Neurology_Adams

Neurology_Adams. proven later to be incorrect. Claims have been made of safety in this regard for lamotrigine, causing many specialists to change from the more conventional drugs to this one in women who anticipate becoming pregnant, but lamotrigine levels tend to fall precipitously during pregnancy. A report by Cunnington and colleagues using registry information suggests that the incidence of major birth defects in the fetuses exposed to lamotrigine during the first trimester is just under 3 percent, similar to risk estimates for the general population but also close to the 3 to 4 percent risk derived from most registries of women on anticonvulsants. Polytherapy with lamotrigine and valproate raised the estimate of risk to 12 percent. For all the drugs, polytherapy has the highest risk and there is a significant dose effect for an individual drug on the likelihood of fetal malformation.


Neurology_Adams

Neurology_Adams. If a woman with epilepsy has not required medications for a time before getting pregnant and has a seizure during pregnancy, the best choice of medication may be phenytoin for its advantage in rapid seizure control, or levetiracetam. Exposure of the fetus late in gestation poses few teratogenic risks. If a woman discovers she is pregnant while on an antiepileptic drug, changing medications is unlikely to reduce the chances of birth defects, even for valproate, but this drug retains the risk of lower IQ in the child. The special case of eclamptic seizures is managed by infusion of magnesium as noted below.


Neurology_Adams

Neurology_Adams. Epileptic women of childbearing age who are on an antiepileptic medication, particularly those which induce cytochrome P450, should be advised that higher doses of the estradiol component of birth control agents are required or they may be exposed to the issues of becoming pregnant while antiepileptic medications. Phenytoin, carbamazepine, and topiramate induce hepatic enzymes and most other medications do not have this effect. Seizures in Eclampsia (See Also Chap. 33)


Neurology_Adams

Neurology_Adams. This syndrome appears during the last trimester of pregnancy or soon after delivery and may announce itself by hypertension and convulsions; the latter are generalized and tend to occur in clusters. The standard practice is to induce labor or perform a cesarean section and manage the seizures as one would manage those of hypertensive encephalopathy (of which this is one type). The administration of magnesium sulfate continues to be the favored treatment by obstetricians for the prevention of eclamptic seizures; two randomized trials have reestablished its value in preventing seizures in preeclamptic women (Lucas et al) and in avoiding a second convulsion once one had occurred (Eclampsia Trial Collaborative Group). Magnesium sulfate, 10 g IM, followed by 5 g every 4 h, proved comparable to standard doses of phenytoin as prophylaxis for seizures. Our colleagues use a regimen of 4 g IV more than 5 to 10 min followed by a maintenance dose of 5 g every 4 h IM or 1 to 2 g/h IV. In nontoxic


Neurology_Adams

Neurology_Adams. standard doses of phenytoin as prophylaxis for seizures. Our colleagues use a regimen of 4 g IV more than 5 to 10 min followed by a maintenance dose of 5 g every 4 h IM or 1 to 2 g/h IV. In nontoxic gestational epilepsy, approximately 25 percent of patients are found to have some disease (neoplastic, vascular, or traumatic) that will persist.


Neurology_Adams

Neurology_Adams. The treatment of epilepsy of all types can be divided into four parts: the use of antiepileptic drugs, the surgical excision of epileptic foci and other surgical measures, the removal of causative and precipitating factors, and the regulation of physical and mental activity.


Neurology_Adams

Neurology_Adams. The goal of drug treatment is to create a seizure-free state if possible and with the fewest side effects. In the past, a few seizures a year had been considered adequate control but with numerous newer medications it is reasonable to eliminate seizures. On the other hand, it is equivalently deleterious to make a patient so mentally dull as to interfere with function at work or school. The choice and dose of medication depends on many factors including sex, age, other medications, and renal or hepatic dysfunction or other medical conditions and psychiatric conditions that might be favorably influenced by a particular agent. As a general rule, starting in the lower dose range and attempting to provide twice daily or daily administration are favored.


Neurology_Adams

Neurology_Adams. In approximately 70 percent of all patients with epilepsy, the seizures are controlled completely or almost completely by medications; in an additional 20 to 25 percent, the attacks are significantly reduced in number and severity. In a series reported by Kwan and Brodie approximately 20 years ago but probably still reflecting current circumstances almost half of patients with a new seizure disorder were controlled with first agent tried, another approximately 15 percent respond to a second as monotherapy, and the third choice controls very few instances—the remaining cases are considered treatment-resistant. In more modern series, such as the one reported by Bonnett and colleagues, the response to a first agent of a newer class was similar but subsequent agent cumulatively was somewhat more successful, achieving 75 percent control. More importantly, the simultaneous use of medications presents special problems and the rates of suppression of seizures with each additional drug are


Neurology_Adams

Neurology_Adams. more successful, achieving 75 percent control. More importantly, the simultaneous use of medications presents special problems and the rates of suppression of seizures with each additional drug are low and generally not additive. This approach, however, may not apply to combinations of some of the newer drugs.


Neurology_Adams

Neurology_Adams. An additional question regards whether to start treatment immediately in an adult with a first unprovoked seizure. The MESS trial, which randomized large groups of patients after a first unprovoked seizure to either immediate treatment or none (Marson and colleagues) concluded that the treated group had fewer subsequent seizures at 6 months (18 vs 26 percent), 2 years (32 vs 39 percent), and 5 years (42 vs 51 percent) and the differences were larger for those who had multiple seizures before randomization and the time to the next seizure was delayed. However, the differences became less significant over time and the side effects of the medications, as judged by practical factors such as keeping a job, were no different between groups. The death rates were comparable. Therefore, factors such as tolerance of the medications, patient preferences, and nature of work must be taken into account when making decisions regarding antiepileptic medicines. Guidelines from the American Academy of


Neurology_Adams

Neurology_Adams. as tolerance of the medications, patient preferences, and nature of work must be taken into account when making decisions regarding antiepileptic medicines. Guidelines from the American Academy of Neurology generally accord with these views (Krumholz et al).


Neurology_Adams

Neurology_Adams. Table 15-5 lists the most commonly used drugs along with their dosages, effective blood levels, and serum half-lives. Because of the long half-lives of phenytoin, phenobarbital, and ethosuximide, these drugs need be taken only once daily, preferably at bedtime. Valproate and carbamazepine have shorter half-lives, and their administration should be spaced during the day. It is useful to be familiar with the serum protein-binding characteristics of antiepileptic drugs and the interactions among these drugs, and between antiepileptic and other drugs.


Neurology_Adams

Neurology_Adams. Certain drugs are somewhat more effective in one type of seizure than in another, and it is necessary to use the proper drugs in optimum dosages for different circumstances. Initially, only one drug should be used and the dosage increased until sustained therapeutic levels have been attained. If the first drug does not control seizures, a different one should be tried, but frequent shifting of drugs is not advisable; each should be given an adequate trial before another is substituted. A general approach to the choice of drug in certain common forms of epilepsy is given in Table 15-6 for adults and Table 15-7 for children, but it must be noted that there are a number of drugs that may be appropriate in each circumstance. Furthermore, the antiepileptic drugs have approved purposes as assigned by the FDA (Federal Drug Administration) and the EMA (European Medicines Agency). These are more restrictive than are found in general use but it is worthwhile being familiar with the standing of


Neurology_Adams

Neurology_Adams. by the FDA (Federal Drug Administration) and the EMA (European Medicines Agency). These are more restrictive than are found in general use but it is worthwhile being familiar with the standing of various medications. A tabular summary of these approvals, main uses, and their dates of inception that divide the agents into three generations can be found in a review by Schmidt that is current as of 2016.


Neurology_Adams

Neurology_Adams. It is difficult to give definitive guidance on combining medications for refractory seizures. Several general principles are worth noting. First, it may seem sensible to avoid drug combinations with similar putative mechanisms because their side effects may be additive, for example, the addition of lamotrigine to carbamazepine or of phenytoin to carbamazepine may not be ideal but at the same time, it should be mentioned that the mechanism of action has little influence on clinical effectiveness and drugs of a similar class are often combined. Second, the clinician should be aware of known interactions through metabolic pathways such as valproate combined with either lamotrigine or phenobarbital as they share the cytochrome P450 degradation pathway. Third, although it is appropriate to use drugs that are known to be effective for the class of seizures under treatment, it is often necessary to extend the choices beyond these restrictions.


Neurology_Adams

Neurology_Adams. The therapeutic dose for any given patient must be determined, to some extent by clinical effect, guided by measurement of serum levels, as described below. Inquiry regarding seizure control and drug side effects is more valuable than adjustment of medication based solely on drug concentrations. Blood for serum levels is ideally drawn in the morning before the first dose of antiepileptic medication (“trough levels”), a practice that introduces consistency in measurement. A drug should not be discarded as being ineffective, even at the upper limits of therapeutic blood levels, when a slight increase in dosage would have led to suppression of attacks. On the other hand, drug levels can be helpful in detecting noncompliance or poor absorption in instances of inadequate seizure control. The management of seizures is facilitated by having patients chart their daily medication and the number, time, and circumstances of each episode. Furthermore, in some instances, asking the patients about


Neurology_Adams

Neurology_Adams. of seizures is facilitated by having patients chart their daily medication and the number, time, and circumstances of each episode. Furthermore, in some instances, asking the patients about seizure frequency may be unreliable. Some patients find it helpful to use a dispenser that is filled with medications with sufficient pills to last the week. This indicates to the patient whether a dose had been missed and whether the supply of medications is running low.


Neurology_Adams

Neurology_Adams. In general, higher serum concentrations of drugs are necessary for the control of focal seizures than for generalized ones. The usual blood level assay is of the total concentration of the drug (see Table 15-5); this is not a precise reflection of the amount of drug entering the brain, because—in the case of the most widely used antiepileptics—the large proportion of drug is bound to albumin and does not penetrate nervous tissue. Also, in patients who are malnourished or chronically ill or who have a constitutional reduction in proteins, there may be intoxication at low total serum levels. Certain antiepileptic drugs also have active metabolites that are not measured by methods ordinarily used to determine serum concentrations but nonetheless produce toxicity. This is particularly true for the epoxide of carbamazepine. The situation may be further complicated by interactions between one drug and the metabolites of another, as, for example, the inhibition of epoxide hydrolase by


Neurology_Adams

Neurology_Adams. for the epoxide of carbamazepine. The situation may be further complicated by interactions between one drug and the metabolites of another, as, for example, the inhibition of epoxide hydrolase by valproic acid, leading to toxicity through the buildup of carbamazepine epoxide. In circumstances of unexplained toxicity in the face of conventionally obtained serum levels that are normal, measurement may be undertaken of the levels of free drug and the concentration of active metabolites.


Neurology_Adams

Neurology_Adams. The use of saliva for measurement of free drug levels has merit but has not been adopted frequently in practice. The measurements correlate with free drug levels. It has the advantage of allowing the patient to collect a sample before breakfast and avoid venipuncture.


Neurology_Adams

Neurology_Adams. Finally, the pharmacokinetics of each drug plays a role in toxicity and the serum level that is achieved with each alteration in the dose. This is particularly true of phenytoin, which, as the result of saturation of liver enzymatic capacity, has nonlinear kinetics once serum concentration exceeds 10 mg/mL. For this reason, a typical increase in dose from 300 to 400 mg daily results in a disproportionate elevation of the serum level and toxic side effects. Elevations in drug concentrations are also accompanied by prolongation of the serum half-life, which increases the time to reach a steady-state concentration of phenytoin after dosage adjustments. Contrariwise, carbamazepine is known to induce its own metabolism, so that doses adequate to control seizures at the outset of therapy are no longer effective several weeks later.


Neurology_Adams

Neurology_Adams. Antiepileptic drugs have manifold interactions with each other and with a wide variety of other drugs. Although many such interactions are known, only a few are of clinical significance and most pertain to older generations of medications, requiring adjustment of drug dosages (see Kutt).


Neurology_Adams

Neurology_Adams. Among the interactions, valproate often leads to accumulation of active phenytoin and of phenobarbital by displacing them from serum proteins, as well as slightly elevating serum total levels. Some of the agents that alter the concentrations of antiepileptic medications are chloramphenicol, which causes the accumulation of phenytoin and phenobarbital, and erythromycin, which causes the accumulation of carbamazepine. Antacids reduce the blood phenytoin concentration, whereas histamine blockers used to reduce gastric acid output do the opposite. Salicylates reduce the total plasma levels of antiepileptic drugs but elevate the free fraction by displacing the drug from its protein carrier. More importantly, warfarin levels are decreased by the addition of phenobarbital or carbamazepine and may be increased by phenytoin although, with this last drug there may be unexpected alterations of the international normalized ratio (INR) in either direction. Enzyme-inducing drugs such as phenytoin,


Neurology_Adams

Neurology_Adams. be increased by phenytoin although, with this last drug there may be unexpected alterations of the international normalized ratio (INR) in either direction. Enzyme-inducing drugs such as phenytoin, carbamazepine, and barbiturates can greatly increase the chance of breakthrough menstrual bleeding in women taking oral contraceptives and may lead to failure of contraceptive medications, and adjustments in the amount of estradiol must be made. These interactions are emphasized further below under the discussions of each agent.


Neurology_Adams

Neurology_Adams. Hepatic function greatly affects antiepileptic drug concentrations, since most of these drugs are metabolized in the liver. Serum levels must be checked more frequently than usual if there is liver failure, and with hypoalbuminemia it is advisable to obtain free drug levels for reasons just mentioned. Renal function has an indirect effect on the concentrations of the commonly used antiepileptics, but some agents, such as levetiracetam, gabapentin, and pregabalin, are excreted through the kidneys and require dosage adjustment in cases of renal failure. The main renal effects for the drugs in general are alterations in protein binding induced by uremia. In end-stage renal failure, serum levels are not an accurate guide to therapy and the goal should be to attain adequate free concentrations, typically, 1 to 2 μg/mL. In addition, uremia causes the accumulation of phenytoin metabolites, which are measured with the parent drug by enzyme-multiplied immunoassay techniques. In patients who


Neurology_Adams

Neurology_Adams. typically, 1 to 2 μg/mL. In addition, uremia causes the accumulation of phenytoin metabolites, which are measured with the parent drug by enzyme-multiplied immunoassay techniques. In patients who are being dialyzed, total blood levels of phenytoin tend to be low because of decreased protein binding; in this situation it is also necessary to track free (unbound) levels as it is for other highly protein bound drugs. Because dialysis removes many drugs, particularly levetiracetam, phenobarbital, topiramate, ethosuximide, and gabapentin, dosage of these drugs may have to be increased or doses may have to be administered after dialysis.


Neurology_Adams

Neurology_Adams. Rashes are the most frequent idiosyncratic reactions to the drugs used to treat epilepsy. The aromatic compounds (phenytoin, carbamazepine, phenobarbital, primidone, and lamotrigine) are the ones most often responsible. Furthermore, there is a high degree of cross-reactivity within this group, particularly between phenytoin, carbamazepine, and phenobarbital, and possibly, lamotrigine. The problem arises most often in the first month of use. The typical eruption is maculopapular, mainly on the trunk; it usually resolves within days of discontinuing the medication. More severe rashes may develop, sometimes taking the form of erythema multiforme and Stevens-Johnson syndrome, or even toxic epidermal necrolysis, especially with lamotrigine.


Neurology_Adams

Neurology_Adams. Certain polymorphisms in HLA genes (HLA-B*1502) have been associated with an increased risk of these types of severe skin reactions, particularly those of Asian ancestry but probably also in Caucasians, in whom this genotype is rare. Another allele HLA-A*3101 may be associated with skin eruptions in Caucasians (McCormack et al), but it (HLA-B*1502) does not seem reasonable at this time to screen non-Asian patients for such an infrequent complication. Another rare systemic hypersensitivity syndrome associated with the use of antiepileptic medications is one of high fever, rash, lymphadenopathy, and pharyngitis. Eosinophilia and hepatitis (or nephritis) may follow. If any of these reactions require that one of the aromatic drugs be replaced, valproate, gabapentin, topiramate, or levetiracetam are reasonable substitutes, depending, of course, on the nature of the seizures. Discontinuation of Antiepileptic Drugs


Neurology_Adams

Neurology_Adams. Withdrawal of medications may be undertaken in patients who have been free of seizures for a prolonged period. There are few firm rules to guide the physician in this decision. One plan, applicable to most forms of epilepsy, is to obtain an EEG whenever withdrawal of medication is contemplated. We have taken the approach that if the tracing is abnormal by way of showing paroxysmal activity, it is generally better to continue treatment. However, a normal EEG may not be helpful in making the decision to discontinue medications. A prospective study by Callaghan and colleagues showed that in patients who had been seizure-free during 2 years of treatment with a single drug, one-third relapsed after discontinuation of the drug, and this relapse rate was much the same in adults and children and whether the drug was reduced over a period of weeks or months. The relapse rate was lower in patients with absence and generalized-onset seizures than in patients with focal seizures. Another study by


Neurology_Adams

Neurology_Adams. the drug was reduced over a period of weeks or months. The relapse rate was lower in patients with absence and generalized-onset seizures than in patients with focal seizures. Another study by Specchio and colleagues gave results similar to those of the large Medical Research Council Antiepileptic Drug Withdrawal Study—namely, that after 2 years on a single anticonvulsant during which no seizures had occurred, the rate of relapse was 40 percent 2.5 years later and 50 percent at 5 years after discontinuation; this compared to a seizure recurrence rate of 20 percent for patients remaining on medication. Some have suggested that a longer seizure-free period is associated with a lesser rate of relapse.


Neurology_Adams

Neurology_Adams. Often in practice, the suggestion to stop medications after a lengthy seizure free period comes from the patient, for example if pregnancy is planned or there are untoward side effects but otherwise, the change is never risk free and therefore is infrequently impelled by the physician. Decisions regarding the cessation of medication are also tempered by patient’s desire to continue driving and their concern that another seizure may prevent a return to driving.


Neurology_Adams

Neurology_Adams. Patients with juvenile myoclonic epilepsy, even those with long seizure-free periods, should probably continue medication life-long, but there have been no thorough studies to support this dictum. In young women with this disorder who plan or a likely to become pregnant, changing from valproate to levetiracetam may be sensible. The appropriate duration of treatment for postinfarction epilepsy has not been studied, and most neurologists continue to use one drug indefinitely. Interestingly, epilepsy caused by military brain wounds tends to wane in frequency or to disappear in 20 to 30 years, thereafter no longer requiring treatment (Caveness). In contrast, childhood uncomplicated absence seizures do not require lifelong treatment.


Neurology_Adams

Neurology_Adams. A curious and unexplained lesion in the splenium of the corpus callosum has been detected in patients who have had their antiepileptic drug(s) withdrawn in the previous few days. A review of 16 patients by Gürtler and colleagues did not find a clinical correlate for this change. A broad range of drugs was implicated and the lesion was most prominent on FLAIR MRI. Various metabolic derangements cause similar lesions but the mechanism in all these instances has not been established as discussed Doherty and colleagues. Specific Drugs in the Treatment of Seizures


Neurology_Adams

Neurology_Adams. Specific Drugs in the Treatment of Seizures The putative mechanisms of action of the most commonly used drugs are reasonably well known but gaps remain. A review by Bialer and White contains a schematic depiction of putative drug actions at excitatory and inhibitory synapses, as adopted in Fig. 15-6 and as summarized in Table 15-5. There it is apparent that for each of these two physiologic classes of neurons, some medications have their main effect on voltage-gated ion channels and others, on membrane receptors or intracellular vesicular activity.


Neurology_Adams

Neurology_Adams. Phenytoin, carbamazepine, levetiracetam, and valproate are representative antiepileptic drugs that may be considered “broad spectrum” and are more or less equally effective in the treatment of both generalized and focal seizures (see Table 15-6 for typical initial dosages). The first two of these drugs act by blocking sodium channels, thus preventing abnormal neuronal firing and seizure spread. Lamotrigine has become an alternative for treating focal seizures with a different side effect profile from the other three (see also Schmidt).


Neurology_Adams

Neurology_Adams. Because carbamazepine (or the related oxcarbazepine) and levetiracetam have somewhat fewer side effects, one or the other is preferred as the initial drug by many neurologists, though phenytoin and valproate have very similar therapeutic and side-effect profiles. In many cases, levetiracetam, phenytoin or carbamazepine alone will control seizures. If not, the use of valproate (which facilitates GABA activity) alone, or the combined use of two medications, produces better control. Levetiracetam has attained popularity largely because of its lack of interactions with other antiepileptic and other medications. Carbamazepine, levetiracetam, and valproate are probably preferable to phenytoin for children because they do not coarsen facial features and do not produce gum hypertrophy or breast enlargement. Because of the high incidence of myoclonic epilepsy in adolescence, it has been the practice of many neurologists to use valproate as the first drug in this age group. Weight gain,


Neurology_Adams

Neurology_Adams. enlargement. Because of the high incidence of myoclonic epilepsy in adolescence, it has been the practice of many neurologists to use valproate as the first drug in this age group. Weight gain, menstrual irregularities (see below) during the period of initiation of valproate, and its teratogenic effects also must be accounted for in the choice of initial drug for otherwise uncomplicated seizures in young women.


Neurology_Adams

Neurology_Adams. Most of the commonly used antiepileptic drugs cause, to varying degrees, a decrease in bone density and an increased risk of fracture from osteoporosis in older patients, particularly in women. Several mechanisms are probably active, among them, induction of the cytochrome P450 system, which enzymatically degrades vitamin D. No specific recommendations have been offered to counteract this effect of bone loss, but many practitioners have advised patients to take calcium supplements, vitamin D, or one of the bisphosphonates if there is no contraindication, and to periodically check bone density.


Neurology_Adams

Neurology_Adams. Finally, several reports and meta-analyses over the past decades have suggested that antiepileptic drugs taken together as a class, increase the incidence of depression and suicide, both in individuals with epilepsy and psychiatric patients. The issue may never be entirely resolved because of confounding factors but a patient level-analysis performed by Arana and colleagues showed no such relationship in epilepsy once underlying depression was accounted for. However, this assessment was contrary to an earlier FDA meta-analysis and it may not hold for certain drugs, for example, levetiracetam.


Neurology_Adams

Neurology_Adams. Phenytoin This sodium channel blocker has been used for decades for focal and generalized seizures. Its advantages are low cost, wide availability, ease of monitoring of blood levels and ability to rapidly achieve therapeutic levels with, oral, intravenous, and intramuscular preparations. Rash, fever, lymphadenopathy, eosinophilia and other blood dyscrasias, and polyarteritis are manifestations of idiosyncratic phenytoin hypersensitivity; their occurrence calls for discontinuation of the medication. Overdose with phenytoin causes ataxia, diplopia, and stupor. The prolonged use of phenytoin leads to hirsutism, enlargement of gums from hyperplasia of connective tissue and epithelium with subsequent periodontal disease, and coarsening of facial features in children. A clinical trial conducted by Arya and colleagues suggested that folate supplementation may prevent gingival hyperplasia in children. Chronic phenytoin use over several decades may occasionally be associated with peripheral


Neurology_Adams

Neurology_Adams. by Arya and colleagues suggested that folate supplementation may prevent gingival hyperplasia in children. Chronic phenytoin use over several decades may occasionally be associated with peripheral neuropathy and probably with a form of cerebellar degeneration (Lindvall and Nilsson); it is not clear if these are strictly dose-related effects or idiosyncratic reactions. An antifolate effect on blood and interference with vitamin K metabolism have also been reported, for which reason pregnant women taking phenytoin (and in fact most other antiepileptic drugs) should be given folate supplementation and vitamin K before delivery and the newborn infant also should receive vitamin K to prevent bleeding. Phenytoin should not be used together with disulfiram, chloramphenicol, sulfamethizole, or cyclophosphamide, and the use of either phenobarbital or phenytoin is not advisable in patients receiving warfarin because of the undesirable interactions already described. Choreoathetosis is a rare


Neurology_Adams

Neurology_Adams. cyclophosphamide, and the use of either phenobarbital or phenytoin is not advisable in patients receiving warfarin because of the undesirable interactions already described. Choreoathetosis is a rare idiosyncratic side effect. Fosphenytoin for intramuscular and intravenous administration allows somewhat faster attainment of serum levels and may have minor advantages in special circumstances, especially the availability of the IM route. Intravenous phenytoin and fosphenytoin, including their risks, are discussed further in the section on status epilepticus.


Neurology_Adams

Neurology_Adams. Carbamazepine This drug, also a blocker of sodium channels like phenytoin, causes many of the same side effects as phenytoin, but to a slightly lesser degree. There is induction of hepatic enzymes and “autoindicution,” leading to declining drug levels after a few weeks of administration. Mild leukopenia is common, and there have been rare instances of pancytopenia, hepatic enzyme abnormalities, pancreatitis, hyponatremia (inappropriate antidiuretic hormone [ADH]), and, rarely, diabetes insipidus as idiosyncratic reactions. It is advisable therefore, that a complete blood count and liver function tests (some practitioners omit the latter because of the infrequency of hepatic problems) be done before or soon after treatment is instituted and that counts are rechecked regularly. Idiosyncratic rashes, some as severe as Stevens-Johnson syndrome may occur, particularly in Asian individuals carrying the HLA-B*1502 haplotype as mentioned above. It has not been considered useful to check


Neurology_Adams

Neurology_Adams. rashes, some as severe as Stevens-Johnson syndrome may occur, particularly in Asian individuals carrying the HLA-B*1502 haplotype as mentioned above. It has not been considered useful to check patients for this haplotype but it may be considered in Asian patients.


Neurology_Adams

Neurology_Adams. Oxcarbazepine, an analogue of carbamazepine, has fewer of these side effects than the parent drug, especially marrow toxicity, but its long-term therapeutic value is not as well established. It has the advantage of being titrated upward at a more rapid rate than carbamazepine. Dose-related side effects are similar to carbamazepine but it has less hepatic enzyme induction. Some patients report weight gain after continued use. Hyponatremia has been reported in 3 percent of patients taking oxcarbazepine. Should drowsiness or increased seizure frequency occur, this complication should be suspected. Rashes occur at the same or slightly lower rate than with carbamazepine and there is considerable cross-reactivity for this side effect. Elevated cholesterol and osteoporosis are lesser effects, shared also with carbamazepine.


Neurology_Adams

Neurology_Adams. Valproate This drug in all its related forms is considered to be GABA-ergic, acting through glutamic acid decarboxylase, but also displaying some sodium channel blocking features. All preparations of this drug are occasionally hepatotoxic, an adverse effect that is usually (but not invariably) limited to children 2 years of age and younger. The use of valproate with hepatic enzyme-inducing drugs increases the risk of liver toxicity. However, mild elevations of serum ammonia and mild impairments of liver function tests in an adult do not require discontinuation of the drug. An increasingly emphasized problem with valproate has been weight gain during the first months of therapy. In one study there was an average addition of 5.8 kg, and even more in those disposed to obesity. In addition, menstrual irregularities and polycystic ovarian syndrome may appear in young women taking the drug, perhaps as a consequence of the aforementioned weight gain. Pancreatitis is a rare but important


Neurology_Adams

Neurology_Adams. menstrual irregularities and polycystic ovarian syndrome may appear in young women taking the drug, perhaps as a consequence of the aforementioned weight gain. Pancreatitis is a rare but important complication of valproate. Tremor and slight bradykinesias have been seen and they vaguely simulate parkinsonism. The major issues, however, pertain to its use in pregnancy as discussed earlier.


Neurology_Adams

Neurology_Adams. An intravenous form of valproate is available and may be useful in status epilepticus. The maximum recommended rate of administration is 3 mg/kg per min.


Neurology_Adams

Neurology_Adams. Phenobarbital Introduced as an antiepileptic drug in 1912, it is as effective as phenytoin and carbamazepine, but because of its dose-related toxic effects—drowsiness and mental dullness, nystagmus, and staggering, as well as the availability of better alternatives—it is now infrequently used in adults. It inhibits sodium currents through the sodium channel and has been found to have some additional GABA-ergic effect. The drug strongly induces cytochrome P450 and therefore has interactions with many medications. There are infrequent disorders of connective tissue, such as frozen shoulder and Duyputren contractures that have been attributed to long-term use. The adverse effects of primidone are much the same. Both drugs may provoke behavioral problems in developmentally delayed children and they are still used to advantage as an adjunctive anticonvulsant and as primary therapy in infantile seizures. The rate of teratogenicity is increased (stated to be approximately 5.5 percent) and


Neurology_Adams

Neurology_Adams. and they are still used to advantage as an adjunctive anticonvulsant and as primary therapy in infantile seizures. The rate of teratogenicity is increased (stated to be approximately 5.5 percent) and comparable to other main line drugs.


Neurology_Adams

Neurology_Adams. Lamotrigine This drug closely resembles phenytoin in having a broad spectrum of antiseizure activity but has different features relating to toxicity. It functions by selectively blocking the slow sodium channel, thereby preventing the release of the excitatory transmitters glutamate and aspartate. It is effective as a first-line and adjunctive drug for generalized and focal seizures, and may be an alternative to valproate in young women because it does not provoke weight gain and ovarian problems. The main limitation to its use has been a serious rash in approximately 1 percent of patients, requiring discontinuation of the drug, and lesser dermatologic eruptions in 12 percent. It should be pointed out that some registries have reported considerably lower rates of these complications and the slow introduction of the medication may reduce the incidence of drug eruptions (see below). Rare cases of reversible chorea have been reported, especially with the concurrent use of phenytoin.


Neurology_Adams

Neurology_Adams. the slow introduction of the medication may reduce the incidence of drug eruptions (see below). Rare cases of reversible chorea have been reported, especially with the concurrent use of phenytoin. Combined use with valproate greatly increases the serum level of lamotrigine. It has been said to have a more favorable teratogenic profile than most other drugs. Dosing depends greatly on the concurrent use of other drugs, reducing its dose and rapidity of escalation if used with other enzyme-inducing AEDs such as phenytoin or carbamazepine and particularly with valproate.


Neurology_Adams

Neurology_Adams. Levetiracetam This novel drug with uncertain mechanism has been useful in the treatment of both partial and generalized seizures. The agent interacts with the SV2A synaptic vesicle protein, but how this relates to its antiepileptic properties is still being investigated. It is well tolerated if initiated slowly, but may produces considerable sleepiness and dizziness and if used at high doses. It also may produce irritability and depression or exaggerate underlying depression. A major advantage is that there are no important interactions with other antiepileptic drugs and it is renally excreted for which reason it is often chosen as a first-line agent in patients who have organ failure and require numerous medications, as well as those receiving hepatically metabolized chemotherapeutics. There are some data showing a favorable teratogenic profile.


Neurology_Adams

Neurology_Adams. Other antiepileptic drugs Two other drugs, gabapentin and vigabatrin, were synthesized specifically to enhance the intrinsic inhibitory system of GABA in the brain. Gabapentin is chemically similar to GABA, but its anticonvulsant mechanism is not known; it has an apparent effect on calcium channels. It is moderately effective in partial and secondary generalized seizures and has the advantage of not being metabolized by the liver. Vigabatrin inhibits GABA transaminase. Vigabatrin is no longer used in adults because of the side effect or retinal damage. Tiagabine is considered to be an inhibitor of GABA reuptake.


Neurology_Adams

Neurology_Adams. Topiramate, has much the same mode of action and probably a broader effectiveness as tiagabine. It will rarely cause serious dermatologic side effects, especially if used with valproate, and appears to induce renal stones in 1.5 percent of patients, lower in women. Angle-closure glaucoma has also been reported as a complication. A minor problem has been the development of hyperchloremic metabolic acidosis. It has high teratogenicity in most studies.


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Neurology_Adams. Lacosamide, a potent drug for seizures that have a focal onset and generalize or remain focal, is currently used mainly as an adjunctive therapy. Like levetiracetam, its mechanism of action is not entirely known but it has been shown to modulate voltage-gated sodium channel activity. It may be titrated upward rapidly and has limited pharmacokinetic interactions but its effective range of blood levels is narrow; also like levetiracetam, it is renally excreted. The availability of an intravenous preparation is also notable. The main but infrequent side effects are headache and diplopia. The drug may prolong the P-R interval and worsen heart failure.


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Neurology_Adams. Ethosuximide and valproate are equally effective for the treatment of absence seizures, the former having fewer cognitive side effects according to a study by Glauser and colleagues. The use of ethosuximide is virtually limited to this indication. It is good practice, so as to avoid excessive sleepiness, to begin with a single dose of 250 mg of ethosuximide per day and to increase it every week until the optimum therapeutic effect is achieved. Methsuximide (Celontin) is useful in individual cases where ethosuximide and valproate have failed. In patients with benign absence attacks that are associated with photosensitivity, myoclonus, and clonic-tonic-clonic seizures (including juvenile myoclonic epilepsy), valproate is the drug of choice. Valproate is particularly useful in children who have both absence and grand mal attacks, as the use of this drug alone often permits the control of both types of seizures. The concurrent use of valproate and clonazepam has been known to produce


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Neurology_Adams. have both absence and grand mal attacks, as the use of this drug alone often permits the control of both types of seizures. The concurrent use of valproate and clonazepam has been known to produce absence status.


Neurology_Adams

Neurology_Adams. Zonisamide, similar to topiramate, seems to be useful for myoclonic epilepsy but its main use is currently as an adjuvant in al epilepsy. It is not predominantly a sodium channel blocker and can be taken in parallel with carbamazepine. Some clinicians have found it to produce fewer cognitive side effects than topiramate. New antiepileptic medications are being introduced regularly, among the newer ones is brivaracetam that is likely to display to broad activity against seizure types and lack of interaction with other medications seen with levetiracetam. Retigabine, rufinamide, pregabalin, gabapentin, felbamate, eslicarbazepine, several in the diazepine class find special use, mostly in epilepsy clinics that treat recalcitrant seizures. The medications used in the neonatal and infant population are discussed below. Treatment of Seizures in the Neonate and Young Child


Neurology_Adams

Neurology_Adams. Treatment of Seizures in the Neonate and Young Child This specialized area of neonatal seizures is discussed by Fenichel and by Volpe and in children by Guerrini. In general, phenobarbital has been preferred for seizure control in infancy. Probably the form of epilepsy that is most difficult to treat is the childhood Lennox-Gastaut syndrome. Some of these patients have as many as 50 or more seizures per day, and there may be no effective combination of anticonvulsant medications. Valproic acid (900 to 2,400 mg/d) will reduce the frequency of spells in approximately half the cases. The newer drugs—lamotrigine, topiramate, vigabatrin—are each effective in approximately 25 percent of cases. Clonazepam also has had limited success. In the special case of Dravet syndrome, a disorder of the sodium channel, antiepileptic drugs that block that same channel are avoided.


Neurology_Adams

Neurology_Adams. In the treatment of infantile spasms, ACTH or adrenal corticosteroids had been used, but vigabatrin is now found to be as effective, including in patients with underlying tuberous sclerosis (see Elterman et al).


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Neurology_Adams. Recurrent generalized convulsions at a frequency that precludes regaining of consciousness in the interval between seizures (convulsive status) constitutes the most serious problem in epilepsy, with an overall mortality of 20 to 30 percent, according to Towne and colleagues, but probably lower in recent years. It is perhaps the most common neurologic emergency. Some patients who die of epilepsy do so because of uncontrolled seizures of this type, complicated by the effects of the underlying illness or an injury sustained as a result of a convulsion. Rising temperature, acidosis, hypotension, and renal failure from myoglobinuria is a sequence of life-threatening events that may be encountered in cases of convulsive status epilepticus. Prolonged convulsive status (for longer than 30 min) also carries a risk of serious neurologic sequelae (epileptic encephalopathy). The MRI during and for days after a bout of status epilepticus may show signal abnormalities in the region of a focal


Neurology_Adams

Neurology_Adams. also carries a risk of serious neurologic sequelae (epileptic encephalopathy). The MRI during and for days after a bout of status epilepticus may show signal abnormalities in the region of a focal seizure or in the hippocampi, most often reversible, but we have had several such patients who awakened and were left in a permanent amnesic state. The MRI changes are most evident on FLAIR and diffusion-weighted sequences and may also appear in the pulvinar of the thalamus. With regard to acute medical complications, from time to time a case of neurogenic pulmonary edema is encountered during or just after the convulsions, and some patients may become extremely hypertensive, making it difficult to distinguish the syndrome from hypertensive encephalopathy.


Neurology_Adams

Neurology_Adams. The etiologies of status epilepticus vary among age groups but all the fundamental causes of seizures are able to produce the syndrome. The most recalcitrant cases we have encountered in adults have been associated with viral or paraneoplastic encephalitis, old traumatic injury, and epilepsy with severe mental retardation. Stroke and brain tumor have, in contrast, been infrequent causes. More recently, several groups, for example, Gaspard and coworkers have emphasized autoimmune forms of encephalitis including the paraneoplastic variety as the most common explanations for new-onset refractory status epilepticus but add that over half of cases remain cryptogenic. Treatment of Convulsive Status Epilepticus (Table 15-8) The many regimens that have been proposed for the treatment of status epilepticus attest to the fact that no one of them is altogether satisfactory and none is clearly superior (Treiman et al).


Neurology_Adams

Neurology_Adams. We have had the success with the following program, which reflects several published approaches. When the patient is first seen, an initial assessment of cardiorespiratory function is made and an oral airway established. As summarized by Bleck, a large-bore intravenous line is inserted; blood is drawn for glucose, BUN, electrolytes, and a metabolic and drug screen. A normal saline infusion is begun and a bolus of glucose is given (with thiamine if malnutrition and alcoholism are potential factors). To rapidly suppress the seizures, we generally use diazepam intravenously at a rate of about 2 mg/min until the seizures stop or a total of 20 mg has been given; alternatively, lorazepam, 0.1 mg/kg given by intravenous push at a rate not to exceed 2 mg/min, is now favored, being marginally more effective than diazepam because of its clinically longer duration of action (see Table 15-8).


Neurology_Adams

Neurology_Adams. Immediately thereafter, a loading dose (20 mg/kg) of phenytoin is administered by vein at a rate of less than 50 mg/min. More rapid administration risks hypotension and heart block; consequently, it is recommended that the blood pressure and electrocardiogram be monitored during the infusion. Phenytoin must be given through a freely running line with normal saline (it precipitates in other fluids) and should not be injected intramuscularly. A study by Treiman and colleagues has demonstrated the superiority of using lorazepam instead of phenytoin as the first drug to control status, but this is not surprising considering the longer latency of onset of phenytoin. Recently intravenous valproate 40 mg/kg or levetiracetam 60 mg/kg have been used as alternatives to phenytoin.


Neurology_Adams

Neurology_Adams. In the field, emergency medical technicians can administer lorazepam drug or midazolam. Attesting to the benefit of rapidly treating seizures, Silbergleit and colleagues have shown that intramuscular administration is slightly superior to the intravenous route simply because of the delay in inserting an intravenous line. Alldredge and colleagues showed that diazepines can be administered by paramedical workers in nursing homes with good effect in status epilepticus, terminating the seizures in about half of cases.


Neurology_Adams

Neurology_Adams. Nonetheless, a long-acting antiepileptic such as phenytoin must be given immediately after a diazepine has controlled the initial seizures. An alternative is the water-soluble drug fosphenytoin, which is administered in the same dose equivalents as phenytoin but can be injected at twice the maximum rate. Moreover, it can be given intramuscularly in cases where venous access is difficult. However, the delay in hepatic conversion of fosphenytoin to active phenytoin makes the latency of clinical effect approximately the same for both drugs.


Neurology_Adams

Neurology_Adams. In an epileptic patient known to be taking seizure medications chronically but in whom the serum level of drug is unknown, it is probably best to administer the full-recommended dose of phenytoin. If it can be established that the serum phenytoin is above 10 mg/mL, a lower loading dose may be advisable. If seizures continue, an additional 5 mg/kg is indicated. If this fails to suppress the seizures and status has persisted for 20 to 30 min, an endotracheal tube should be inserted and O2 administered. Having emphasized the dangers of this syndrome, at each stage of treatment it is worthwhile considering if a refractory convulsive episode is of psychogenic, nonepileptic nature. The reader is referred to the previous section on this subject.


Neurology_Adams

Neurology_Adams. Several approaches have been suggested to control status epilepticus that persists after these efforts. At this stage we have resorted to the approach suggested by Kumar and Bleck of giving high doses of midazolam (0.2 mg/kg loading dose followed by an infusion of 0.1 to 0.4 mg/kg/h as determined by clinical and EEG monitoring). If seizures continue, the dose can be raised as blood pressure permits. We have used in excess of 20 mg/h because of a diminishing effect over days. This regimen of midazolam and phenytoin may be maintained for several days without major ill effect in previously healthy patients. Propofol given in a bolus of 2 mg/kg and then as an intravenous drip of 2 to 8 mg/kg/h is an effective alternative to midazolam, but after 24 h the drug behaves like a high dose of barbiturate and there may be hypotension. Prolonged use of propofol may precipitate hypertriglyceridemia-associated pancreatitis or a fatal shock and acidosis (propofol syndrome).


Neurology_Adams

Neurology_Adams. Valproate and levetiracetam are available as intravenous preparations, making them suitable for administration in status, but their role in this circumstance has not been extensively studied. Another dependable approach is infusion of either pentobarbital, starting with 5 mg/kg, or phenobarbital, at a rate of 100 mg/min until the seizures stop or a total dose of 20 mg/kg is reached; a long period of stupor must be anticipated after. Hypotension often limits the continued use of the barbiturates, but Parviainen and colleagues were able to manage this problem by fluid infusions, dopamine, and neosynephrine.


Neurology_Adams

Neurology_Adams. If none of these measures controls the seizures, a more aggressive approach is taken to subdue all brain electrical activity by the use of general anesthesia. The preferred medications for this purpose have been pentobarbital or propofol, which, despite their moderate efficacy as primary anticonvulsants, are easier to manage than the alternative inhalational anesthetic agents. An initial intravenous dose of 5 mg/kg pentobarbital or 2 mg/kg propofol is given slowly to induce an EEG burst-suppression pattern, which is then maintained by the administration of pentobarbital, 0.5 to 2 mg/kg/h, or propofol, up to 10 mg/kg/h. Every 12 to 24 h, the rate of infusion is slowed to determine whether the seizures have stopped. The experience of Lowenstein and Aldredge, like our own, is that most instances of status epilepticus that cannot be controlled with the combination of standard anticonvulsants and midazolam will respond to high doses of barbiturates or to propofol, but that these infusions


Neurology_Adams

Neurology_Adams. of status epilepticus that cannot be controlled with the combination of standard anticonvulsants and midazolam will respond to high doses of barbiturates or to propofol, but that these infusions cause hypotension and cannot be carried out for long periods. Even a ketogenic diet, more commonly employed in childhood epilepsy as discussed further on, has been suggested as an ancillary treatment in these difficult cases of truly refractory status epilepticus as discussed by Thakur and colleagues.


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Neurology_Adams. Should the seizures continue, either clinically or electrographically, despite all these medications, one is justified in the assumption that the convulsive tendency is so strong that it cannot be checked by reasonable quantities of medications. However, a few patients in this predicament have survived and awakened, even at times with minimal neurologic damage depending on the underlying cause.


Neurology_Adams

Neurology_Adams. The volatile anesthetic agent isoflurane has also been used in these circumstances with good effect, as we have reported (Ropper et al), but the continuous administration of inhalational anesthetic agents is impractical in most critical care units. Halothane has been relatively ineffective as an anticonvulsant, but ether, although impractical, has in the past been effective in some. In the end, in patients with truly intractable status, one usually depends on phenytoin, phenobarbital (smaller doses in infants and children than are shown in Table 15-8), and on measures that safeguard the patient’s vital functions. Ketamine infusions have been a last resort, in combination with a midazolam infusion. A few times over the years, we have also resorted to inducing ketosis in adults by manipulating the nutrition given through a nasogastric tube. As a cautionary note, a series reported by Sutter and colleagues (2014) suggested that adverse events such as infection as well as mortality are


Neurology_Adams

Neurology_Adams. the nutrition given through a nasogastric tube. As a cautionary note, a series reported by Sutter and colleagues (2014) suggested that adverse events such as infection as well as mortality are higher in patients receiving intravenous anesthetic drugs compared to those who did not receive them but the possibility of confounding by the severity of illness must be taken into account before accepting a causal relationship.


Neurology_Adams

Neurology_Adams. A word is added here concerning neuromuscular paralysis and continuous EEG monitoring in status epilepticus. With failure of aggressive anticonvulsant and anesthetic treatment, there may be a temptation to paralyze all muscular activity, an effect easily attained with drugs such as pancuronium, while neglecting the underlying seizures. The use of neuromuscular blocking drugs without a concomitant attempt to suppress seizure activity is inadvisable. If such measures are undertaken, continuous or frequent intermittent EEG monitoring is essential; this may also be also helpful in the early stages of status epilepticus in that it guides the dosages of anticonvulsants required to suppress the seizures.


Neurology_Adams

Neurology_Adams. In the related but less-serious condition of acute repetitive seizures, in which the patient awakens between convulsions, a diazepam gel, which is well absorbed if given rectally, is available and has been found useful in institutional and home care of epileptic patients, although it is quite expensive. A similar effect has been attained by the nasal or buccal (transmucosal) administration of midazolam, which is absorbed from these sites (5 mg/mL, 0.2 mg/kg nasally; 2 mL to 10 mg buccally). Midazolam may be preferred among the diazepines for transmucosal use because it produces somewhat less respiratory depression than the others in the class and has been more effective at controlling seizures according to a study by McIntyre and colleagues. Still, only half were controlled. These approaches have found their main use in children with frequent seizures who live in supervised environments, where a nurse or parent is available to administer the medication.


Neurology_Adams

Neurology_Adams. Absence status should be managed by intravenous lorazepam, valproic acid, or both, followed by ethosuximide. Nonconvulsive generalized status is treated along the lines of grand mal status, usually stopping short of using anesthetic agents (see Meierkord and Holtkamp). In the case of epilepsia partialis continua, typically a difficult condition to control, a balance must be found between stopping the phenomenon and the risk of overuse of medications that can produce stupor. The patient must be involved by way of determining how troubling the movements are to him. Surgical Treatment of Epilepsy


Neurology_Adams

Neurology_Adams. Surgical Treatment of Epilepsy The surgical excision of epileptic foci that have not responded to intensive and prolonged medical therapy is being used with increasing effectiveness. At these centers, it has been estimated that approximately 25 percent of all patients with epilepsy are candidates for surgical therapy and more than half of these may benefit from extirpation of the epileptic cortical focus. With increasing experience and standardized approaches, especially in patients with temporal lobe epilepsy, it has been suggested that many patients are waiting too long before the surgical option is employed. A perspective that may promote surgery in even further is the observation that approximately 60 percent of patients with focal seizures will respond to a conventional anticonvulsant, but that among the remainder, few will respond to the addition of a second or third drug.


Neurology_Adams

Neurology_Adams. However, considerable effort, time and technology are required to determine the site of epileptic discharge and the method of safe removal of the cortical tissue. To locate the discharging focus requires a careful analysis of clinical, imaging, and EEG findings, often including those obtained by long-term video/EEG monitoring and, sometimes, intracranial EEG recording by means of intraparenchymal depth electrodes, subdural strip electrodes, and subdural grids. Recently, functional imaging, magnetoencephalography, and specialized EEG analysis have been introduced to supplement these methods.


Neurology_Adams

Neurology_Adams. The most favorable candidates for surgery are those with focal seizures that induce altered consciousness and a unilateral temporal lobe focus. In this group, rates of cure and significant improvement approach 90 percent in some series but overall, are probably closer to 50 percent after 5 years. A randomized trial conducted by Wiebe and colleagues gave representative results after temporal lobectomy of 58 percent of 40 carefully studied patients remaining seizure-free after 1 year, in contrast to 8 percent on medication alone. Furthermore, as reported by Yoon and colleagues, among those patients who remain free of seizures for 1 year after surgery, more than half are still free of seizures after 10 years and most of the remainder had one or fewer episodes per year. It should be emphasized that most of the patients who underwent surgery in these studies still required anticonvulsant medication. Even in the special group of patients with temporal lobe foci who have no lesion on MRI but


Neurology_Adams

Neurology_Adams. that most of the patients who underwent surgery in these studies still required anticonvulsant medication. Even in the special group of patients with temporal lobe foci who have no lesion on MRI but have subtle signal changes in the hippocampus, Bell et al report that 60 percent of patients can be made free of disabling seizures with surgery.


Neurology_Adams

Neurology_Adams. Excision of cortical tissue that contains a structural lesion outside of the temporal lobe accomplishes complete seizure-free states in approximately 50 percent. Taking all seizure types together, only approximately 10 percent of patients obtain no improvement at all and less than 5 percent are worse. The matter of resection of areas of focal cortical dysplasias in children is a highly specialized area. It has been indicated that the histologic features of the dysplasia are important determinants of the success of surgery (Fauser et al).


Neurology_Adams

Neurology_Adams. Other surgical procedures of value in highly selected cases are sectioning of the corpus callosum, which is for the most part palliative, and hemispherectomy, which may be curative in special circumstances. The most encouraging results with callosotomy have been obtained in the control of intractable partial and secondarily generalized seizures, particularly when atonic drop attacks are the most disabling seizure type. Removal of the entire cortex of one hemisphere, in addition to the amygdala and hippocampus, has been of value in children, as well as in some adults with severe and extensive unilateral cerebral disease and intractable contralateral motor seizures and hemiplegia. Rasmussen encephalitis, Sturge-Weber disease, and large porencephalic cysts at times fall into this category. Surgical, focused radiation, or endovascular reduction of arteriovenous malformations may reduce the frequency of seizures, but the results in this regard are somewhat unpredictable (see Chap. 34).


Neurology_Adams

Neurology_Adams. This technique has found some favor in cases of intractable partial and secondarily generalizing seizures. A pacemaker-like device is implanted in the anterior chest wall and stimulating electrodes are connected to the vagus at the left carotid bifurcation. The procedure is well tolerated except for hoarseness in some cases. Several trials have demonstrated an average of 25 percent reduction in seizure frequency among patients who were resistant to all manner of anticonvulsant drugs (see Chadwick for a discussion of clinical trials). The mechanism by which vagal stimulation produces its effects is unclear, and its role in the management of seizures is still being defined. Stimulation of the cerebellum and of other sites in the brain has also been used in the control of seizures, with no clear evidence of success. They must currently be considered to be experimental.


Neurology_Adams

Neurology_Adams. Since the 1920s, interest in this form of seizure control has varied, being revived periodically in centers caring for many children with intractable epilepsy. Despite the absence of controlled studies showing its efficacy or an agreed upon hypothesis for its mechanism, several trials in the first half of the twentieth century, and again more recently, demonstrated a reduction in seizures in half of the patients, including handicapped children with severe and sometimes intractable episodes. The diet is used mainly in children between the ages of 1 and 10 years. The regimen is initiated during hospitalization by starvation for a day or two in order to induce ketosis, followed by a diet in which 80 to 90 percent of the calories are derived from fat (Vining). The difficulties in making such a diet palatable leads to its abandonment by about one-third of children and their families.


Neurology_Adams

Neurology_Adams. A summary of experience from the numerous trials of the ketogenic diet can be found in the review by Lefevre and Aronson and in the report of its use in 58 children by Kinsman and colleagues. They both concluded that the diet is effective in refractory cases of epilepsy in childhood, reducing seizure frequency in two-thirds of children and allowing a reduction in the amount of anticonvulsant medication in many. It has also been commented that some benefit persists even after the diet has been stopped. Nephrolithiasis is a complication in somewhat less than 10 percent of children, and this risk is particularly high if topiramate is being used. Keotgenic diet is the main treatment for children with GLUT1 deficiency syndrome, as discussed earlier.


Neurology_Adams

Neurology_Adams. Keotgenic diet is the main treatment for children with GLUT1 deficiency syndrome, as discussed earlier. For lack of a better place to comment, we note that cannabinoids are being introduced for the treatment of epilepsy, prominently in special cases such as Dravet syndrome, but as reviewed by Friedman and Devinsky, no firm conclusions as to their effectiveness can be made at this time. Safety and Regulation of Physical


Neurology_Adams

Neurology_Adams. A person with incompletely controlled epilepsy should not be allowed to drive an automobile. Only a few states in the United States and most provinces of Canada mandate that physicians report patients with seizures under their care to the state motor vehicle bureau. Nonetheless, physicians should counsel such a patient regarding the obvious danger to himself and others if a seizure should occur while driving (the same holds for the risks of swimming unattended). What few data are available suggest that accidents caused directly by a seizure are rare and, in any case, 15 percent have been the result of a first episode of seizure that could not have been anticipated. In some states where a driver’s license has been suspended on the occurrence of a seizure, there is usually some provision for its reinstatement—such as a physician’s declaration that the patient is under medical care and has been seizure-free for some period of time (usually 6 months or 1 to 2 years). The Epilepsy


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Neurology_Adams. for its reinstatement—such as a physician’s declaration that the patient is under medical care and has been seizure-free for some period of time (usually 6 months or 1 to 2 years). The Epilepsy Foundation website can be consulted for updated information regarding restrictions on driving, and this serves as an excellent general resource for patients and their families (http://www.efa.org).


Neurology_Adams

Neurology_Adams. The most important factors in seizure breakthrough, next to the abandonment of medication or a natural reduction of serum levels of medication, are loss of sleep and abuse of alcohol or other drugs. The need for moderation in the use of alcohol must be stressed, as well as the need to maintain regular hours of sleep. Advice to collegians about moderating alcohol is particularly important. With proper safeguards, even potentially more dangerous sports, such as swimming, may be permitted. However, operating unguarded machinery, climbing ladders, or taking baths behind locked doors are not advisable; such a person should swim only in the company of a good swimmer. There is concern about epileptic mothers bathing their infants without additional safety guards.


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Neurology_Adams. Psychosocial difficulties are common and must be identified and addressed early. The stigma of epilepsy remains an issue in society. Advice and reassurance to attempt to pursue a normal life will aid in preventing or overcoming any feelings of inferiority and self-consciousness of many younger patients with epilepsy. However, the situation is rarely so simple and patients and their families may benefit from more extensive counseling. Afawi Z, Oliver KL, Kivity S, et al: Multiplex families with epilepsy. Neurology 86:718, 2016. Alldredge BK, Gelb AM, Isaacs SM, et al: A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 345:631, 2001. Andermann F (ed): Chronic Encephalitis and Epilepsy: Rasmussen Syndrome. Boston, Butterworth-Heinemann, 1991. Annegers JF, Hauser WA, Shirts SB, Kurland LT: Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 316:493, 1987.


Neurology_Adams

Neurology_Adams. Annegers JF, Hauser WA, Shirts SB, Kurland LT: Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 316:493, 1987. Antel JP, Rasmussen T: Rasmussen’s encephalitis and the new hat. Neurology 46:9, 1996. Arana A, Wentworth CE, Ayuso-Mateos JL, Arellano FM: Suicide-related events in patients treated with antiepileptic drugs. N Engl J Med 363:542, 2010. Arya R, Gulati S, Kabra M, et al: Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children. Neurology 76:1338, 2011. Baykan B, Altindag EA, Bebek N, et al: Myoclonic seizures subside in the fourth decade in juvenile myoclonic epilepsy. Neurology 70:2123, 2008. Bear DM, Fedio P: Quantitative analysis of interictal behavior in temporal lobe epilepsy. Arch Neurol 34:454, 1977. Bell ML, Rao So EL, et al: Epilepsy surgery outcomes in temporal lobe epilepsy with a normal MRI. Epilepsia 50:2053, 2009.


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Neurology_Adams. Bell ML, Rao So EL, et al: Epilepsy surgery outcomes in temporal lobe epilepsy with a normal MRI. Epilepsia 50:2053, 2009. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 51:676, 2010. Bialer N, White HS: Key factors in the discovery and development of new antiepileptic drugs. Nature Rev Drug Discov 9:68, 2010. Bien CG, Benninger FO, Urbach H, et al: Localizing value of epileptic visual auras. Brain 123:244, 2000. Bien CG, Granata T, Antozzi C, et al: Pathogenesis, diagnosis and treatment of Rasmussen encephalitis. Brain 128:454, 2005. Bleck TP: Intensive care unit management of patients with status epilepticus. Epilepsia 48 (Suppl 8):59, 2007. Blumer D, Montouris G, Hermann B: Psychiatric morbidity in seizure patients on a neurodiagnostic monitoring unit. J Neuropsychiatry Clin Neurosci 7:445, 1995.


Neurology_Adams

Neurology_Adams. Blumer D, Montouris G, Hermann B: Psychiatric morbidity in seizure patients on a neurodiagnostic monitoring unit. J Neuropsychiatry Clin Neurosci 7:445, 1995. Bonnett LJ, Smith CT, Donegan S, Marson AG: Treatment outcome after failure of a first antiepileptic drug. Neurology 83:552, 2014. Callaghan N, Garrett A, Goggin T: Withdrawal of anticonvulsant drugs in patients free of seizures for two years. N Engl J Med 318:942, 1988. Cascino GD: Intractable partial epilepsy: Evaluation and treatment. Mayo Clin Proc 65:1578, 1990. Caveness WF: Onset and cessation of fits following craniocerebral trauma. J Neurosurg 20:570, 1963. Chadwick D: Vagal nerve stimulation for epilepsy. Lancet 357:1726, 2001. Chinchilla D, Dulac O, Roban O, et al: Reappraisal of Rasmussen syndrome with special emphasis on treatment with high dose steroids. J Neurol Neurosurg Psychiatry 57:1325, 1994.


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Neurology_Adams. Chinchilla D, Dulac O, Roban O, et al: Reappraisal of Rasmussen syndrome with special emphasis on treatment with high dose steroids. J Neurol Neurosurg Psychiatry 57:1325, 1994. Commission on Classification and Terminology of the International League against Epilepsy: Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 22:489, 1981. Commission on Classification and Terminology of the International League against Epilepsy: Classification of epilepsy and epileptic syndromes. Epilepsia 30:389, 1989. Cunningham M, Tennis P: Lamotrigine and the risk of malformations in pregnancy. Neurology 64:955, 2005. Currie S, Heathfield KWG, Henson RA, Scott DF: Clinical course and prognosis of temporal lobe epilepsy. Brain 94:173, 1971. Devinsky O: Sudden unexpected death in epilepsy. N Engl J Med 365:1801, 2011.


Neurology_Adams

Neurology_Adams. Devinsky O: Sudden unexpected death in epilepsy. N Engl J Med 365:1801, 2011. Devinsky O, Kelley K, Yacubian EM, et al: Postictal behavior: A clinical and subdural electroencephalographic study. Arch Neurol 51:254, 1994. Dixit S, Kurle P, Buyan-Dent L, Sheth RD: Status epilepticus associated with cefepime. Neurology 54:2153, 2000. Doherty MJ, Jayadev S, Watson NF, et al: Clinical implications of splenium magnetic resonance imaging changes. Arch Neurol 62:433, 2005. Ebner A, Dinner DS, Noachtar S, Luders H: Automatisms with preserved responsiveness: A lateralizing sign in psychomotor seizures. Neurology 45:61, 1995. Eclampsia Trial Collaborative Group: Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 345:1455, 1995. Elterman RD, Shields WD, Mansfield KA, et al: Randomized trial of vigabatrin in patients with infantile spasms. Neurology 57:1416, 2001. Engel J Jr: Surgery for epilepsy. N Engl J Med 334:647, 1996.


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Neurology_Adams. Engel J Jr: Surgery for epilepsy. N Engl J Med 334:647, 1996. Engel J Jr, Pedley TA: Epilepsy: A Comprehensive Textbook. Philadelphia, Davis, 1998. EURAP Study Group. Seizure control and treatment in pregnancy. Neurology 66:354, 2006. Falconer MA: Genetic and related aetiological factors in temporal lobe epilepsy: A review. Epilepsia 12:13, 1971–1972. Fauser S, Bast T, Altenmüller DM, et al: Factors influencing surgical outcome in patients with focal cortical dysplasia. J Neurol Neurosurg Psychiatry 79:103, 2008. Fenichel GM: Neonatal Neurology, 3rd ed. Philadelphia, Saunders, 1990. Fisher RS, Chan DW, Bare M, Lesser RP: Capillary prolactin measurements for diagnosis of seizures. Ann Neurol 29:187, 1991. Forster FM: Reflex Epilepsy, Behavioral Therapy, and Conditional Reflexes. Springfield, IL, Charles C Thomas, 1977.


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Neurology_Adams. Forster FM: Reflex Epilepsy, Behavioral Therapy, and Conditional Reflexes. Springfield, IL, Charles C Thomas, 1977. French JA, Williamson PD, Thadani VM, et al: Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann Neurol 34:774, 1993. Friedman D, Devinsky O: Cannabinoids in the treatment of epilepsy. New Engl J Med 373:1048, 2015. Gaspard N, Foreman BP, Alvarez V, et al: New-onset refractory status epilepticus. Neurology 85:1604, 2015. Gastaut H, Aguglia U, Tinuper P: Benign versive or circling epilepsy with bilateral 3-cps spike and wave discharges in late childhood. Ann Neurol 9:301, 1986. Gastaut H, Gastaut JL: Computerized transverse axial tomography in epilepsy. Epilepsia 47:325, 1978. Geschwind N: Interictal behavioral changes in epilepsy. Epilepsia 24(Suppl):523, 1983. Glauser TA, Craan A, Shinnar S, et al: Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 362:790, 2010.


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Neurology_Adams. Glauser TA, Craan A, Shinnar S, et al: Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 362:790, 2010. Gloor P: Experiential phenomena of temporal lobe epilepsy: Facts and hypothesis. Brain 113:1673, 1990. Goldensohn E: The relevance of secondary epileptogenesis to the treatment of epilepsy: Kindling and the mirror focus. Epilepsia 25(Suppl 2):156, 1984. Gowers WR: Epilepsy and Other Chronic Convulsive Diseases: Their Causes, Symptoms and Treatment. New York, Dover, 1964 (originally published in 1885; reprinted as volume 1 in The American Academy of Neurology reprint series). Guerrini R: Epilepsy in children. Lancet 367:499, 2006. Gürtler S, Ebner A, Tuxhorn I, et al: Transient lesion in the splenium of the corpus callosum and antiepileptic drug withdrawal. Neurology 11;65(7):1032, 2005.


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Neurology_Adams. Gürtler S, Ebner A, Tuxhorn I, et al: Transient lesion in the splenium of the corpus callosum and antiepileptic drug withdrawal. Neurology 11;65(7):1032, 2005. Hauser WA, Annegers JF: Epidemiology of epilepsy. In: Laidlaw JP, Richens A, Chadwick D (eds): Textbook of Epilepsy, 4th ed. New York, Churchill Livingstone, 1992, pp 23–45. Hauser WA, Annegers JF: Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota, 1935–1984. Epilepsia 34:453, 1993. Hauser WA, Kurland LT: The epidemiology of epilepsy in Rochester, Minnesota, 1935–1967. Epilepsia 16:1, 1975. Hauser WA, Rich SS, Lee JR, et al: Risk of recurrent seizures after two unprovoked seizures. N Engl J Med 338:429, 1998. Hesdorfer DC, Logroscina G, Cascino G, et al: Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus. Ann Neurol 44:908, 1998. Holmes LB, Harvey EA, Coull BA, et al: The teratogenicity of anticonvulsants. N Engl J Med 344:1132, 2001.


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Neurology_Adams. Holmes LB, Harvey EA, Coull BA, et al: The teratogenicity of anticonvulsants. N Engl J Med 344:1132, 2001. Huttenlocher PR, Hapke RJ: A follow-up study of intractable seizures in childhood. Ann Neurol 28:699, 1990. Jellinger K: Neuropathologic aspects of infantile spasms. Brain Dev 9:349, 1987. Jetnik J, Loane MA, Dolk H, et al: Valproic acid monotherapy in pregnancy and major congenital malformations. N Eng J Med 362:285, 2010. Kinsman SL, Vining EP, Quaskey SA, et al: Efficacy of the ketogenic diet for intractable seizure disorders. Epilepsia 33:1132, 1992. Krumholz A, Wiebe S, Gronseth GS, et al: Evidence-based guideline: Management of an unprovoked first seizure in adults. Neurology 84:1705, 2015. Kumar A, Bleck TP: Intravenous midazolam for the treatment of status epilepticus. Crit Care Med 20:438, 1992. Kutt H: Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia 25(Suppl 2):188, 1984.


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Neurology_Adams. Kutt H: Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia 25(Suppl 2):188, 1984. Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med 342:314, 2000. Landau WM, Kleffner FR: Syndrome of acquired aphasia with convulsive disorder in children. Neurology 7:523, 1957. Leestma JE, Walczak T, Hughes JR, et al: A prospective study on sudden unexpected death in epilepsy. Ann Neurol 26:195, 1989. Lefevre F, Aronson N: Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy. Pediatrics 105:46, 2000. Lempert T, Bauer M, Schmidt D: Syncope: A videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol 36:233, 1994. Lennox MA: Febrile convulsions in childhood. Am J Dis Child 78:868, 1949. Lennox W, Lennox MA: Epilepsy and Related Disorders. Boston, Little, Brown, 1960.


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Neurology_Adams. Lennox MA: Febrile convulsions in childhood. Am J Dis Child 78:868, 1949. Lennox W, Lennox MA: Epilepsy and Related Disorders. Boston, Little, Brown, 1960. Leppert M, Anderson VE, Quattelbaum T, et al: Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature 337:647, 1989. Leutzmezer F, Serles W, Lehner J, et al: Postictal nose wiping: A lateralizing sign in temporal lobe complex partial seizures. Neurology 51:1175, 1998. Le Van Quyen M, Martinerie J, Navarro V, et al: Anticipation of epileptic seizures from standard EEG recordings. Lancet 357:189, 2001. Lindvall O, Nilsson B: Cerebellar atrophy following phenytoin intoxication. Ann Neurol 16:258, 1984. Litt B, Esteller R, Echauz J, et al: Epileptic seizures may begin hours in advance of clinical onset: A report of five patients. Neuron 30:51, 2001. Lowenstein DH, Aldredge BK: Status epilepticus. N Engl J Med 338:970, 1998.


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Neurology_Adams. Lowenstein DH, Aldredge BK: Status epilepticus. N Engl J Med 338:970, 1998. Lucas MJ, Leveno KJ, Cunningham FG: A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 333:201, 1995. Luders H, Lesser RP, Dimmer DS, Morris HH III: Benign focal epilepsy of childhood. In: Luders H, Lesser RP (eds): Epilepsy: Electro-clinical Syndromes. London, Springer-Verlag, 1987, pp 303–346. Marson A, Jacoby A, Johnson A, et al: Medical Research Council MESS Study Group: Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: A randomised controlled trial. Lancet 365:2007, 2005. Mattson RH, Cramer JA, Collins JF, et al: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 313:145, 1985.


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Neurology_Adams. McCormack M, Alfirevic A, Bourgeois S, et al: HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 354:12, 2011. McIntyre J, Robertson S, Norris E, et al: Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: A randomised controlled trial. Lancet 366:205, 2005. Meador KJ, Baker GA, Browning N, et al: Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Eng J Med 360:1597, 2009. Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet 337:1175, 1991. Meierkord H, Holtkamp M. Non-convulsive status epilepticus in adults: Clinical forms and treatment. Lancet Neurology 6:329, 2007. Messouak O, Yayaoui M, Benabdeljalil M, et al: La maladie de Lafora a revelation tardive. Rev Neurol 158:74, 2002.


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Neurology_Adams. Messouak O, Yayaoui M, Benabdeljalil M, et al: La maladie de Lafora a revelation tardive. Rev Neurol 158:74, 2002. Nabbout R, Prud’homme J, Herman A, et al: A locus for simple pure febrile seizures maps to chromosome 6q22-24. Brain 125:2668, 2002. Niedermeyer E: The Epilepsies: Diagnosis and Management. Baltimore, Urban and Schwarzenberg, 1990. Obeso JA, Rothwell JC, Marsden CD: The spectrum of cortical myoclonus. Brain 108:193, 1985. Ohtahara S: Seizure disorders in infancy and childhood. Brain Dev 6:509, 1984. Olsen H, Shen Y, Avallone J, et al: Copy number variation plays and important role in clinical epilepsy. Ann Neurol 75:943, 2014. Palmini AL, Gloor P, Jones-Gotman M: Pure amnestic seizures in temporal lobe epilepsy. Brain 115:749, 1992. Panayiotopoulos CP: Early-onset benign childhood occipital seizure susceptibility syndrome: A syndrome to recognize. Epilepsia 40:621, 1999.


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Neurology_Adams. Panayiotopoulos CP: Early-onset benign childhood occipital seizure susceptibility syndrome: A syndrome to recognize. Epilepsia 40:621, 1999. Parviainen I, Usaro A, Kalviainen R, et al: High-dose thiopental in the treatment of refractory status epilepticus in intensive care unit. Neurology 59:1249, 2002. Pedley TA: Discontinuing antiepileptic drugs. N Engl J Med 318:982, 1988. Pedley TA (ed): Epilepsy: A Comprehensive Textbook. Philadelphia, Lippincott-Raven, 1998. Penfield W, Jasper HH: Epilepsy and Functional Anatomy of the Human Brain. Boston, Little, Brown, 1954. Penfield W, Kristiansen K: Epileptic Seizure Patterns. Springfield, IL, Charles C Thomas, 1951. Penry JK, Porter RJ, Dreifuss FE: Simultaneous recording of absence seizures with video tape and electroencephalography. Brain 98:427, 1975.


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Neurology_Adams. Penry JK, Porter RJ, Dreifuss FE: Simultaneous recording of absence seizures with video tape and electroencephalography. Brain 98:427, 1975. Plouin P: Benign neonatal convulsions (familial and nonfamilial). In: Roger J, Drevet C, Bureau M, et al (eds): Epileptic Syndromes in Infancy, Childhood, and Adolescence. London, John Libbey Eurotext, 1985, pp 2–9. Plum F, Howse DC, Duffy TE: Metabolic effects of seizures. Res Publ Assoc Res Nerv Ment Dis 53:141, 1974. Rasmussen T, Olszewski J, Lloyd-Smith D: Focal seizures due to chronic localized encephalitis. Neurology 8:435, 1958. Rocca WA, Sharbrough FW, Hauser WA, et al: Risk factors for complex partial seizures: A population-based case-control study. Ann Neurol 21:22, 1987. Rodin E, Schmaltz S: The Bear-Fedio personality inventory and temporal lobe epilepsy. Neurology 34:591, 1984. Ropper AH: “Convulsions” in basilar artery disease. Neurology 38:1500, 1988.


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Neurology_Adams. Rodin E, Schmaltz S: The Bear-Fedio personality inventory and temporal lobe epilepsy. Neurology 34:591, 1984. Ropper AH: “Convulsions” in basilar artery disease. Neurology 38:1500, 1988. Ropper AH, Kofke A, Bromfield E, Kennedy S: Comparison of isoflurane, halothane and nitrous oxide in status epilepticus. Ann Neurol 19:98, 1986. Salanova V, Andermann F, Rasmussen T, et al: Parietal lobe epilepsy. Clinical manifestations and outcome in 82 patients treated surgically between 1929 and 1988. Brain 118:607, 1995. Scheibel ME, Scheibel AB: Hippocampal pathology in temporal lobe epilepsy: A Golgi survey. In: Brazier MAB (ed): Epilepsy: Its Phenomena in Man. New York, Academic Press, 1973, pp 315–357. Schmidt D: Starting, choosing, changing and discontinuing drug treatment for epilepsy patients. Neurol Clin 34:363, 2016. Silbergleit R, Durkalski V, Lowenstein D, et al: Intramuscular therapy for prehospital status epilepticus. N Engl J Med 366:591, 2012.


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Neurology_Adams. Silbergleit R, Durkalski V, Lowenstein D, et al: Intramuscular therapy for prehospital status epilepticus. N Engl J Med 366:591, 2012. Sillanpää M, Shinnar S: Long-term mortality in childhood onset epilepsy. N Engl J Med 363:252, 2010. Specchio LM, Tramacere L, LaNeve A, Beghi E: Discontinuing anti-epileptic drugs in patients who are seizure-free on monotherapy. J Neurol Neurosurg Psychiatry 72:22, 2002. Sung C, Chu N: Status epilepticus in the elderly: Aetiology, seizure type and outcome. Acta Neurol Scand 80:51, 1989. Sutter R, Rüegg, Tschudin-Sutter S: Seizures as adverse events of antibiotic drugs. Neurology 85:1332, 2015. Sutter R, Marsch S, Fuhr P, et al: Anesthetic drugs in status epilepticus: Risk or rescue. Neurology 82:656, 2014. Sutula TP, Pitkänen A: More evidence for seizure-induced neuron loss. Is hippocampal sclerosis both cause and effect of epilepsy? Neurology 57:169, 2001.


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Neurology_Adams. Sutula TP, Pitkänen A: More evidence for seizure-induced neuron loss. Is hippocampal sclerosis both cause and effect of epilepsy? Neurology 57:169, 2001. Taylor I, Scheffer IE, Berkovic SF: Occipital epilepsies: Identification of specific and newly recognized syndromes. Brain 126:753, 2003. Thakur KT, Probasco JC, Hocker SE, et al. Ketogenic diet for adults in super-refractory status epilepticus. Neurology 82:665, 2014. Thomas JE, Regan TJ, Klass DW: Epilepsia partialis continua: A review of 32 cases. Arch Neurol 34:266, 1977. Towne AR, McGee FE, Mercer EL, et al: Mortality in a community-based status epilepticus study. Neurology 40(Suppl 1):229, 1990. Treiman DM, Meyers PD, Walton NY, et al: A comparison of four treatments for generalized status epilepticus. N Engl J Med 339:792, 1998. Trimble MR: Personality disturbance in epilepsy. Neurology 33:1332, 1983.


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Neurology_Adams. Trimble MR: Personality disturbance in epilepsy. Neurology 33:1332, 1983. Tumani H, Jobs C, Brettschneider I: Effect of epileptic seizures on the cerebrospinal fluid: A systematic retrospective analysis. Epilepsy Res 114:23, 2015. Twyman RE, Gahring LC, Spiess J, Rogers SW: Glutamate receptor antibodies activate a subset of receptors and reveal an agonist binding site. Neuron 14:755, 1995. Vadlamudi L, Milne RL, Lawrence K, et al: Genetics of epilepsy. The testimony of twins in the molecular era. Neurology 83:1042, 2014. Victoroff J: DSM-III-R psychiatric diagnoses in candidates for epilepsy surgery: Lifetime prevalence. Neuropsychiatry Neuropsychol Behav Neurol 7:87, 1994. Villani F, Pincherle A, Antozzi C, et al: Adult-onset Rasmussen’s encephalitis: Anatomical-electrographic-clinical features. Epilepsia 47:41, 2006. Vining EP: The ketogenic diet. Adv Exp Med Biol 497:225, 2002. Volpe JJ: Neurology of the Newborn, 4th ed. Philadelphia, Saunders, 2001.


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Neurology_Adams. Vining EP: The ketogenic diet. Adv Exp Med Biol 497:225, 2002. Volpe JJ: Neurology of the Newborn, 4th ed. Philadelphia, Saunders, 2001. Walder B, Tramer MR, Seeck M: Seizure-like phenomena and propofol. A systematic review. Neurology 58:1327, 2002. Wendl H, Bien CG, Bernasconi P, et al: GluR3 antibodies: Prevalence in focal epilepsy but not specific for Rasmussen’s encephalitis. Neurology 57:1511, 2001. Wiebe S, Blume WT, Girvin JP, et al: A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 345:311, 2001. Wylie E, Luders H, Morris HH, et al: The lateralizing significance of versive head and eye movements during epileptic seizures. Neurology 36:606, 1212, 1986. Yoon HH, Kwon HL, Mattson RH: Long-term seizure outcome in patients initially seizure-free after resective epilepsy surgery. Neurology 61:445, 2003.


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Neurology_Adams. Yoon HH, Kwon HL, Mattson RH: Long-term seizure outcome in patients initially seizure-free after resective epilepsy surgery. Neurology 61:445, 2003. Zeman AZ, Boniface SJ, Hodges JR: Transient epileptic amnesia: A description of the clinical and neuropsychological features in 10 cases and a review of the literature. J Neurol Neurosurg Psychiatry 64:435, 1998. Figure 15-1. ILAE proposal for terminology for organization of seizures and epilepsies 2010 classification of seizures. (From http://www.ilae.org/Visitors/Centre/ctf/documents/ILAEHandoutV10_000.pdf.)


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Neurology_Adams. One example of how syndromes can be organized:Arranged by typical age at onset*Electroclinical syndromesDistinctive constellations/surgical syndromesNeonatal periodBenign neonatal seizuresˆBenign familial neonatal epilepsy(BFNE)Ohtahara syndromeEarly myoclonicencephalopathy(EME)Distinctive constellations/surgical syndromesMesial temporal lobe epilepsy with hippocampalsclerosis (MTLE with HS)Rasmussen syndromeGelastic seizures with hypothalamic hamartomaHemiconvulsion-hemiplegia-epilepsyNonsyndromic epilepsies**Epilepsies attributed to and organizedby structural-metabolic causesMalformations of cortical development(hemimegalencephaly, heterotopias, etc.)Neurocutaneous syndromes (tuberous sclerosiscomplex, Sturge-Weber, etc.)Tumor, infection, trauma, angioma, antenataland perinatal insults, stroke, etc.Epilepsies of unknown causeInfancyFebrile seizuresˆ, Febrile seizures plus (FS+)Benign infantile epilepsyBenign familial infantile epilepsy(BFIE)West syndromeDravet syndromeMyoclonic


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Neurology_Adams. stroke, etc.Epilepsies of unknown causeInfancyFebrile seizuresˆ, Febrile seizures plus (FS+)Benign infantile epilepsyBenign familial infantile epilepsy(BFIE)West syndromeDravet syndromeMyoclonic epilepsy in infancy (MEI)Myoclonic encephalopathy innonprogressivedisordersEpilepsy of infancy with migratingfocal seizuresAdolescence AdultJuvenile absence epilepsy (JAE)Juvenile myoclonicepilepsy (JME)Epilepsy with generalized tonic-clonic seizures aloneAutosomal dominantepilepsy with auditoryfeatures (ADEAF)Other familial temporallobe epilepsiesVariable age at onsetFamilial focal epilepsywith variable foci(childhood to adult)Progressive myoclonus epilepsies(PME)Reflex epilepsiesChildhoodFebrile seizuresˆ, Febrile seizures plus (FS+)Early onset childhood occipital epilepsy (Panayiotopoulossyndrome)Epilepsy with myoclonic atonic(previously astatic) seizuresChildhood absence epilepsy (CAE)Benign epilepsy with centrotemporal spikes (BECTS)Autosomal dominant nocturnal frontal lobe epilepsy


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Neurology_Adams. with myoclonic atonic(previously astatic) seizuresChildhood absence epilepsy (CAE)Benign epilepsy with centrotemporal spikes (BECTS)Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)Late onset childhood occipitalepilepsy (Gastaut type)Epilepsy with myoclonic absencesLennox-Gastaut syndrome (LGS)Epileptic encephalopathy withcontinuous spike-and-wave during sleep (CSWS)+Landau-Kleffner syndrome (LKS)


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Neurology_Adams. Figure 15-2. ILAE proposal for revised terminology for organization of seizures and epilepsies 2010 electroclinical syndromes and other epilepsies grouped by specificity of diagnosis. (From http://www.ilae.org/Visitors/Centre/ctf/documents/ILAEHandoutV10_000.pdf.) 6050403020100Complex partialSimple partialPartial, unclassifiedGeneralized tonic-clonicAbsenceMyoclonicGeneralized, otherUnknown, multiple0–1415–3435–64YearsType of seizurePercent of incident cases>65 Figure 15-3. The distribution of the main types of epilepsy by age. The overrepresentation of absence and myoclonic seizures in childhood and of complex partial seizures in older individuals is evident. Complex partial=focal with dyscognitive features; simple partial=focal without dyscognitive features. (Adapted from Hauser and Annegers and the texts of Engel and of Pedley.)


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Neurology_Adams. Figure 15-4. Medial temporal sclerosis. A. T1-weighted MRI in the coronal plane, showing reduced volume of the left hippocampus (shown by arrow) and secondary enlargement of the adjacent temporal horn of the lateral ventricle. B. Coronal T2-FLAIR image showing abnormal hyperintense signal within the left hippocampus (shown by arrow). Figure 15-5. Distribution of the main causes of epilepsy at different ages. Evident is the prevalence of congenital causes in childhood and the emergence of cerebrovascular disease in older patients. (Adapted from several sources including Hauser and Annegers and the texts of Engel and Pedley.)


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Neurology_Adams. Figure 15-6. Schematic depiction of sites and mechanisms of action of antiepileptic drugs on excitatory and inhibitory synapses. GABA, gamma amino butyric acid; GAD: glutamic acid decarboxylase; GATI: GABA transporter (also known as SLC6A1). (Adapted by permission of Nature Publishing Group and authors from Bialer M, White HS: Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 9:68–82, 2010.)


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Neurology_Adams. Generalized seizuresArising within and rapidly engagingbilaterally distributed networksFocal seizuresOriginating within networkslimited to one hemisphereTonic-ClonicTypicalAtypicalTonicAtonicMyoclonicClonicAbsenceMyoclonicMyoclonic-atonicMyoclonic-tonicAbsence withspecial featuresCharacterized according toone or more features:AuraMotorAutonomicAwareness/responsiveness:altered (dyscognitive) or retainedUnknownInsufficient evidence to characterizeas focal, generalized or bothEpileptic spasmsOtherBilateral convulsive seizureMay evolve toMyoclonic absenceEyelid myoclonia


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Neurology_Adams. BAInhibitory SynapseGlutamateGABAGABA-TGABA-TGABAGATISuccinicsemialdehydeSuccinicsemialdehydeGABAGABAAreceptorCl–GADPostsynapticneuronInhibitorypresynapticterminalGlial cellFelbamate,topiramate,zonisamideBenzodiazepinesVigabatrinTiagabineBarbituratesPropagatedaction potentialNa+DepolarizationVesicularrelease˜2° subunitof L-type Ca2+channelSV2AGlutamateAMPA andkainate receptorsNa+ (Ca2+)K+K+NMDAreceptorCa2+, Na+ Voltage-gatedNa+ channelPostsynapticneuronExcitatorypresynapticterminalTopiramateFelbamateLevetiracetamPhenytoin, carbamazepine,valproic acid, felbamate,rufinamide, lamotrigine,lacosamide, topiramate,zonisamide, oxcarbazepineGabapentin,PregabalinExcitatory Synapse Coma and Related Disorders of Consciousness


Neurology_Adams

Neurology_Adams. Coma and Related Disorders of Consciousness In hospital and emergency neurology, the clinical analysis of unresponsive and comatose patients becomes a practical necessity. There is an urgent need to determine the disease underlying a diminished state of consciousness and the direction in which it is evolving in order to protect the brain against irreversible damage. When called upon, the physician must therefore be prepared to implement a rapid, systematic investigation of the comatose patient and prompt action that allows little time for deliberate, leisurely investigation.


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Neurology_Adams. Some idea of the dimensions of the problem of coma can be obtained from published statistics. Eighty years ago, in two large municipal hospitals, it was estimated that 3 percent of all admissions to the emergency wards were for diseases that had caused coma. Alcoholism, cerebral trauma, and cerebrovascular diseases were the most common, accounting for 82 percent of the comatose patients admitted to the Boston City Hospital (Solomon and Aring). Epilepsy, drug intoxication, diabetes, and severe infections were the other major causes for admission. It is perhaps surprising to learn that contemporary figures from large city hospitals differ only slightly, with intoxication, stroke, and cranial trauma standing as the “big three” of coma-producing conditions. For example, in the series collected by Plum and Posner (Table 16-1) a majority was the result of exogenous (drug overdose) and endogenous (metabolic) intoxications and hypoxia, 25 percent of cases proved to have cerebrovascular


Neurology_Adams

Neurology_Adams. by Plum and Posner (Table 16-1) a majority was the result of exogenous (drug overdose) and endogenous (metabolic) intoxications and hypoxia, 25 percent of cases proved to have cerebrovascular disease, and intracranial masses—such as tumors, abscesses, and hemorrhages—made up about one-third of cases. Subarachnoid hemorrhage, meningitis, and encephalitis accounted for another 5 percent. Common in some series, although obvious and often transient, is coma that follows seizures or resuscitation from cardiac arrest.


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Neurology_Adams. The terms consciousness, confusion, stupor, unconsciousness, and coma have been endowed with so many different meanings that it is almost impossible to avoid ambiguity in their usage. They are not strictly medical terms but are also literary, philosophic, and psychologic ones. The word consciousness is the most ambiguous of all. William James remarked that everyone knows what consciousness is until they attempt to define it. To the psychologist, consciousness denotes a state of continuous awareness of one’s self and environment, essentially self-consciousness. Knowledge of self includes all “feelings, attitudes and emotions, impulses, volitions, and the active or striving aspects of conduct”; in short, a near continuous self-awareness of a person’s mental functioning, particularly of cognitive processes. These can be judged only by the individual’s verbal account of his introspections and indirectly, by his actions.


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Neurology_Adams. Physicians, aspiring to be more practical and objective, give greater credence to the patient’s behavior and reactions to stimuli than to what the patient reports. In this way the term consciousness is used in its broadest operational meaning—namely, the state of awareness of self and environment, and normal responsiveness to external stimulation and inner need. This narrow definition has an advantage in that unconsciousness has the opposite meaning: a state of unawareness of self and environment or a suspension of those mental activities by which people are made aware of themselves and their environment, coupled with an overtly observable diminished responsiveness to environmental stimuli. The last of these qualities, arousal, or the level of consciousness, refers to the appearance of being awake as displayed by the facial muscles, eye opening, fixity of gaze, and body posture, that is, wakefulness.