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InternalMed_Harrison. DEPDC5 (22q12.2) Disheveled, Egl-10 and pleckstrin domain containing protein 5; exerts an inhibitory effect on mammalian target of rapamycin (mTOR)-mediated processes, such as cell growth and proliferation CSTB (21q22.3) Cystatin B, a noncaspase cysteine protease inhibitor; normal protein may block neuronal apoptosis by inhibiting caspases directly or indirectly (via cathepsins), or controlling proteolysis EPM2A (6q24) Laforin, a protein tyrosine phosphatase (PTP); involved in glycogen metabolism and may have antiapoptotic activity Doublecortin (Xq21-24) Doublecortin, expressed primarily in frontal lobes; directly regulates micro-tubule polymerization and bundling Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE); childhood onset; brief, nighttime seizures with prominent motor movements; often misdiagnosed as primary sleep disorder


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InternalMed_Harrison. Benign familial neonatal seizures (BFNS); 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% 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; numerous other syndromes, including almost 80% of patients with Dravet’s syndrome (severe myoclonic epilepsy of infancy) and some cases of Lennox-Gastaut syndrome Autosomal dominant partial epilepsy with auditory features (ADPEAF); a form of idiopathic lateral temporal lobe epilepsy with auditory symptoms or aphasia as a major focal seizure manifestation; age of onset usually between 10 and 25 years


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InternalMed_Harrison. Autosomal dominant familial focal epilepsy with variable foci (FFEVF); family members have seizures originating from different cortical regions; neuroimaging usually normal but may harbor subtle malformations; recent studies also suggest association with benign epilepsy with centrotemporal spikes Progressive myoclonus epilepsy (PME) (Unverricht-Lundborg disease); autosomal recessive inheritance; age of onset between 6 and 15 years, myoclonic seizures, ataxia, and progressive cognitive decline; brain shows neuronal degeneration Progressive myoclonus epilepsy (Lafora’s disease); autosomal recessive inheritance; age of onset 6–19 years, death within 10 years; brain degeneration associated with polyglucosan intracellular inclusion bodies in numerous organs


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InternalMed_Harrison. Classic lissencephaly associated with severe mental retardation and seizures in males; sub-cortical band heterotopia with more subtle findings in females (presumably due to random X-inactivation); X-linked dominant 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 Rare; other families found to have mutations in KCNQ3 or an inversion in chromosomal 5; sequence and functional homology to KCNQ1, mutations of which cause long QT syndrome and a cardiac-auditory syndrome Incidence uncertain; GEFS+ identified in other families with mutations in other sodium channel subunits (SCN2B and SCN2A) and GABAA receptor subunit (GABRG2 and GABRA1); significant phenotypic heterogeneity within same family, including members with febrile seizures only


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InternalMed_Harrison. Mutations found in up to 50% of families containing two or more subjects with idiopathic localization-related epilepsy with ictal auditory symptoms, suggesting that at least one other gene may underlie this syndrome. Study of families with limited number of affected members revealed mutations in approximately 12% of families; thus may be a relatively common cause of lesion-negative focal epilepsies with suspected genetic basis 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 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


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InternalMed_Harrison. Relatively rare but of uncertain incidence; recent increased ascertainment due to improved imaging techniques; relationship between migration defect and seizure phenotype unknown aThe first five syndromes listed in the table (ADNFLE, BFNC, GEFS+, ADPEAF, and FFEVF) are examples of idiopathic 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. Abbreviations: GABA, γ-aminobutyric acid; PME, progressive myoclonus epilepsy.


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InternalMed_Harrison. Abbreviations: GABA, γ-aminobutyric acid; PME, progressive myoclonus epilepsy. These observations emphasize the concept that the many causes of seizures and epilepsy result from a dynamic interplay between endogenous factors, epileptogenic factors, and precipitating factors. The potential role of each needs to be carefully considered when determining the appropriate management of a patient with seizures. For example, the identification of predisposing factors (e.g., family history of epilepsy) in a patient with febrile seizures may increase the necessity for closer follow-up and a more aggressive diagnostic evaluation. Finding an epileptogenic lesion may help in the estimation of seizure recurrence and duration of therapy. Finally, 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.


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InternalMed_Harrison. In practice, it is useful to consider the etiologies of seizures based on the age of the patient, because age is one of the most important factors determining both the incidence and the likely causes of seizures or epilepsy (Table 445-4). 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 2–3 days after birth. Pyridoxine (vitamin B6) deficiency, an important cause of neonatal seizures, can be effectively treated with pyridoxine replacement. The idiopathic


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InternalMed_Harrison. feeding begins, typically 2–3 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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InternalMed_Harrison. The most common seizures arising in late infancy and early childhood are febrile seizures, which are seizures associated with fevers but without evidence of CNS infection or other defined causes. The overall prevalence 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 Abbreviations: EEG, electroencephalogram; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography.


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InternalMed_Harrison. Abbreviations: EEG, electroencephalogram; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography. is 3–5% and even higher in some parts of the world such as Asia. Patients often have a family history of febrile seizures or epilepsy. Febrile seizures usually occur between 3 months and 5 years of age and have a 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


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InternalMed_Harrison. FIGURE 445-1 Mesial temporal lobe epilepsy. The electroencephalogram and seizure semiology were consistent with a left temporal lobe focus. This coronal high-resolution T2-weighted fast spin echo magnetic resonance image obtained at 3 tesla is at the level of the hippocampal bodies, and shows abnormal high signal intensity, blurring of internal laminar architecture, and reduced size of the left hippocampus (arrow) relative to the right. This triad of imaging findings is consistent with hippocampal sclerosis. taBLe 445-4 Causes of seiZures Abbreviation: CNS, central nervous system.


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InternalMed_Harrison. taBLe 445-4 Causes of seiZures Abbreviation: CNS, central nervous system. 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. A simple febrile seizure is a single, isolated event, brief, and symmetric in appearance. Complex febrile seizures are characterized by repeated seizure activity, duration >15 minutes, or by 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, while complex febrile seizures have a risk of 2–5%; other risk factors include the presence of preexisting neurologic deficits and a family history of nonfebrile seizures.


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InternalMed_Harrison. Childhood marks the age at which many of the well-defined epilepsy syndromes present. Some children who are otherwise normal develop idiopathic, generalized tonic-clonic seizures without other features that fit into specific syndromes. Temporal lobe epilepsy usually presents in childhood and may be related to mesial temporal lobe sclerosis (as part of the MTLE syndrome) or other focal abnormalities such as cortical dysgenesis. Other types of focal seizures, including those that evolve into generalized seizures, 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.


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InternalMed_Harrison. The period of adolescence and early adulthood is one 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 that arise in patients in this age range may be associated with head trauma, CNS infections (including parasitic infections such as cysticercosis), brain tumors, congenital CNS abnormalities, illicit drug use, or alcohol withdrawal. Autoantibodies directed against CNS antigens such as potassium channels or glutamate receptors are a newly recognized cause of epilepsy that also begins to appear in this age group (although cases of autoimmunity are being increasingly described in the pediatric population), including patients without an identifiable cancer. This etiology should be suspected when a previously normal individual presents with a particularly aggressive seizure pattern developing over weeks to


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InternalMed_Harrison. patients without an identifiable cancer. This etiology should be suspected when a previously normal individual presents with a particularly aggressive seizure pattern developing over weeks to months and characterized by increasingly frequent and prolonged seizures combined with cognitive decline (Chap. 122).


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InternalMed_Harrison. Head trauma is a common cause of epilepsy in adolescents and adults. The head injury can be caused by a variety of mechanisms, and the likelihood of developing epilepsy is strongly correlated with the severity of the injury. A patient with a penetrating head wound, depressed skull fracture, intracranial hemorrhage, or prolonged post-traumatic coma or amnesia has a 30–50% risk of developing epilepsy, whereas a patient with a closed head injury and cerebral contusion has a 5–25% 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 focal seizures within hours or days of a mild head injury and subsequently develop chronic seizures of the same type; such cases may


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InternalMed_Harrison. Nonetheless, most epileptologists know of patients who have focal 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.


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InternalMed_Harrison. 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 age 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, hypoor hyperglycemia, renal failure, and hepatic failure may cause seizures at any age. Similarly, endocrine disorders, hematologic disorders, vasculitides, and many other systemic diseases may cause seizures over a broad age range. A wide variety of medications and abused substances are known to precipitate seizures as well (Table 445-5).


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InternalMed_Harrison. Focal seizure activity can begin in a very discrete region of cortex and then slowly invade the surrounding regions. The hallmark of an established seizure is typically an electrographic “spike” due to intense near-simultaneous firing of a large number of local excitatory neurons, resulting in an apparent hypersynchronization of the excitatory bursts across a relatively large cortical region. The bursting activity in individual neurons (the “paroxysmal depolarization shift”) 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 hyper-polarizing 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. The spreading seizure wavefront is slowed and ultimately halted by intact hyperpolarization and a “surround” inhibition created by feed-forward activation of inhibitory neurons. With sufficient activation, there is a recruitment of surrounding neurons via a number of synaptic and nonsynaptic mechanisms, including: (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; (3) depolarization-induced Alkylating agents (e.g., busulfan, chlorambucil) Antimalarials (chloroquine, mefloquine) Cyclosporine OKT3 (monoclonal antibodies to T cells) Tacrolimus Interferons Antidepressants (e.g., bupropion) Antipsychotics (e.g., clozapine) Lithium Drugs of abuse aIn benzodiazepine-dependent patients.


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InternalMed_Harrison. Antidepressants (e.g., bupropion) Antipsychotics (e.g., clozapine) Lithium Drugs of abuse aIn benzodiazepine-dependent patients. activation of the N-methyl-d-aspartate (NMDA) subtype of the excitatory amino acid receptor, which causes additional Ca2+ influx and neuronal activation; and (4) ephaptic interactions related to changes in tissue osmolarity and cell swelling. The recruitment of a sufficient number of neurons leads to the propagation of excitatory currents into contiguous areas via local cortical connections and to more distant areas via long commissural pathways such as the corpus callosum.


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InternalMed_Harrison. Many factors control neuronal excitability, and thus there are many potential mechanisms for altering a neuron’s propensity to have bursting activity. Mechanisms intrinsic to the neuron include changes in the conductance of ion channels, response characteristics of membrane receptors, cytoplasmic buffering, second-messenger systems, and protein expression as determined by gene transcription, translation, and posttranslational modification. Mechanisms extrinsic to the neuron include changes in the amount or type of neurotransmitters present at the synapse, modulation of receptors by extracellular ions and other molecules, and temporal and spatial properties of synaptic and nonsynaptic input. Nonneural cells, such as astrocytes and oligodendrocytes, have an important role in many of these mechanisms as well.


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InternalMed_Harrison. Certain recognized causes of seizures are explained by these mechanisms. For example, accidental ingestion of domoic acid, which is an 2548 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. The basic mechanisms of other precipitating factors of seizures such as sleep deprivation, fever, alcohol withdrawal, hypoxia, and infection, are not as well understood but presumably involve analogous perturbations in neuronal excitability. Similarly, the endogenous factors that determine an individual’s seizure threshold may relate to these properties as well. Knowledge of the mechanisms responsible for initiation and propagation of most generalized seizures (including tonic-clonic,


InternalMed_Harrison

InternalMed_Harrison. an individual’s seizure threshold may relate to these properties as well. Knowledge of the mechanisms responsible for initiation and propagation of most generalized seizures (including tonic-clonic, myoclonic, and atonic types) remains rudimentary and reflects the limited understanding of the connectivity of the brain at a systems level. 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. Pharmacologic studies indicate that modulation of these receptors and channels can induce absence seizures, and there is good evidence that the genetic forms of absence epilepsy may be associated with mutations of components of this system.


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InternalMed_Harrison. 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. The injury appears to initiate a process that gradually lowers the seizure threshold in the affected region until a spontaneous seizure occurs. In many genetic and idiopathic forms of epilepsy, epileptogenesis is presumably determined by developmentally regulated events.


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InternalMed_Harrison. 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. For example, many patients with MTLE have a highly selective loss of neurons that may contribute to inhibition of the main excitatory neurons within the dentate gyrus. There is also evidence that, in response to the loss of neurons, there is reorganization or “sprouting” of surviving neurons in a way that affects the excitability of the network. Some of these changes can be seen in experimental models of prolonged electrical seizures or traumatic brain injury. Thus, an initial injury such as head injury may lead to a very focal, confined region of structural change that causes local hyperexcitability. The local hyperexcitability leads to further structural changes that evolve over time until the focal lesion produces clinically evident seizures. Similar models have provided strong evidence


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InternalMed_Harrison. The local hyperexcitability leads to further structural changes that evolve over time until the focal lesion produces clinically evident seizures. Similar models have provided strong evidence for long-term alterations in intrinsic, biochemical properties of cells within the network such as chronic changes in glutamate or GABA receptor function. Recent work has suggested that induction of inflammatory cascades may be a critical factor in these processes as well.


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InternalMed_Harrison. The most important recent progress in epilepsy research has been the identification of genetic mutations associated with a variety of epilepsy syndromes (Table 445-2). Although most of the mutations identified to date cause rare forms of epilepsy, their discovery has led to extremely important conceptual advances. For example, it appears that many of the inherited, idiopathic epilepsies (i.e., the relatively “pure” forms of epilepsy in which seizures are the phenotypic abnormality and brain structure and function are otherwise normal) are due to mutations affecting ion channel function. These syndromes are therefore part of the larger group of channelopathies causing paroxysmal disorders such as cardiac arrhythmias, episodic ataxia, periodic weakness, and familial hemiplegic migraine. In contrast, gene mutations observed in symptomatic epilepsies (i.e., disorders in which other neurologic abnormalities such as cognitive impairment coexist with seizures) are proving to be associated


InternalMed_Harrison

InternalMed_Harrison. contrast, gene mutations observed in symptomatic epilepsies (i.e., disorders in which other neurologic abnormalities such as cognitive impairment coexist with seizures) are proving to be associated with pathways influencing CNS development or neuronal homeostasis. De novo mutations may explain a significant proportion of these syndromes, especially those with onset in early childhood. A current challenge is to identify the multiple susceptibility genes that underlie the more common forms of idiopathic epilepsies. Recent studies suggest that ion channel mutations and copy number variants may contribute to causation in a subset of these patients.


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InternalMed_Harrison. Antiepileptic drugs appear to act primarily by blocking the initiation or spread of seizures. This occurs through a variety of mechanisms that modify the activity of ion channels or neurotransmitters, and in most cases, the drugs have pleiotropic effects. The mechanisms include inhibition of Na+-dependent action potentials in a frequency-dependent manner (e.g., phenytoin, carbamazepine, lamotrigine, topiramate, zonisamide, lacosamide, rufinamide), inhibition of voltage-gated Ca2+ channels (phenytoin, gabapentin, pregabalin), facilitating the opening of potassium channels (ezogabine), attenuation of glutamate activity (lamotrigine, topiramate, felbamate), potentiation of GABA receptor function (benzodiazepines and barbiturates), increase in the availability of GABA (valproic acid, gabapentin, tiagabine), and modulation of release of synaptic vesicles (levetiracetam). The two most effective drugs for absence seizures, ethosuximide and valproic acid, probably act by inhibiting T-type


InternalMed_Harrison

InternalMed_Harrison. tiagabine), and modulation of release of synaptic vesicles (levetiracetam). The two most effective drugs for absence seizures, ethosuximide and valproic acid, probably act by inhibiting T-type Ca2+ channels in thalamic neurons.


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InternalMed_Harrison. 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. The eventual development of such “antiepileptogenic” drugs will provide an important means of preventing the emergence of epilepsy following injuries such as head trauma, stroke, and CNS infection. APPROACH TO THE PATIENT: 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 (see “Treatment: Seizures and Epilepsy”). Life-threatening conditions such as CNS infection, metabolic derangement, or drug toxicity must be recognized and managed appropriately.


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InternalMed_Harrison. When the patient is not acutely ill, the evaluation will initially focus on whether there is a history of earlier seizures (Fig. 445-2). 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.


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InternalMed_Harrison. The first goal is to determine whether the event was truly a seizure. An in-depth history is essential, because in many cases the diagnosis of a seizure is based solely on clinical grounds—the examination and laboratory studies are often normal. Questions should focus on the symptoms before, during, and after the episode in order to differentiate a seizure from other paroxysmal events (see “Differential Diagnosis of Seizures” below). Seizures frequently occur out-of-hospital, and the patient may be unaware of the ictal and immediate postictal phases; thus, witnesses to the event should be interviewed carefully. The history should also focus on risk factors and predisposing events. 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 CNS infection should be identified.


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InternalMed_Harrison. Normal Adult Patient with a Seizure History of epilepsy; currently treated with antiepileptics Assess: adequacy of antiepileptic therapy Side effects Serum levels No history of epilepsy Laboratory studies CBC Electrolytes, calcium, magnesium Serum glucose Liver and renal function tests Urinalysis Toxicology screen Negative metabolic screen Positive metabolic screen or symptoms/signs suggesting a metabolic or infectious disorder Abnormal or change in neurologic exam Treat identifiable metabolic abnormalities Assess cause of neurologic change Lumbar puncture Cultures Endocrine studies CT MRI if focal features present MRI scan and EEG Subtherapeutic antiepileptic levels Appropriate increase or resumption of dose Increase antiepileptic therapy to maximum tolerated dose; consider alternative antiepileptic drugs Therapeutic antiepileptic levels Focal features of seizures Focal abnormalities on clinical or lab examination Other evidence of neurologic dysfunction Treat underlying


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InternalMed_Harrison. antiepileptic drugs Therapeutic antiepileptic levels Focal features of seizures Focal abnormalities on clinical or lab examination Other evidence of neurologic dysfunction Treat underlying metabolic abnormality Idiopathic seizures Treat underlying disorder Yes No Consider: Mass lesion; stroke; CNS infection; trauma; degenerative disease Consider: Antiepileptic therapy Further workup Other causes of episodic cerebral dysfunction Syncope Transient ischemic attack Migraine Acute psychosis History Physical examination Exclude Consider: Antiepileptic therapy Consider: Antiepileptic therapy Consider CBC Electrolytes, calcium, magnesium Serum glucose Liver and renal function tests Urinalysis Toxicology screen FIGURE 445-2 Evaluation of the adult patient with a seizure. CBC, complete blood count; CNS, central nervous system; CT, computed tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging.


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InternalMed_Harrison. In children, a careful assessment of developmental milestones may The general physical examination includes a search for signs of provide evidence for underlying CNS disease. Precipitating factors infection or systemic illness. Careful examination of the skin may such as sleep deprivation, systemic diseases, electrolyte or metabolic reveal signs of neurocutaneous disorders such as tuberous sclerosis derangements, acute infection, drugs that lower the seizure threshold or neurofibromatosis, or chronic liver or renal disease. A finding of (Table 445-5), or alcohol or illicit drug use should also be identified. organomegaly may indicate a metabolic storage disease, and limb 2550 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


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InternalMed_Harrison. 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 (Chap. 437). 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.


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InternalMed_Harrison. Routine blood studies are indicated to identify the more common metabolic causes of seizures such as abnormalities in electrolytes, glucose, calcium, or magnesium, and hepatic or renal disease. A screen for toxins in blood and urine should also be obtained from all patients in appropriate risk groups, especially when no clear precipitating factor has been identified. A lumbar puncture is indicated if there is any suspicion of meningitis or encephalitis, and it is mandatory in all patients infected with HIV, even in the absence of symptoms or signs suggesting infection. Testing for autoantibodies in the serum and cerebrospinal fluid (CSF) should be considered in patients presenting with a seemingly aggressive form of epilepsy associated with other abnormalities such as cognitive disturbances. All patients who have a possible seizure disorder should be evaluated with an EEG as soon as possible. Details about the EEG are covered in Chap. 442e.


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InternalMed_Harrison. In the evaluation of a patient with suspected epilepsy, the presence of electrographic seizure activity during the clinically evident event (i.e., abnormal, repetitive, rhythmic activity having a discrete onset and termination) clearly establishes the diagnosis. The absence of electrographic seizure activity does not exclude a seizure disorder, however, because focal seizures may originate from a region of the cortex that cannot be detected by standard scalp electrodes. The EEG is always abnormal during generalized tonic-clonic seizures. Because 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 for ≥24 h in ambulatory patients has made it easier to capture the electrophysiologic accompaniments of clinical events. In particular, video-EEG telemetry is now


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InternalMed_Harrison. to record the EEG continuously for ≥24 h in ambulatory patients has made it easier to capture the electrophysiologic accompaniments of clinical events. In particular, video-EEG telemetry is now a routine approach for the accurate diagnosis of epilepsy in patients with poorly characterized events or seizures that are difficult to control.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. The EEG is also used for classifying seizure disorders and aiding in the selection of anticonvulsant medications. For example, episodic generalized spike-wave activity is usually seen in patients with typical absence epilepsy and may be seen with other generalized epilepsy syndromes. Focal interictal epileptiform discharges would support the diagnosis of a focal seizure disorder such as temporal lobe epilepsy or frontal lobe seizures, depending on the location of the discharges.


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InternalMed_Harrison. 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 outcome. 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.


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InternalMed_Harrison. Magnetoencephalography (MEG) provides another way of looking noninvasively at cortical activity. Instead of measuring electrical activity of the brain, it measures the small magnetic fields that are generated by this activity. The source of epileptiform activity seen on MEG can be analyzed, and its source in the brain can be estimated using a variety of mathematical techniques. These source estimates can then be plotted on an anatomic image of the brain such as an MRI (discussed below), to generate a magnetic source image (MSI). MSI can be useful to localize potential seizure foci.


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InternalMed_Harrison. 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 urgent therapy. The availability of newer MRI methods such as 3-tesla scanners, parallel imaging with multichannel head coils, three-dimensional structural imaging at submillimeter resolution, and widespread use of pulse sequences such as fluid-attenuated inversion recovery (FLAIR), has increased the sensitivity for detection of abnormalities of cortical architecture, including hippocampal atrophy associated


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InternalMed_Harrison. of pulse sequences 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, as well as abnormalities of cortical neuronal migration. In such cases, the findings may not lead to immediate therapy, but they do provide an explanation for the patient’s seizures and point to the need for chronic antiepileptic drug therapy or possible surgical resection.


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InternalMed_Harrison. 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 (discussed below). Disorders that may mimic seizures are listed in Table 445-6. In most cases, seizures can be distinguished 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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InternalMed_Harrison. (See also Chap. 27) The diagnostic dilemma encountered most frequently is the distinction between a generalized seizure and syncope. Observations by the patient and bystanders that can help differentiate between the two are listed in Table 445-7. Characteristics of a seizure include the presence of an aura, cyanosis, unconsciousness, motor manifestations lasting >15 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., 1–10 s) of convulsive motor activity is


InternalMed_Harrison

InternalMed_Harrison. relatively brief loss of consciousness. Headache or incontinence usually suggests a seizure but may on occasion also occur with syncope. A brief period (i.e., 1–10 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


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InternalMed_Harrison. DiffereNtiaL DiaGNosis of seiZures Vasovagal syncope Basilar artery TIA Cardiac arrhythmia Sleep disorders Valvular heart disease Narcolepsy/cataplexy Cardiac failure Benign sleep myoclonus Orthostatic hypotension Movement disorders Psychological disorders Tics Psychogenic seizure Nonepileptic myoclonus Hyperventilation Paroxysmal choreoathetosis Panic attack Special considerations in children Metabolic disturbances Breath-holding spells Alcoholic blackouts Migraine with recurrent abdominal (e.g., hallucinogens) Sleepwalking 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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InternalMed_Harrison. 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 sideto-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 minutes to hours. However, the distinction is sometimes difficult on clinical grounds alone, and there are many examples of diagnostic errors made by experienced epileptologists. This is especially true for psychogenic seizures that resemble focal seizures with dyscognitive features, because the behavioral manifestations of focal seizures (especially of frontal lobe origin) can be extremely unusual, and in both cases, the routine surface EEG may be normal. Video-EEG monitoring is very useful when historic features are


InternalMed_Harrison

InternalMed_Harrison. focal seizures (especially of frontal lobe origin) can be extremely unusual, and in both cases, the routine surface EEG may be normal. Video-EEG monitoring is very useful when historic features are nondiagnostic. Generalized tonic-clonic seizures always produce marked EEG abnormalities during and after the seizure. For suspected focal seizures of temporal lobe origin, the use of additional electrodes beyond the standard scalp locations (e.g., sphenoidal electrodes) may be required to localize a seizure focus. Measurement of serum prolactin levels may also help to distinguish between organic and psychogenic seizures, because most generalized seizures and some focal 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, because the two often coexist.


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InternalMed_Harrison. Therapy for a patient with a seizure disorder is almost always multi-modal 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 (see below).


InternalMed_Harrison

InternalMed_Harrison. 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 2552 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”). Because there is often an association between stress and seizures, stress reduction techniques such as physical exercise, meditation, or counseling may be helpful.


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InternalMed_Harrison. 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, because 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 the patient’s specific needs, especially his or her assessment of side effects.


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InternalMed_Harrison. 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. 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,


InternalMed_Harrison

InternalMed_Harrison. 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 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.


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InternalMed_Harrison. Selection of Antiepileptic Drugs Antiepileptic drugs available in the United States are shown in Table 445-8, and the main pharmacologic characteristics of commonly used drugs are listed in Table 445-9. Worldwide, older medications such as phenytoin, valproic acid, carbamazepine, phenobarbital, and ethosuximide are generally used as first-line therapy for most seizure disorders because, overall, they are as effective as recently marketed drugs and significantly less expensive overall. Most of the new drugs that have become available in the past decade are used as add-on or alternative therapy, although many are now being used as first-line monotherapy.


InternalMed_Harrison

InternalMed_Harrison. 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. In this regard, a number of the newer drugs have the advantage of reduced drug-drug interactions and easier dosing. Almost all of the commonly used antiepileptic drugs can cause similar, dose-related side effects such as sedation, ataxia, and diplopia. Long-term use of some agents in adults, especially the elderly, can lead to osteoporosis. Close follow-up is required to ensure these side effects are promptly recognized and reversed. Most of the older drugs and some of the newer ones 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 must be instructed about symptoms or signs that should signal the need to alert their health care provider. For some drugs,


InternalMed_Harrison

InternalMed_Harrison. these side effects should be considered during drug selection, and patients must be instructed about symptoms or signs that should signal the need to alert their health care provider. For some drugs, laboratory tests (e.g., complete blood count and liver function tests) are recommended prior to the institution of therapy (to establish baseline values) and during initial dosing and titration of the agent. Importantly, studies have shown that Asian individuals carrying the human leukocyte antigen allele, HLA-B*1502, are at particularly high risk of developing serious skin reactions from carbamazepine and phenytoin. As a result, racial background and genotype are additional factors to consider in drug selection.


InternalMed_Harrison

InternalMed_Harrison. Antiepileptic Drug Selection for focAl SeizureS Carbamazepine (or a related drug, oxcarbazepine), lamotrigine, phenytoin, and levetiracetam are currently the drugs of choice approved for the initial treatment of focal seizures, including those that evolve into generalized seizures. Overall they have very similar efficacy, but differences in pharmacokinetics and toxicity are the main determinants for use in a given patient. For example, an advantage of carbamazepine (which is also available in an extended-release form) is that its metabolism follows first-order pharmacokinetics, which allows for a linear relationship between drug dose, serum levels, and toxicity. Carbamazepine can cause leukopenia, aplastic anemia, or hepatotoxicity and would therefore be contraindicated in patients with predispositions to these problems. Oxcarbazepine has the advantage of being metabolized in a way that avoids an intermediate metabolite associated with some of the side effects of carbamazepine.


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InternalMed_Harrison. with predispositions to these problems. Oxcarbazepine has the advantage of being metabolized in a way that avoids an intermediate metabolite associated with some of the side effects of carbamazepine. Oxcarbazepine also has fewer drug interactions than carbamazepine. Lamotrigine tends to be well tolerated in terms of side effects. However, patients need to be particularly vigilant about the possibility of a skin rash during the initiation of therapy. This can be extremely severe and lead to Stevens-Johnson syndrome if unrecognized and if the medication is not discontinued immediately. This risk can be reduced by the use of low initial doses and slow titration. Lamotrigine must be started at lower initial doses when used as add-on therapy with valproic acid, because valproic acid inhibits lamotrigine metabolism and results in a substantially prolonged half-life. Phenytoin has a relatively long half-life and offers the advantage of once or twice daily dosing compared to two or three


InternalMed_Harrison

InternalMed_Harrison. lamotrigine metabolism and results in a substantially prolonged half-life. Phenytoin has a relatively long half-life and offers the advantage of once or twice daily dosing compared to two or three times daily dosing for many of the other drugs. However, phenytoin shows properties of nonlinear 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, gingival hypertrophy) and effects on bone metabolism. Due to these side effects, phenytoin is often avoided in young patients who are likely to require the drug for many years. Levetiracetam has aExamples only; please refer to other sources for comprehensive listings of all potential drug-drug interactions. bPhenytoin, carbamazepine, phenobarbital. cExtended-release product available.


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InternalMed_Harrison. 2556 the advantage of having no known drug-drug interactions, making it especially useful in the elderly and patients on other medications. However, a significant number of patients taking levetiracetam complain of irritability, anxiety, and other psychiatric symptoms. Topiramate can be used for both focal and generalized seizures. Similar to some of the other antiepileptic drugs, topiramate can cause significant psychomotor slowing and other cognitive problems. Additionally, it should not be used in patients at risk for the development of glaucoma or renal stones. Valproic acid is an effective alternative for some patients with focal seizures, especially when the seizures generalize. Gastrointestinal side effects are fewer when using the delayed-release formulation (Depakote). Laboratory testing is required to monitor toxicity because valproic acid can rarely cause reversible bone marrow suppression and hepatotoxicity. This drug should generally be avoided in patients with


InternalMed_Harrison

InternalMed_Harrison. Laboratory testing is required to monitor toxicity because valproic acid can rarely cause reversible bone marrow suppression and hepatotoxicity. 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 anti-epileptic drugs or with inborn errors of metabolism. Zonisamide, tiagabine, gabapentin, lacosamide, and ezogabine are additional drugs currently used for the treatment of focal seizures with or without evolution into generalized seizures. Phenobarbital and other barbiturate compounds were commonly used in the past 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Antiepileptic Drug Selection for generAlizeD SeizureS Lamotrigine and valproic acid are currently considered the best initial choice for the treatment of primary generalized, tonic-clonic seizures. Topiramate, zonisamide, phenytoin, carbamazepine, and oxcarbazepine are suitable alternatives. Valproic acid is also particularly effective in absence, myoclonic, and atonic seizures. It is therefore the drug of choice in patients with generalized epilepsy syndromes having mixed seizure types. Importantly, carbamazepine, oxcarbazepine, 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 focal seizures. Periodic monitoring of blood cell counts is required since ethosuximide rarely causes bone marrow suppression. Lamotrigine appears to be particularly effective in epilepsy syndromes


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InternalMed_Harrison. focal seizures. Periodic monitoring of blood cell counts is required since ethosuximide rarely causes bone marrow suppression. Lamotrigine appears to be particularly 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.


InternalMed_Harrison

InternalMed_Harrison. Because the response to any antiepileptic drug is unpredictable, patients should be carefully educated about the approach to therapy. The goal is to prevent seizures and minimize the side effects of treatment; 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 antiepileptic drugs need to be introduced relatively slowly to minimize side effects. 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 445-9. 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).


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InternalMed_Harrison. Monitoring of serum antiepileptic drug levels can be very useful for establishing the initial dosing schedule. However, the published therapeutic ranges of serum drug concentrations are only an approximate guide for determining the proper dose for a given patient. The key determinants are the clinical measures of seizure frequency and presence of side effects, not the laboratory values. 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


InternalMed_Harrison

InternalMed_Harrison. 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 adherence.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 1–5 years; (2) single seizure type, either focal 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 2–3 months. Most recurrences occur in the first 3 months after discontinuing therapy, and patients should be advised to avoid potentially


InternalMed_Harrison

InternalMed_Harrison. is preferable to reduce the dose of the drug gradually over 2–3 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.


InternalMed_Harrison

InternalMed_Harrison. 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, oxcarbazepine, lamotrigine, valproic acid, levetiracetam, and phenytoin). If these drugs are unsuccessful, then the addition of other drugs such as topiramate, zonisamide, lacosamide, or tiagabine is indicated. Patients with myoclonic seizures resistant to valproic acid may benefit from the addition of clonazepam or clobazam, and those with absence seizures may


InternalMed_Harrison

InternalMed_Harrison. lacosamide, or tiagabine is indicated. Patients with myoclonic seizures resistant to valproic acid may benefit from the addition of clonazepam or clobazam, and those with absence seizures 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.


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InternalMed_Harrison. Approximately 20–30% of patients with epilepsy continue to have seizures despite efforts to find an effective combination of anti-epileptic 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 a patient’s seizures are not controlled with initial treatment, as such patients often do not respond to subsequent medication trials. 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.


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InternalMed_Harrison. 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). Localized neocortical resection without a clear lesion identified on MRI is also possible when other tests (e.g. MEG, PET, SPECT) implicate a focal cortical region as a seizure onset zone. 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 hemimegalencephaly or other dysplastic abnormalities, and corpus callosotomy has been shown to be effective for


InternalMed_Harrison

InternalMed_Harrison. useful for some patients with severe seizures due to hemispheric abnormalities such as hemimegalencephaly 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).


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InternalMed_Harrison. 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 scalpsphenoidal recordings and a high-resolution MRI scan are usually sufficient for localization of the epileptogenic focus, especially when the findings are concordant. Functional imaging studies such as SPECT, PET, and MEG are adjunctive tests that may help to reveal or verify the localization of an apparent epileptogenic region. Once the presumed location of the seizure onset is identified, additional studies, including neuropsychological testing, the intracarotid amobarbital test (Wada test), and functional MRI may be used to assess language and memory localization and to determine the possible functional consequences of surgical removal of the


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InternalMed_Harrison. intracarotid amobarbital test (Wada test), and functional MRI 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, standard noninvasive evaluation is not sufficient to localize the seizure onset zone, and invasive electrophysiologic monitoring, such as implanted depth or subdural electrodes, is required for more definitive localization. The exact extent of the resection to be undertaken can also be 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 on the awake patient to determine the


InternalMed_Harrison

InternalMed_Harrison. region to be resected is within or near brain regions suspected of having sensorimotor or language function, electrical cortical stimulation mapping is performed on 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.


InternalMed_Harrison

InternalMed_Harrison. 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 15–25% 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 resective surgery can have a very beneficial effect on quality of life.


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InternalMed_Harrison. Not all medically refractory patients are suitable candidates for resective surgery. For example, some patients have seizures arising from more than one location, making the risk of ongoing seizures 2557 or potential harm from the surgery unacceptably high. Vagus nerve stimulation (VNS) has been used in some of these cases, although the results are limited and it is difficult to predict who will benefit. A new implantable device that can detect the onset of a seizure (in some instances before the seizure becomes clinically apparent) and deliver an electrical stimulation (Responsive NeuroStimulation) has recently been approved and may be of benefit in selected patients. Studies are currently evaluating the efficacy of stereotactic radio-surgery, laser thermoablation, and deep brain stimulation (DBS) as other options for surgical treatment of refractory epilepsy.


InternalMed_Harrison

InternalMed_Harrison. Status epilepticus refers to continuous seizures or repetitive, discrete seizures with impaired consciousness in the interictal period. Status epilepticus has numerous subtypes, including generalized convulsive status epilepticus (GCSE) (e.g., persistent, generalized electrographic seizures, coma, and tonic-clonic movements) and nonconvulsive status epilepticus (e.g., persistent absence seizures or focal seizures with confusion or partially impaired consciousness, and minimal motor abnormalities). The duration of seizure activity sufficient to meet the definition of status epilepticus has traditionally been specified as 15–30 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. For GCSE, this is typically when seizures last beyond 5 min.


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InternalMed_Harrison. GCSE is an emergency and must be treated immediately, because 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 GCSE are anticonvulsant withdrawal or noncompliance, metabolic disturbances, drug toxicity, CNS infection, CNS tumors, refractory epilepsy, and head trauma.


InternalMed_Harrison

InternalMed_Harrison. GCSE is obvious when the patient is having overt convulsions. However, after 30–45 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. This is obviously also essential when a patient with GCSE has been paralyzed with neuromuscular blockade in the process of protecting the airway.


InternalMed_Harrison

InternalMed_Harrison. The first steps in the management of a patient in GCSE are to attend to any acute cardiorespiratory problems or hyperthermia, perform a brief medical and neurologic examination, establish venous access, and send samples for laboratory studies to identify metabolic abnormalities. Anticonvulsant therapy should then begin without delay; a treatment approach is shown in Fig. 445-3. The treatment of nonconvulsive status epilepticus is thought to be less urgent than GCSE, because the ongoing seizures are not accompanied by the severe metabolic disturbances seen with GCSE. However, evidence suggests that nonconvulsive status epilepticus, especially that caused by ongoing, focal seizure activity, is associated with cellular injury in the region of the seizure focus; therefore this condition should be treated as promptly as possible using the general approach described for GCSE. BEYOND SEIZURES: OTHER MANAGEMENT ISSUES


InternalMed_Harrison

InternalMed_Harrison. BEYOND SEIZURES: OTHER MANAGEMENT ISSUES The adverse effects of epilepsy often go beyond clinical seizures, and the extent of these effects largely depends on the etiology of epilepsy, seizure frequency and severity, and side effects from antiepileptic therapy. Many epilepsy patients are completely normal between seizures and 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 are 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.


InternalMed_Harrison

InternalMed_Harrison. 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 personal or family history of psychiatric disorder. Depression occurs in ~20% of patients, and the incidence of suicide is higher in patients with epilepsy than in the general population. Depression should be treated through counseling or medication. The selective serotonin reuptake inhibitors (SSRIs) typically have minimal effect on seizures, whereas tricyclic antidepressants may lower the seizure threshold. Anxiety can be a seizure symptom, and anxious or psychotic behavior can occur during a postictal delirium. 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


InternalMed_Harrison

InternalMed_Harrison. 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 usually resolves spontaneously but frequently will require short-term treatment with antipsychotic or anxiolytic medications.


InternalMed_Harrison

InternalMed_Harrison. 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 atypical personality traits occur in diverse epilepsies (e.g., generalized and frontal lobe epilepsy) and may result from an underlying structural brain lesion, antiepileptic drug effects, and psychosocial factors related to suffering from a chronic disease, as well as the epilepsy itself.


InternalMed_Harrison

InternalMed_Harrison. Other approaches Surgery, VNS, rTMS, ECT, hypothermia Other anesthetics Isoflurane, desflurane, ketamine IV MDZ 0.2 mg/kg ˜ 0.2–0.6 mg/kg/h and/or IV PRO 2 mg/kg ˜ 2–10 mg/kg/h Focal-complex, myoclonic or absence SE Generalized convulsive or “subtle” SE Impending and early SE (5–30 minutes) Established and early refractory SE (30 minutes–48 hours) Late refractory SE (>48 hours) Further IV/PO antiepileptic drug VPA, LEV, LCM, TPM, PGB, or other Other medications Lidocaine, verapamil, magnesium, ketogenic diet, immunomodulation IV antiepileptic drug PHT 20 mg/kg, or VPA 20–30 mg/kg, or LEV 20–30 mg/kg IV benzodiazepine LZP 0.1 mg/kg, or MDZ 0.2 mg/kg, or CLZ 0.015 mg/kg PTB (THP) 5 mg/kg (1 mg/kg) ˜ 1–5 mg/kg/h FIGURE 445-3 Pharmacologic treatment of generalized tonic-clonic status epilepticus (SE) in adults. CLZ, clonazepam; ECT, electrocon-vulsive therapy; LCM, lacosamide; LEV, levetiracetam; LZP, lorazepam; MDZ, midazolam; PGB, pregabalin; PHT, phenytoin or fos-phenytoin; PRO,


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InternalMed_Harrison. (SE) in adults. CLZ, clonazepam; ECT, electrocon-vulsive therapy; LCM, lacosamide; LEV, levetiracetam; LZP, lorazepam; MDZ, midazolam; PGB, pregabalin; PHT, phenytoin or fos-phenytoin; PRO, propofol; PTB, pentobarbital; rTMS, repetitive transcranial magnetic stimulation; THP, thiopental; TPM, topiramate; VNS, vagus nerve stimulation; VPA, valproic acid. (From AO Rossetti, DH Lowenstein: Lancet Neurol 10:922, 2011.)


InternalMed_Harrison

InternalMed_Harrison. Patients with epilepsy have a risk of death that is roughly two to three 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 epilepsy (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 pulmonary, cardiac, and arousal functions. Recent studies suggest that, in some cases, a genetic mutation may be the cause of both epilepsy and a cardiac conduction defect that gives rise to sudden death.


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InternalMed_Harrison. 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. These issues need to be carefully addressed by educating the patient about epilepsy and by ensuring that family members, teachers, fellow employees, and other associates are equally well informed. A useful source of educational material is the Web site www.epilepsy.com. EMPLOYMENT, DRIVING, AND OTHER ACTIVITIES


InternalMed_Harrison

InternalMed_Harrison. EMPLOYMENT, DRIVING, AND OTHER ACTIVITIES Many patients with epilepsy face difficulty in obtaining or maintaining employment, even when their seizures are well controlled. Federal and state legislation is designed to prevent employers from discriminating against patients with epilepsy, and patients should be encouraged to understand and claim their legal rights. Patients in these circumstances also benefit greatly from the assistance of health providers who act as strong patient advocates.


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InternalMed_Harrison. Loss of driving privileges is one of the most disruptive social consequences of epilepsy. Physicians should be very clear about local regulations concerning driving and epilepsy, because the laws vary considerably among states and countries. In all cases, it is the physician’s responsibility to warn patients of the danger imposed on themselves and others while driving if their seizures are uncontrolled (unless the seizures are not associated with impairment of consciousness or motor control). In general, most states allow patients to drive after a seizure-free interval (on or off medications) of between 3 months and 2 years.


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InternalMed_Harrison. Patients with incompletely controlled seizures must also contend with the risk of being in other situations where an impairment of consciousness or loss of motor control could lead to major injury or death. Thus, depending on the type and frequency of seizures, many patients need to be instructed to avoid working at heights or with machinery or to have someone close by for activities such as bathing and swimming. Some women experience a marked increase in seizure frequency around the time of menses. This is believed to be mediated by either the effects of estrogen and progesterone on neuronal excitability or changes in antiepileptic drug levels due to altered protein binding or metabolism. Some patients may benefit from increases in antiepileptic drug dosages during menses. Natural progestins or intramuscular medroxyprogesterone may be of benefit to a subset of women.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. The overall incidence of fetal abnormalities in children born to mothers with epilepsy is 5–6%, compared to 2–3% 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., 10–20% risk of malformations with three drugs) and possibly with higher doses. A meta-analysis of published pregnancy registries and cohorts found that the most common malformations were defects in the cardiovascular and musculoskeletal system (1.4–1.8%). Valproic acid is strongly associated with an increased risk of adverse fetal outcomes (7–20%). Recent findings from a large pregnancy registry suggest that, other than topiramate, the newer antiepileptic drugs are far safer than valproic acid.


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InternalMed_Harrison. Because the potential harm of uncontrolled convulsive 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. For some women, however, the type and frequency of their seizures may allow for them to safely wean off antiepileptic drugs prior to conception. Patients should also take folate (1–4 mg/d), because 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.


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InternalMed_Harrison. Enzyme-inducing drugs such as phenytoin, carbamazepine, oxcarbazepine, topiramate, 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 2559 mg/d, phylloquinone) in the last 2 weeks of pregnancy, and the infant should receive intramuscular vitamin K (1 mg) at birth. 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 decrease the efficacy 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.


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InternalMed_Harrison. Antiepileptic medications are excreted into breast milk to a variable degree. The ratio of drug concentration in breast milk relative to serum ranges from ~5% (valproic acid) to 300% (levetiracetam). 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. Wade S. Smith, S. Claiborne Johnston, J. Claude Hemphill, III


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InternalMed_Harrison. Cerebrovascular diseases include some of the most common and devastating disorders: ischemic stroke and hemorrhagic stroke. Stroke is the second leading cause of death worldwide, causing 6.2 million deaths in 2011, and is double the rate of heart disease in China. Strokes cause ~200,000 deaths each year in the United States and are a major cause of disability. The incidence of cerebrovascular diseases increases with age, and the number of strokes is projected to increase as the elderly population grows, with a doubling in stroke deaths in the United States by 2030. A stroke, or cerebrovascular accident, is defined as an abrupt onset of a neurologic deficit that is attributable to a focal vascular cause. Thus, the definition of stroke is clinical, and laboratory studies including brain imaging are used to support the diagnosis. The clinical manifestations of stroke are highly variable because of the complex anatomy of the brain and its vasculature. Cerebral ischemia is caused by a


InternalMed_Harrison

InternalMed_Harrison. imaging are used to support the diagnosis. The clinical manifestations of stroke are highly variable because of the complex anatomy of the brain and its vasculature. Cerebral ischemia is caused by a reduction in blood flow that lasts longer than several seconds. Neurologic symptoms are manifest within seconds because neurons lack glycogen, so energy failure is rapid. If the cessation of flow lasts for more than a few minutes, infarction or death of brain tissue results. When blood flow is quickly restored, brain tissue can recover fully and the patient’s symptoms are only transient: this is called a transient ischemic attack (TIA). The definition of TIA requires that all neurologic signs and symptoms resolve within 24 h without evidence of brain infarction on brain imaging. Stroke has occurred if the neurologic signs and symptoms last for >24 h or brain infarction is demonstrated. A generalized reduction in cerebral blood flow due to systemic hypotension (e.g., cardiac arrhythmia,


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InternalMed_Harrison. occurred if the neurologic signs and symptoms last for >24 h or brain infarction is demonstrated. A generalized reduction in cerebral blood flow due to systemic hypotension (e.g., cardiac arrhythmia, myocardial infarction, or hemorrhagic shock) usually produces syncope (Chap. 27). If low cerebral blood flow persists for a longer duration, then infarction in the border zones between the major cerebral artery distributions may develop. In more severe instances, global hypoxia-ischemia causes widespread brain injury; the constellation of cognitive sequelae that ensues is called hypoxic-ischemic encephalopathy (Chap. 330). Focal ischemia or infarction, conversely, is usually caused by thrombosis of the cerebral vessels themselves or by emboli from a proximal arterial source or the heart. Intracranial hemorrhage is caused by bleeding directly into or around the brain; it produces neurologic symptoms by producing a 2560 mass effect on neural structures, from the toxic effects of blood


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InternalMed_Harrison. Intracranial hemorrhage is caused by bleeding directly into or around the brain; it produces neurologic symptoms by producing a 2560 mass effect on neural structures, from the toxic effects of blood itself, or by increasing intracranial pressure.


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InternalMed_Harrison. with acute neurologic symptoms due to hemorrhage, seizure, or hydrocephalus. Surprisingly, migraine (Chap. 447) can mimic stroke, even in patients without a significant migraine history. When migraine develops without head pain (acephalgic migraine), the diagnosis can be especially difficult. Patients without any prior history of migraine may develop acephalgic migraine even after age 65. A sensory disturbance is often prominent, and the sensory deficit, as well as any motor deficits, tends to migrate slowly across a limb, over minutes rather than seconds as with stroke. The diagnosis of migraine becomes more secure as the cortical disturbance begins to cross vascular boundaries or if typical visual symptoms are present such as scintillating scotomata. At times it may be impossible to make the diagnosis of migraine until there have been multiple episodes with no residual symptoms or signs and no changes on brain magnetic resonance imaging (MRI). Metabolic encephalopathies typically


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InternalMed_Harrison. the diagnosis of migraine until there have been multiple episodes with no residual symptoms or signs and no changes on brain magnetic resonance imaging (MRI). Metabolic encephalopathies typically produce fluctuating mental status changes without focal neurologic findings. However, in the setting of prior stroke or brain injury, a patient with fever or sepsis may manifest a recurrent hemiparesis, which clears rapidly when the infection is treated. The metabolic process serves to “unmask” a prior deficit.


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InternalMed_Harrison. Once the diagnosis of stroke is made, a brain imaging study is necessary to determine if the cause of stroke is ischemia or hemorrhage (Fig. 446-1). Computed tomography (CT) imaging of the brain is the standard imaging modality to detect the presence or absence of intracranial hemorrhage (see “Imaging Studies,” below). If the stroke is ischemic, administration of recombinant tissue plasminogen activator (rtPA) or endovascular mechanical thrombectomy may be beneficial in restoring cerebral perfusion (see “Treatment: Acute Ischemic Stroke”). Medical management to reduce the risk of complications becomes the next priority, followed by plans for secondary prevention. For ischemic stroke, several strategies can reduce the risk of subsequent stroke in all patients, while other strategies are effective for patients with specific causes of stroke such as cardiac embolus and carotid atherosclerosis. For hemorrhagic stroke, aneurysmal subarachnoid hemorrhage (SAH) and hypertensive intracerebral


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InternalMed_Harrison. for patients with specific causes of stroke such as cardiac embolus and carotid atherosclerosis. For hemorrhagic stroke, aneurysmal subarachnoid hemorrhage (SAH) and hypertensive intracerebral hemorrhage are two important causes. The treatment and prevention of hypertensive intracerebral hemorrhage are discussed later in this chapter. SAH is discussed in Chap. 330.


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InternalMed_Harrison. Acute occlusion of an intracranial vessel causes reduction in blood flow to the brain region it supplies. The magnitude of flow reduction is a function of collateral blood flow, and this depends on individual


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InternalMed_Harrison. Stroke or TIA ABCs, glucose Ischemic stroke/ TIA, 85% Hemorrhage 15% Consider thrombolysis/ thrombectomy Consider BP lowering Obtain brain imaging Establish cause Establish cause Atrial fibrillation, 17% Carotid disease, 4% Aneurysmal SAH, 4% Hyperten-sive ICH, 7% Other, 64% Other, 4% Consider warfarin Consider CEA or stent Clip or coil (Chap. 330) Consider surgery Treat specific cause Treat specific cause APPROACH TO THE PATIENT: Cerebrovascular Disease Rapid evaluation is essential for use of time-sensitive treatments such as thrombolysis. However, patients with acute stroke often do not seek medical assistance on their own because they are rarely in pain and also may lose the appreciation that something is wrong (anosognosia); it is often a family member or a bystander who calls for help. Therefore, patients and their family members should be counseled to call emergency medical services immediately if they experience or witness the sudden onset of any of the following: loss of


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InternalMed_Harrison. help. Therefore, patients and their family members should be counseled to call emergency medical services immediately if they experience or witness the sudden onset of any of the following: loss of sensory and/or motor function on one side of the body (nearly 85% of ischemic stroke patients have hemiparesis); change in vision, gait, or ability to speak or understand; or a sudden, severe headache. Other causes of sudden-onset neurologic symptoms that may mimic stroke include seizure, intracranial tumor, migraine, and metabolic encephalopathy. An adequate history from an observer that no convulsive activity occurred at the onset usually excludes seizure, although ongoing complex partial seizures without tonic-clonic activity can on occasion mimic stroke. Tumors may present


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InternalMed_Harrison. Deep venous thrombosis prophylaxis Physical, occupational, speech therapy Evaluate for rehab, discharge planning Secondary prevention based on disease FIGURE 446-1 Medical management of stroke and TIA. Rounded boxes are diagnoses; rectangles are interventions. Numbers are percentages of stroke overall. ABCs, airway, breathing, circulation; BP, blood pressure; CEA, carotid endarterectomy; ICH, intracerebral hemorrhage; SAH, subarachnoid hemorrhage; TIA, transient ischemic attack.


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InternalMed_Harrison. vascular anatomy (which may be altered by disease), the site of occlusion, and systemic blood pressure. A decrease in cerebral blood flow to zero causes death of brain tissue within 4–10 min; values <16–18 mL/100 g tissue per minute cause infarction within an hour; and values <20 mL/100 g tissue per minute cause ischemia without infarction unless prolonged for several hours or days. If blood flow is restored to ischemic tissue before significant infarction develops, the patient may experience only transient symptoms, and the clinical syndrome is called a TIA. Another important concept is the ischemic penumbra, defined as the ischemic but reversibly dysfunctional tissue surrounding a core area of infarction. The penumbra can be imaged by perfusion-diffusion imaging using MRI or CT (see below and Figs. 446-15 and 446-16). The ischemic penumbra will eventually progress to infarction if no change in flow occurs, and hence saving the ischemic penumbra is the goal of revascularization


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InternalMed_Harrison. below and Figs. 446-15 and 446-16). The ischemic penumbra will eventually progress to infarction if no change in flow occurs, and hence saving the ischemic penumbra is the goal of revascularization therapies.


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InternalMed_Harrison. Focal cerebral infarction occurs via two distinct pathways (Fig. 446-2): (1) a necrotic pathway in which cellular cytoskeletal breakdown is rapid, due principally to energy failure of the cell; and (2) an apoptotic pathway in which cells become programmed to die. Ischemia produces necrosis by starving neurons of glucose and oxygen, which in turn results in failure of mitochondria to produce ATP. Without ATP, membrane ion pumps stop functioning and neurons depolarize, allowing intracellular calcium to rise. Cellular depolarization also causes glutamate release from synaptic terminals; excess extracellular glutamate produces neurotoxicity by activating postsynaptic glutamate receptors that increase neuronal calcium influx. Free radicals are produced by degradation of membrane lipids and mitochondrial dysfunction. Free radicals cause catalytic destruction of membranes and likely damage other vital functions of cells. Lesser degrees of ischemia, as are seen within the ischemic penumbra,


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InternalMed_Harrison. dysfunction. Free radicals cause catalytic destruction of membranes and likely damage other vital functions of cells. Lesser degrees of ischemia, as are seen within the ischemic penumbra, favor apoptotic cellular death causing cells to die days to weeks later. Fever dramatically worsens brain injury during ischemia, as does hyperglycemia (glucose >11.1 mmol/L [200 mg/dL]), so it is reasonable to suppress fever and prevent


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InternalMed_Harrison. FIGURE 446-2 Major steps in the cascade of cerebral ischemia. See text for details. iNOS, inducible nitric oxide synthase; PARP, poly-A ribose polymerase. hyperglycemia as much as possible. The value of induced mild hypothermia to improve stroke outcomes is the subject of continuing clinical research.