opening of voltage-dependent sodium (Na+) channels, influx of Na+, and generation of repetitive action potentials.
This is followed by a hyperpolarizing afterpotential mediated by γ-aminobutyric acid (GABA) receptors or potassium (K+) channels, depending on the cell type. The synchronized bursts from a sufficient number of neurons result in a so-called spike discharge on the EEG.
Normally, the spread of bursting activity is prevented by intact hyperpolarization and a region of surrounding inhibition created by inhibitory neurons. With sufficient activation there is a recruitment of surrounding neurons via a number of mechanisms.
Repetitive discharges lead to the following:
(1) an increase in extracellular K+, which blunts hyperpolarization and depolarizes neighboring neurons;
(2) accumulation of Ca2+ in presynaptic terminals, leading to enhanced neurotransmitter release; and
(3) depolarization-induced activation of the N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptor, which causes Ca2+ influx and neuronal activation.
The recruitment of a sufficient number of neurons leads to a loss of the surrounding inhibition and propagation of seizure activity into contiguous areas via local cortical connections, and to more distant areas via long commissural pathways such as the corpus callosum.
Certain recognized causes of seizures are explained by these mechanisms.
For example, accidental ingestion of domoic acid, which is an analogue of glutamate (the principal excitatory neurotransmitter in the brain), causes profound seizures via direct activation of excitatory amino acid receptors throughout the CNS.
Penicillin, which can lower the seizure threshold in humans and is a potent convulsant in experimental models, reduces inhibition by antagonizing the effects of GABA at its receptor.
Much more is understood about the origin of generalized spike-and-wave discharges in absence seizures. These appear to be related to oscillatory rhythms normally generated during sleep by circuits connecting the thalamus and cortex. This oscillatory behavior involves an interaction between GABAB receptors, T-type Ca2+ channels, and K+ channels located within the thalamus.
MECHANISMS OF EPILEPTOGENESIS
Epileptogenesis refers to the transformation of a normal neuronal network into one that is chronically hyperexcitable. There is often a delay of months to years between an initial CNS injury such as trauma, stroke, or infection and the first seizure.
Pathologic studies of the hippocampus from patients with temporal lobe epilepsy have led to the suggestion that some forms of epileptogenesis are related to structural changes in neuronal networks. Similar models have also provided strong evidence for long-term alterations in intrinsic, biochemical properties of cells within the network, such as chronic changes in glutamate receptor function.
GENETIC CAUSES OF EPILEPSY
The most important recent progress in epilepsy research has been the identification of genetic mutations associated with a variety of epilepsy syndromes.
MECHANISMS OF ACTION OF ANTIEPILEPTIC DRUGS
Antiepileptic drugs appear to act primarily by blocking the initiation or spread of seizures. The mechanisms include:
1-inhibition of Na+-dependent action potentials in a frequency-dependent manner (e.g., phenytoin, carbamazepine, lamotrigine, topiramate, zonisamide),
2-inhibition of voltage-gated Ca2+ channels (phenytoin),
3-decrease of glutamate release (lamotrigine),
4-potentiation of GABA receptor function (benzodiazepines and barbiturates), and
5-increase in the availability of GABA (valproic acid, gabapentin, tiagabine).
6-The two most effective drugs for absence seizures, ethosuximide and valproic acid, probably act by inhibiting T-type Ca2+ channels in thalamic neurons.
In contrast to the relatively large number of antiepileptic drugs that can attenuate seizure activity, there are currently no drugs known to prevent the formation of a seizure focus following CNS injury.
EVALUATION OF THE PATIENT WITH A SEIZURE
When a patient presents shortly after a seizure, the first priorities are attention to vital signs, respiratory and cardiovascular support, and treatment of seizures if they resume.
Life-threatening conditions such as CNS infection, metabolic derangement, or drug toxicity must be recognized and managed appropriately.
When the patient is not acutely ill, the evaluation will initially focus on whether there is a history of earlier seizures (Fig. 348-2).
If this is the first seizure, then the emphasis will be to:
(1) establish whether the reported episode was a seizure rather than another paroxysmal event,
(2) determine the cause of the seizure by identifying risk factors and precipitating events, and
(3) decide whether anticonvulsant therapy is required in addition to treatment for any underlying illness.
In the patient with prior seizures or a known history of epilepsy, the evaluation is directed toward:
(1) identification of the underlying cause and precipitating factors, and
(2) determination of the adequacy of the patient's current therapy.
HISTORY AND EXAMINATION
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.
Clues for a predisposition to seizures include a history of febrile seizures, earlier auras or brief seizures not recognized as such, and a family history of seizures. Epileptogenic factors such as prior head trauma, stroke, tumor, or vascular malformation should be identified. In children, a careful assessment of developmental milestones may provide evidence for underlying CNS disease. Precipitating factors such as sleep deprivation, systemic diseases, electrolyte or metabolic derangements, acute infection, drugs that lower the seizure threshold (Table 348-5), or alcohol or illicit drug use should also be identified.
The general physical examination includes a search for signs of infection or systemic illness. Careful examination of the skin may reveal signs of neurocutaneous disorders, such as tuberous sclerosis or neurofibromatosis, or chronic liver or renal disease. A finding of organomegaly may indicate a metabolic storage disease, and limb asymmetry may provide a clue to brain injury early in development. Signs of head trauma and use of alcohol or illicit drugs should be sought. Auscultation of the heart and carotid arteries may identify an abnormality that predisposes to cerebrovascular disease.
All patients require a complete neurologic examination, with particular emphasis on eliciting signs of cerebral hemispheric disease.
Careful assessment of mental status (including memory, language function, and abstract thinking) may suggest lesions in the anterior frontal, parietal, or temporal lobes.
Testing of visual fields will help screen for lesions in the optic pathways and occipital lobes.
Screening tests of motor function such as pronator drift, deep tendon reflexes, gait, and coordination may suggest lesions in motor (frontal) cortex, and
cortical sensory testing (e.g., double simultaneous stimulation) may detect lesions in the parietal cortex.
LABORATORY STUDIES
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 is mandatory in all patients infected with HIV, even in the absence of symptoms or signs suggesting infection.
Electroencephalography (EEG)
All patients who have a possible seizure disorder should be evaluated with an EEG as soon as possible. The EEG measures electrical activity of the brain by recording from electrodes placed on the scalp. The potential difference between pairs of electrodes is amplified and displayed on a computer monitor, oscilloscope, or paper. The characteristics of the normal EEG depend on the patient's age and level of arousal.
فعالیت ثبت شده، نشاندهنده پتانسیلهای پس سیناپسی سلولهای پیرامیدال است که به صورت عمودی در کورتکس مغز قرار گرفته اند و توسط فرکانس شان مشخص می شوند.
The recorded activity represents the postsynaptic potentials of vertically oriented pyramidal cells in the cerebral cortex and is characterized by its frequency.
In normal awake adults lying quietly with the eyes closed, an 8- to 13-Hz alpha rhythm is seen posteriorly in the EEG, intermixed with a variable amount of generalized faster beta activity (>13 Hz), and it is attenuated when the eyes are opened (Fig. 348-3).
During drowsiness, the alpha rhythm is also attenuated;
کاهش آلفا: باز کردن چشمها- خواب آلودگی
with light sleep, slower activity in the theta (4 to 7 Hz) and delta (<4 Hz) ranges becomes more apparent.
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FIGURE 348-3A. A normal EEG showing a posteriorly situated 9-Hz alpha rhythm that attenuates with eye opening. B. Onset of a tonic seizure showing generalized repetitive sharp activity with synchronous onset over both hemispheres. C. Burst of repetitive spikes in the right temporal region during a clinical spell suggestive of a complex partial seizure. D. Generalized 3-Hz spike-wave activity occurring synchronously over both hemispheres during an absence seizure. Horizontal calibration: 1s; vertical calibration: 200 µV in A and C, 400 µV in B, and 750 µV in D. Electrode placements are indicated at the left of each panel in accord with the international
The EEG is best recorded from several different electrode arrangements (montages) in turn, and activating procedures are usually performed in an attempt to provoke abnormalities. Such procedures commonly include hyperventilation (for 3 or 4 min), photic stimulation, sleep, and sleep deprivation on the night prior to the recording.
In the evaluation of a patient with suspected epilepsy, the presence of electrographic seizure activity during the clinically evident event, i.e., of abnormal, repetitive, rhythmic activity having an abrupt onset and termination, clearly establishes the diagnosis.
The absence of electrographic seizure activity does not exclude a seizure disorder, however, because simple or complex seizures may originate from a region of cortex that is not within range of the 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 h in ambulatory patients has made it easier to capture the electrophysiologic accompaniments of clinical events.
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 partial 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.
تصویربرداری مغز:
Brain Imaging
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 computed tomography (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 fluid-attenuated inversion recovery (FLAIR), has increased the sensitivity for detection of abnormalities of cortical architecture, including hippocampal atrophy associated with mesial temporal sclerosis, and 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.
در بیمار مشکوک به عفونت CNS یا توده ، هنگامی که MRI فوری در دسترس نباشد، CT اورژانس باید انجام شود.
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.
Functional imaging procedures such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) are also used to evaluate certain patients with medically refractory seizures.
تشخیصهای افتراقی تشنج:
DIFFERENTIAL DIAGNOSIS OF SEIZURES
Disorders that may mimic seizures are listed in Table 348-6. In most cases seizures can be distingished from other conditions by meticulous attention to the history and relevant laboratory studies. On occasion, additional studies, such as video-EEG monitoring, sleep studies, tilt table analysis, or cardiac electrophysiology, may be required to reach a correct diagnosis. Two of the more common nonepileptic syndromes in the differential diagnosis are detailed below.
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TABLE 348-6 Differential Diagnosis of Seizures | ||||||
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سنکوپ:
Syncope
The diagnostic dilemma encountered most frequently is the distinction between a generalized seizure and syncope. Observations by the patient and bystanders that can help discriminate between the two are listed in Table 348-7.
Characteristics of a seizure include the presence of an aura, cyanosis, unconsciousness, motor manifestations lasting >30 s, 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 to 10 s) 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.
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TABLE 348-7 Features That Distinguish Generalized Tonic-Clonic Seizure from Syncope | |||||||||||||||||||||||||||||||||||||||||||||||||||
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تشنجهای سایکوژنیک:
Psychogenic 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 complex partial seizures, since the behavioral manifestations of complex partial 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 often useful when historic features are nondiagnostic.
Generalized tonic-clonic seizures always produce marked EEG abnormalities during and after the seizure. For suspected complex partial 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 discriminate between organic and psychogenic seizures, since most generalized seizures and many complex partial seizures are accompanied by rises in serum prolactin (during the immediate 30-min 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.
Therapy for a patient with a seizure disorder is almost always multimodal and includes treatment of underlying conditions that cause or contribute to the seizures, avoidance of precipitating factors, suppression of recurrent seizures by prophylactic therapy with antiepileptic medications or surgery, and addressing a variety of psychological and social issues. Treatment plans must be individualized, given the many different types and causes of seizures as well as the differences in efficacy and toxicity of antiepileptic medications for each patient. In almost all cases a neurologist with experience in the treatment of epilepsy should design and oversee implementation of the treatment strategy. Furthermore, patients with refractory epilepsy or those who require polypharmacy with antiepileptic drugs should remain under the regular care of a neurologist.
درمان بیماریهای زمینه ای:
Treatment of Underlying Conditions
If the sole cause of a seizure is a metabolic disturbance such as an abnormality of serum electrolytes or glucose, then treatment is aimed at reversing the metabolic problem and preventing its recurrence. Therapy with antiepileptic drugs is usually unnecessary unless the metabolic disorder cannot be corrected promptly and the patient is at risk of having further seizures.
If the apparent cause of a seizure was a medication (e.g., theophylline) or illicit drug use (e.g., cocaine), then appropriate therapy is avoidance of the drug; there is usually no need for antiepileptic medications unless subsequent seizures occur in the absence of these precipitants.
Seizures caused by a structural CNS lesion such as a brain tumor, vascular malformation, or brain abscess may not recur after appropriate treatment of the underlying lesion. However, despite removal of the structural lesion, there is a risk that the seizure focus will remain in the surrounding tissue or develop de novo as a result of gliosis and other processes induced by surgery, radiation, or other therapies. Most patients are therefore maintained on an antiepileptic medication for at least 1 year, and an attempt is made to withdraw medications only if the patient has been completely seizure-free. If seizures are refractory to medication, the patient may benefit from surgical removal of the epileptic brain region.
پرهیز از عوامل تسریع کننده:
Avoidance of Precipitating Factors
Unfortunately, little is known about the specific factors that determine precisely when a seizure will occur in a patient with epilepsy. Some patients can identify particular situations that appear to lower their seizure threshold; these situations should be avoided. For example, a patient who has seizures in the setting of sleep deprivation should obviously be advised to maintain a normal sleep schedule. Many patients note an association between alcohol intake and seizures, and they should be encouraged to modify their drinking habits accordingly. There are also relatively rare cases of patients with seizures that are induced by highly specific stimuli such as a video game monitor, music, or an individual's voice (“reflex epilepsy”). If there is an association between stress and seizures, stress reduction techniques such as physical exercise, meditation, or counseling may be helpful.
درمان با داروهای ضدصرع:
Antiepileptic Drug Therapy
Antiepileptic drug therapy is the mainstay of treatment for most patients with epilepsy.
The overall goal is to completely prevent seizures without causing any untoward side effects, preferably with a single medication and a dosing schedule that is easy for the patient to follow.
Seizure classification is an important element in designing the treatment plan, since some antiepileptic drugs have different activities against various seizure types. However, there is considerable overlap between many antiepileptic drugs, such that the choice of therapy is often determined more by specific needs of the patient, especially the patient's assessment of side effects.
چه زمانی باید داروی ضد صرع را شروع کرد:
WHEN TO INITIATE ANTIEPILEPTIC DRUG THERAPY
Antiepileptic drug therapy should be started in any patient with recurrent seizures of unknown etiology or a known cause that cannot be reversed.
Whether to initiate therapy in a patient with a single seizure is controversial.
Patients with a single seizure due to an identified lesion such as a CNS tumor, infection, or trauma, in which there is strong evidence that the lesion is epileptogenic, should be treated. The risk of seizure recurrence in a patient with an apparently unprovoked or idiopathic seizure is uncertain, with estimates ranging from 31 to 71% in the first 12 months after the initial seizure. This uncertainty arises from differences in the underlying seizure types and etiologies in various published epidemiologic studies.
ریسک فاکتورهای زیر با تشنجهای راجعه مرتبط بوده وبیمارانی که حداقل یکی از این موارد را داشته باشند، باید درمان شوند:
Generally accepted risk factors associated with recurrent seizures include the following:
(1) an abnormal neurologic examination,
(2) seizures presenting as status epilepticus,
(3) postictal Todd's paralysis,
(4) a strong family history of seizures, or
(5) an abnormal EEG.
Most patients with one or more of these risk factors should be treated.
Issues such as employment or driving may influence the decision whether or not to start medications as well. For example, a patient with a single, idiopathic seizure whose job depends on driving may prefer taking antiepileptic drugs rather than risk a seizure recurrence and the potential loss of driving privileges.
انتخاب داروی ضد صرع:
SELECTION OF ANTIEPILEPTIC DRUGS
Antiepileptic drugs available in the United States are shown in Table 348-8, and the main pharmacologic characteristics of commonly used drugs are listed in Table 348-9. Older medications such as phenytoin, valproic acid, carbamazepine, and ethosuximide are generally used as first-line therapy for most seizure disorders since, overall, they are as effective as recently marketed drugs and significantly less expensive. Most of the new drugs that have become available in the past decade are used as add-on or alternative therapy.
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TABLE 348-8 Selection of Antiepileptic Drugs | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TABLE 348-9 Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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In addition to efficacy, factors influencing the choice of an initial medication include the convenience of dosing (e.g., once daily versus three or four times daily) and potential side effects.
Almost all of the commonly used antiepileptic drugs can cause similar, dose-related side effects such as sedation, ataxia, and diplopia.
Close follow-up is required to ensure these are promptly recognized and reversed. Most of the drugs can also cause idiosyncratic toxicity such as rash, bone marrow suppression, or hepatotoxicity. Although rare, these side effects should be considered during drug selection, and patients require laboratory tests (e.g., complete blood count and liver function tests) prior to the institution of a drug (to establish baseline values) and during initial dosing and titration of the agent.
انتخاب داروی ضد صرع در تشنجهای پارشیال:
Antiepileptic Drug Selection for Partial Seizures
Carbamazepine, phenytoin, or lamotrigine is currently the initial drug of choice for the treatment of partial seizures, including those that secondarily generalize. Overall they have very similar efficacy, but differences in pharmacokinetics and toxicity are the main determinants for use in a given patient.
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 carbamazepine (although a more expensive, extended-release form of carbamazepine is now available) and lamotrigine.
An advantage of carbamazepine is that its metabolism follows first-order pharmacokinetics, and the relationship between drug dose, serum levels, and toxicity is linear.
By contrast, 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.
Carbamazepine can cause leukopenia, aplastic anemia, or hepatotoxicity and would therefore be contraindicated in patients with predispositions to these problems.
A major concern with lamotrigine is the occurrence of 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 can inhibit its metabolism, thereby substantially prolonging its half-life.
Valproic acid is an effective alternative for some patients with partial seizures, especially when the seizures secondarily generalize.
Gastrointestinal side effects are fewer when using the valproate semisodium formulation (Depakote). Valproic acid also rarely causes reversible bone marrow suppression and hepatotoxicity, and laboratory testing is required to monitor toxicity. This drug should generally be avoided in patients with preexisting bone marrow or liver disease. Irreversible, fatal hepatic failure appearing as an idiosyncratic rather than dose-related side effect is a relatively rare complication; its risk is highest in children <2 years old, especially those taking other antiepileptic drugs or with inborn errors of metabolism.
Topiramate, tiagabine, levetiracetam, zonisamide, gabapentin, and oxcarbazepine are additional drugs currently used for the treatment of partial seizures with or without secondary generalization. Until recently, phenobarbital and other barbiturate compounds were commonly used as first-line therapy for many forms of epilepsy. However, the barbiturates frequently cause sedation in adults, hyperactivity in children, and other more subtle cognitive changes; thus, their use should be limited to situations in which no other suitable treatment alternatives exist.
انتخاب داروی ضد صرع در تشنجهای ژنرالیزه:
Antiepileptic Drug Selection for Generalized Seizures
Valproic acid is currently considered the best initial choice for the treatment of primarily generalized, tonic-clonic seizures.
Lamotrigine, followed by carbamazepine and phenytoin, are suitable alternatives.
Valproic acid is also particularly effective in absence, myoclonic, and atonic seizures and is therefore the drug of choice in patients with generalized epilepsy syndromes having mixed seizure types.
Importantly, both carbamazepine and phenytoin can worsen certain types of generalized seizures, including absence, myoclonic, tonic, and atonic seizures.
Ethosuximide is a particularly effective drug for the treatment of uncomplicated absence seizures, but it is not useful for tonic-clonic or partial seizures. Ethosuximide rarely causes bone marrow suppression, so that periodic monitoring of blood cell counts is required.
Although approved for use in partial seizure disorders, lamotrigine appears to be effective in epilepsy syndromes with mixed, generalized seizure types such as JME and Lennox-Gastaut syndrome. Topiramate, zonisamide, and felbamate may have similar broad efficacy.
Clinical trials are underway to establish the usefulness of levetiracetam in generalized seizure syndromes.
شروع و پایش درمان:
INITIATION AND MONITORING OF THERAPY
determination of the optimal dose is often a matter of trial and error. This process may take months or longer if the baseline seizure frequency is low.
Most anticonvulsant drugs need to be introduced relatively slowly to minimize side effects, and patients should expect that minor side effects such as mild sedation, slight changes in cognition, or imbalance will typically resolve within a few days.
Starting doses are usually the lowest value listed under the dosage column in Table 348-9. Subsequent increases should be made only after achieving a steady state with the previous dose (i.e., after an interval of five or more half-lives).
Monitoring of serum antiepileptic drug levels can be very useful for establishing the initial dosing schedule. Conventional assays of serum drug levels measure the total drug (i.e., both free and protein-bound). However, it is the concentration of free drug that reflects extracellular levels in the brain and correlates best with efficacy.
Thus, patients with decreased levels of serum proteins (e.g., decreased serum albumin due to impaired liver or renal function) may have an increased ratio of free to bound drug, yet the concentration of free drug may be adequate for seizure control. These patients may have a “subtherapeutic” drug level, but the dose should be changed only if seizures remain uncontrolled, not just to achieve a “therapeutic” level. It is also useful to monitor free drug levels in such patients. In practice, other than during the initiation or modification of therapy, monitoring of antiepileptic drug levels is most useful for documenting compliance.
If seizures continue despite gradual increases to the maximum tolerated dose and documented compliance, then it becomes necessary to switch to another antiepileptic drug. This is usually done by maintaining the patient on the first drug while a second drug is added. The dose of the second drug should be adjusted to decrease seizure frequency without causing toxicity. Once this is achieved, the first drug can be gradually withdrawn (usually over weeks unless there is significant toxicity). The dose of the second drug is then further optimized based on seizure response and side effects. Monotherapy should be the goal whenever possible.
چه زمانی می توان درمان را قطع کرد:
WHEN TO DISCONTINUE THERAPY
Overall, about 70% of children and 60% of adults who have their seizures completely controlled with antiepileptic drugs can eventually discontinue therapy.
The following patient profile yields the greatest chance of remaining seizure-free after drug withdrawal:
(1) complete medical control of seizures for 1 to 5 years;
(2) single seizure type, either partial or generalized;
(3) normal neurologic examination, including intelligence; and
(4) normal EEG.
The appropriate seizure-free interval is unknown and undoubtedly varies for different forms of epilepsy. However, it seems reasonable to attempt withdrawal of therapy after 2 years in a patient who meets all of the above criteria, is motivated to discontinue the medication, and clearly understands the potential risks and benefits. In most cases it is preferable to reduce the dose of the drug gradually over 2 to 3 months.
Most recurrences occur in the first 3 months after discontinuing therapy, and patients should be advised to avoid potentially dangerous situations such as driving or swimming during this period.
درمان صرع مقاوم:
TREATMENT OF REFRACTORY EPILEPSY
Approximately one-third of patients with epilepsy do not respond to treatment with a single antiepileptic drug, and it becomes necessary to try a combination of drugs to control seizures.
Patients who have focal epilepsy related to an underlying structural lesion or those with multiple seizure types and developmental delay are particularly likely to require multiple drugs.
There are currently no clear guidelines for rational polypharmacy, although in theory a combination of drugs with different mechanisms of action may be most useful.
In most cases the initial combination therapy combines first-line drugs, i.e., carbamazepine, phenytoin, valproic acid, and lamotrigine.
If these drugs are unsuccessful, then the addition of a newer drug such as topiramate or levetiracetam is indicated.
Patients with myoclonic seizures resistant to valproic acid à may benefit from the addition of clonazepam, and
those with absence seizures à may respond to a combination of valproic acid and ethosuximide.
The same principles concerning the monitoring of therapeutic response, toxicity, and serum levels for monotherapy apply to polypharmacy, and potential drug interactions need to be recognized. If there is no improvement, a third drug can be added while the first two are maintained.
If there is a response, the less effective or less well-tolerated of the first two drugs should be gradually withdrawn.
درمان جراحی صرع مقاوم:
Surgical Treatment of Refractory Epilepsy
Approximately 20% of patients with epilepsy are resistant to medical therapy despite efforts to find an effective combination of antiepileptic drugs.
For some, surgery can be extremely effective in substantially reducing seizure frequency and even providing complete seizure control. Understanding the potential value of surgery is especially important when, at the time of diagnosis, a patient has an epilepsy syndrome that is considered likely to be drug-resistant. Rather than submitting the patient to years of unsuccessful medical therapy and the psychosocial trauma and increased mortality associated with ongoing seizures, the patient should have an efficient but relatively brief attempt at medical therapy and then be referred for surgical evaluation.
The most common surgical procedure for patients with temporal lobe epilepsy involves resection of the anteromedial temporal lobe (temporal lobectomy) or a more limited removal of the underlying hippocampus and amygdala (amygdalohippocampectomy).
Focal seizures arising from extratemporal regions may be abolished by a focal neocortical resection with precise removal of an identified lesion (lesionectomy).
When the cortical region cannot be removed, multiple subpial transection, which disrupts intracortical connections, is sometimes used to prevent seizure spread.
Hemispherectomy or multilobar resection is useful for some patients with severe seizures due to hemispheric abnormalities such as hemimegaloencephaly or other dysplastic abnormalities, and
corpus callosotomy has been shown to be effective for disabling tonic or atonic seizures, usually when they are part of a mixed-seizure syndrome (e.g., Lennox-Gastaut syndrome).
Presurgical evaluation is designed to identify the functional and structural basis of the patient's seizure disorder. Inpatient video-EEG monitoring is used to define the anatomic location of the seizure focus and to correlate the abnormal electrophysiologic activity with behavioral manifestations of the seizure. Routine scalp or scalp-sphenoidal recordings are usually sufficient for localization, and advances in neuroimaging have made the use of invasive electrophysiologic monitoring such as implanted depth electrodes or subdural electrodes less common. A high-resolution MRI scan is routinely used to identify structural lesions. Functional imaging studies such as SPECT and PET are adjunctive tests that may help verify the localization of an apparent epileptogenic region. Once the presumed location of the seizure onset is identified, additional studies, including neuropsychological testing and the intracarotid amobarbital test (Wada test) may be used to assess language and memory localization and to determine the possible functional consequences of surgical removal of the epileptogenic region. In some cases, the exact extent of the resection to be undertaken is determined by performing cortical mapping at the time of the surgical procedure, allowing for a tailored resection. This involves electrocorticographic recordings made with electrodes on the surface of the brain to identify the extent of epileptiform disturbances. If the region to be resected is within or near brain regions suspected of having sensorimotor or language function, electrical cortical stimulation mapping is performed in the awake patient to determine the function of cortical regions in question in order to avoid resection of so-called eloquent cortex, and thereby minimize postsurgical deficits.
Advances in presurgical evaluation and microsurgical techniques have led to a steady increase in the success of epilepsy surgery. Clinically significant complications of surgery are <5%, and the use of functional mapping procedures has markedly reduced the neurologic sequelae due to removal or sectioning of brain tissue.
For example, about 70% of patients treated with temporal lobectomy will become seizure-free, and another 15 to 25% will have at least a 90% reduction in seizure frequency. Marked improvement is also usually seen in patients treated with hemispherectomy for catastrophic seizure disorders due to large hemispheric abnormalities.
Postoperatively, patients generally need to remain on antiepileptic drug therapy, but the marked reduction of seizures following surgery can have a very beneficial effect on quality of life.
Vagus Nerve Stimulation (VNS)
VNS is a new treatment option for patients with medically refractory epilepsy who are not candidates for resective brain surgery.
The procedure involves placement of a bipolar electrode on the midcervical portion of the left vagus nerve. The electrode is connected to a small, subcutaneous generator located in the infraclavicular region, and the generator is programmed to deliver intermittent electrical pulses to the vagus nerve.
Unlike medications, there may be a delay between the initiation of VNS and the appearance of antiseizure effects. 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.
In practice, the efficacy of VNS appears to be no greater than recently introduced anticonvulsant medications. Adverse effects of the surgery are rare, and stimulation-induced side effects, including transient hoarseness, cough, and dyspnea, are usually mild and well tolerated.
صرع پایدار:
STATUS EPILEPTICUS
Status epilepticus refers to continuous seizures or repetitive, discrete seizures with impaired consciousness in the interictal period.
The duration of seizure activity sufficient to meet the definition of status epilepticus has traditionally been specified as 15 to 30 min.
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, typically when seizures last beyond 5 min.
Status epilepticus is an emergency and must be treated immediately, since cardiorespiratory dysfunction, hyperthermia, and metabolic derangements can develop as a consequence of prolonged seizures, and these can lead to irreversible neuronal injury.
Furthermore, CNS injury can occur even when the patient is paralyzed with neuromuscular blockade but continues to have electrographic seizures.
The most common causes of status epilepticus are:
1-anticonvulsant withdrawal or
2-noncompliance,
3-metabolic disturbances,
4-drug toxicity,
5-CNS infection,
6-CNS tumors,
7-refractory epilepsy, and
8-head trauma.
Generalized status epilepticus is obvious when the patient is having overt convulsions.
However, after 30 to 45 min of uninterrupted seizures, the signs may become increasingly subtle. Patients may have mild clonic movements of only the fingers, or fine, rapid movements of the eyes. There may be paroxysmal episodes of tachycardia, hypertension, and pupillary dilation. In such cases, the EEG may be the only method of establishing the diagnosis.
Thus, if the patient stops having overt seizures, yet remains comatose, an EEG should be performed to rule out ongoing status epilepticus.
The first step in the management of a patient in status epilepticus is 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 delay;
A treatment approach is shown in Fig. 348-4.
FIGURE 348-4 Pharmacologic treatment of generalized tonic-clonic status epilepticus in adults. IV, intravenous; PE, phenytoin equivalents. The horizontal bars indicate the approximate duration of drug infusions.
BEYOND SEIZURES: OTHER MANAGEMENT ISSUES
Interictal Behavior
Many patients with epilepsy are completely normal between seizures and able to live highly successful and productive lives.
In contrast, patients with seizures secondary to developmental abnormalities or acquired brain injury may have impaired cognitive function and other neurologic deficits.
Frequent interictal EEG abnormalities have been shown to be associated with subtle dysfunction of memory and attention.
Patients with many seizures, especially those emanating from the temporal lobe, often note an impairment of short-term memory that may progress over time.
Patients with epilepsy are at risk of developing a variety of psychiatric problems including depression, anxiety, and psychosis. This risk varies considerably depending on many factors, including the etiology, frequency, and severity of seizures and the patient's age and previous history.
افسردگی:
Depression occurs in ~20% of patients, and the incidence of suicide is higher in epileptic patients than in the general population. Depression should be treated through counseling or medication.
The selective serotonin reuptake inhibitors àtypically have no effect on seizures,
while the tricyclic antidepressantsà may lower the seizure threshold.
Anxiety can appear as a manifestation of a seizure, and anxious or psychotic behavior can sometimes be observed as part of a postictal delirium.
سایکوز پست ایکتال:
Postictal psychosis is a rare phenomenon that typically occurs after a period of increased seizure frequency. There is usually a brief lucid interval lasting up to a week, followed by days to weeks of agitated, psychotic behavior. The psychosis will usually resolve spontaneously but may require treatment with antipsychotic or anxiolytic medications.
There is ongoing controversy as to whether some patients with epilepsy (especially temporal lobe epilepsy) have a stereotypical “interictal personality.” The predominant view is that the unusual or abnormal personality traits observed in such patients are, in most cases, not due to epilepsy but result from an underlying structural brain lesion, the effects of antiepileptic drugs, or psychosocial factors related to suffering from a chronic disease.
مورتالیته صرع:
Mortality of Epilepsy
Patients with epilepsy have a risk of death that is roughly 2 to 3 times greater than expected in a matched population without epilepsy.
Most of the increased mortality is due to the underlying etiology of epilepsy, e.g., tumors or strokes in older adults.
However, a significant number of patients die from accidents, status epilepticus, and a syndrome known as sudden unexpected death in epileptic patients (SUDEP), which usually affects young people with convulsive seizures and tends to occur at night.
The cause of SUDEP is unknown; it may result from brainstem-mediated effects of seizures on cardiac rhythms or pulmonary function.
Psychosocial Issues
There continues to be a cultural stigma about epilepsy, although it is slowly declining in societies with effective health education programs. Many patients with epilepsy harbor fears, such as the fear of becoming mentally retarded or dying during a seizure.
Employment and Driving
In general, most states allow patients to drive after a seizure-free interval (on or off medications) between 3 months and 2 years.
SPECIAL ISSUES RELATED TO WOMEN AND EPILEPSY
صرع قاعدگی:
Catamenial Epilepsy
Some women experience a marked increase in seizure frequency around the time of menses.
This is thought to reflect either:
The effects of estrogen and progesterone on neuronal excitability or
changes in antiepileptic drug levels due to altered protein binding.
Acetazolamide (250 to 500 mg/d) may be effective as adjunctive therapy in some cases when started 7 to 10 days prior to the onset of menses and continued until bleeding stops.
Some patients may benefit from increases in antiepileptic drug dosages during this time or from control of the menstrual cycle through the use of oral contraceptives.
Natural progestins may be of benefit to a subset of women.
حاملگی:
Pregnancy
Most women with epilepsy who become pregnant will have an uncomplicated gestation and deliver a normal baby. However, epilepsy poses some important risks to a pregnancy.
Seizure frequency during pregnancy will remain
unchanged in ~50% of women,
increase in 30%, and
decrease in 20%.
Changes in seizure frequency are attributed to endocrine effects on the CNS, variations in antiepileptic drug pharmacokinetics (such as acceleration of hepatic drug metabolism or effects on plasma protein binding), and changes in medication compliance. It is useful to see patients at frequent intervals during pregnancy and monitor serum antiepileptic drug levels. Measurement of the unbound drug concentrations may be useful if there is an increase in seizure frequency or worsening of side effects of antiepileptic drugs.
The overall incidence of fetal abnormalities in children born to mothers with epilepsy is 5 to 6%, compared to 2 to 3% in healthy women.
Part of the higher incidence is due to teratogenic effects of antiepileptic drugs, and the risk increases with the number of medications used (e.g., 10% risk of malformations with three drugs).
A syndrome comprising facial dysmorphism, cleft lip, cleft palate, cardiac defects, digital hypoplasia, and nail dysplasia was originally ascribed to phenytoin therapy, but it is now known to occur with other first-line antiepileptic drugs (i.e., valproic acid and carbamazepine) as well.
Also, valproic acid and carbamazepine are associated with a 1 to 2% incidence of neural tube defects compared with a baseline of 0.5 to 1%. Little is currently known about the safety of newer drugs.
Since the potential harm of uncontrolled seizures on the mother and fetus is considered greater than the teratogenic effects of antiepileptic drugs, it is currently recommended that pregnant women be maintained on effective drug therapy.
When possible, it seems prudent to have the patient on monotherapy at the lowest effective dose, especially during the first trimester.
Patients should also take folate (1 to 4 mg/d), since the antifolate effects of anticonvulsants are thought to play a role in the development of neural tube defects, although the benefits of this treatment remain unproved in this setting.
فنی توئین، فنوباربیتال و پریمیدون --› کمبود موقتی و قابل برگشت فاکتورهای انعقادی وابسته به ویتامین K در 50% نوزادان--› درمان با ویتامینK خوراکی برای مادر در 2 هفته آخر حاملگی(20میلی روزانه) + 1 میلیگرم ویتامین K هنگام تولد به نوزاد
Enzyme-inducing drugs such as phenytoin, phenobarbital, and primidone cause a transient and reversible deficiency of vitamin K–dependent clotting factors in ~50% of newborn infants. Although neonatal hemorrhage is uncommon, the mother should be treated with oral vitamin K (20 mg daily) in the last 2 weeks of pregnancy, and the infant should receive vitamin K (1 mg) at birth.
جلوگیری از بارداری:
Contraception
Special care should be taken when prescribing antiepileptic medications for women who are taking oral contraceptive agents.
Drugs such as carbamazepine, phenytoin, phenobarbital, and topiramate can significantly antagonize the effects of oral contraceptives via enzyme induction and other mechanisms.
Patients should be advised to consider alternative forms of contraception, or their contraceptive medications should be modified to offset the effects of the antiepileptic medications.
شیردهی:
Breast Feeding
Antiepileptic medications are excreted into breast milk to a variable degree.
The ratio of drug concentration in breast milk relative to serum is
~80% for ethosuximide,
40 to 60% for phenobarbital,
40% for carbamazepine,
15% for phenytoin, and
5% for valproic acid.
Given the overall benefits of breast feeding and the lack of evidence for long-term harm to the infant by being exposed to antiepileptic drugs, mothers with epilepsy can be encouraged to breast feed. This should be reconsidered, however, if there is any evidence of drug effects on the infant, such as lethargy or poor feeding.
