Aseizureتشنج :(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 hasrecurrentseizures 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
TABLE 348-1 Classification of Seizures
a. Simple partial seizures (with motor, sensory, autonomic, or psychic signs)
b. Complex partial seizures
c. Partial seizures with secondary generalization
2.Primarily generalized seizures
a. Absence (petit mal)
b. Tonic-clonic (grand mal)
a. Neonatal seizures
b. Infantile spasms
Partial seizuresà seizure activity is restricted to discrete areas of the cerebral cortex. Associated with structural abnormalities of the brain.
Generalized seizuresàdiffuse regions of the brain simultaneously. Result from cellular, biochemical, or structural abnormalities that have a more widespread distribution
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 Jackson and known as a “Jacksonian march,” represents the spread of seizure activity over a progressively larger region of motor cortex.
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 cortexà 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.
generalized seizures may be practically defined as bilateral clinical and electrographic eventswithout 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 ) or early adolescence and are the main seizure type in 15 to 20% of children with epilepsy.
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 epilepsyàunexplained “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 burstsof 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 abruptin 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 frommetabolic derangements.
The seizure usually begins abruptlywithout warning.
This prodrome is distinct from the stereotypic auras associated with focal seizures that secondarily generalize.
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.
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.
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.
2-pure clonic seizures.
3-Brief tonic seizures lasting only a few seconds are associated Lennox-Gastaut syndrome.
characterized by suddenloss 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.
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 movementobserved 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.
Epilepsy is a predominant feature, and there is sufficient evidence to suggest a common underlying mechanism.
TABLE 348-2 Examples of Genes Associated with Epilepsy Syndromesa
Function of Gene
Nicotinic acetylcholine receptor subunit; mutations cause alterations in Ca2+ flux through the receptor; this may reduce amount of GABA release in presynaptic terminals
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE); childhood onset; brief, nighttime seizures with prominent motor movements; often misdiagnosed as primary sleep disorder
Rare; first identified in a large Australian family; other families found to have mutations in CHRNA2 or CHRNB2, and some families appear to have mutations at other loci
Voltage-gated potassium channel subunits; mutation in pore regions may cause a 20–40% reduction of potassium currents, which will lead to impaired repolarization
Benign familial neonatal convulsions (BFNC); autosomal dominant inheritance; onset in 1st week of life in infants who are otherwise normal; remission usually within weeks to months; long-term epilepsy in 10–15%
Rare; sequence and functional homology to KCNQ1, mutations of which cause long QT syndrome and a cardiac-auditory syndrome
β-subunit of a voltage-gated sodium channel; mutation disrupts disulfide bridge that is crucial for structure of extracellular domain; mutated β-subunit leads to slower sodium channel inactivation
Generalized epilepsy with febrile seizures plus (GEFS+); autosomal dominant inheritance; presents with febrile seizures at median 1 year, which may persist >6 years, then variable seizure types not associated with fever
Incidence uncertain; GEFS+ identified in other families with mutations in other sodium channel subunits (SCN1A and SCN2A) and GABAA receptor subunit (GABRG2); significant phenotypic heterogeneity within same family, including members with febrile seizures only
Leucine-rich glioma-inactivated gene; previous evidence for role in glial tumor progression; likely to be involved in nervous system development
Autosomal dominant partial epilepsy with auditory features (ADPEAF); temporal lobe epilepsy with wide range of auditory and other sensory symptoms as major manifestation; age of onset usually between 10 and 25 years
Rare; at least one family with similar syndrome has mutation(s) elsewhere; LGI1 mutation is the only known mutation identified in temporal lobe epilepsy and the only non-ion-channel gene mutation known in idiopathic epilepsy
Cystatin B, a noncaspase cysteine protease inhibitor; normal protein may block neuronal apoptosis by inhibiting caspases directly or indirectly (via cathepsins), or controlling proteolysis
Progressive myoclonus epilepsy (PME) (Unverricht-Lundborg disease); autosomal recessive inheritance; age of onset between 6–15 years, myoclonic seizures, ataxia, and progressive cognitive decline; brain shows neuronal degeneration
Overall rare, but relatively common in Finland and Western Mediterranean (>1 in 20,000); precise role of cystatin B in human disease unknown, although mice with null mutations of cystatin B have similar syndrome
Laforin, a protein tyrosine phosphatase (PTP); may influence glycogen metabolism, which is known to be regulated by phosphatases
Progressive myoclonus epilepsy (Lafora's disease); autosomal recessive inheritance; onset age 6–19 years, death within 10 years; brain degeneration associated with polyglucosan intracellular inclusion bodies in numerous organs
Most common PME in Southern Europe, Middle East, Northern Africa, and Indian subcontinent; genetic heterogeneity; unknown whether seizure phenotype due to degeneration or direct effects of abnormal laforin expression.
Doublecortin, expressed primarily in frontal lobes; function unknown; potentially an intracellular signalling molecule
Classic lissencephaly associated with severe mental retardation and seizures in males; subcortical band heterotopia with more subtle findings in females (presumably due to random X-inactivation); X-linked dominant
Relatively rare but of uncertain incidence, recent increased ascertainment due to improved imaging techniques; relationship between migration defect and seizure phenotype unknown
a The first four syndromes listed in the table (ADNFLE, BFNC, GEFS+, and ADPEAF) are examples of idiopathic generalized epilepsies associated with identified gene mutations. The last three syndromes are examples of the numerous Mendelian disorders in which seizures are one part of the phenotype.
Note: GABA, γ-aminobutyric acid.
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 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.
TABLE 348-3 Characteristics of the Mesial Temporal Lobe Epilepsy Syndrome
History of febrile seizures
Family history of epilepsy
Rare secondarily generalized seizures
Seizures may remit and reappear
Seizures often intractable
Postictal disorientation, memory loss, dysphasia (with focus in dominant hemisphere)
Unilateral or bilateral anterior temporal spikes on EEG
Hypometabolism on interictal PET
Hypoperfusion on interictal SPECT
Material-specific memory deficits on intracranial amobarbital (Wada) test
Small hippocampus with increased signal on T2-weighted sequences
Small temporal lobe
Enlarged temporal horn
Highly selective loss of specific cell populations within hippocampus in most cases
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 factorsthat 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 orprecipitating factorsthat 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:
congenital CNS abnormalities, and
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.
Alzheimer's disease and other degenerative CNS diseases
Note: CNS, central nervous system.
علل تشنج طی اواخر شیرخوارگی و اوایل کودکی:
The most common seizures arising in late infancy and early childhoodare:
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:
Childhoodà many of the well-defined epilepsy syndromes present.
Someàidiopathic, generalized tonic-clonic seizures without other features that fit into specific syndromes.
Temporal lobe epilepsyàusually in childhood - may be related to mesial temporal lobe sclerosisor 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:
CNS infections (including parasitic infections such as cysticercosis),
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 adultsinclude:
trauma (including subdural hematoma),
CNS tumors, and
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 embolicrather 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.
TABLE 348-5 Drugs and Other Substances That Can Cause Seizures
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
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.
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 punctureis 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.
All patients who have a possible seizure disorder should beevaluated 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-Hzalpha 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;
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with light sleep, slower activity in the theta (4 to 7 Hz) and delta (<4 Hz) ranges becomes more apparent.
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 system. A, earlobe; C, central; F, frontal; Fp, frontal polar; P, parietal; T, temporal; O, occipital. Right-sided placements are indicated by even numbers, left-sided placements by odd numbers, and midline placements by Z. [From MJ Aminoff (ed): Electrodiagnosis in Clinical Neurology, 4th ed. New York, Churchill Livingstone, 1999.]
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 activityconsists 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 anticonvulsantmedications.
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.
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 childrenwho 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.
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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.
TABLE 348-6 Differential Diagnosis of Seizures
Valvular heart disease
Psychoactive drugs (e.g., hallucinogens)
Transient ischemic attack (TIA)
Basilar artery TIA
Benign sleep myoclonus
Special considerations in children
Migraine with recurrent abdominal pain and cyclic vomiting
Benign paroxysmal vertigo
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.
TABLE 348-7 Features That Distinguish Generalized Tonic-Clonic Seizure from Syncope
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.