The goal of epilepsy therapy is to control seizures completely without adverse drug effects. This objective is frequently compromised when complete seizure control cannot be achieved because of secondary drug toxicity.^25,26 Dose-related neurotoxic effects of antiepileptic drugs (AEDs) are bothersome, but with patient education they can be minimized and often tolerated. Part of good patient management is to establish a therapeutic alliance with active patient involvement. Toxic effects of drugs provide one endpoint, independent of blood level monitoring, to allow clinical titration to efficacy. However, idiosyncratic effects of drugs, although rare, may be life-threatening. Some have suggested that monitoring programs be established to detect patients at risk for serious systemic toxicity. For example, DeVries⁶ proposed that regularly scheduled monitoring of drug blood levels should be embedded within a program of data collection that includes hematologic assessment, routine serum chemistry studies, and urinalysis. Pharmaceutical companies endorsed this approach by incorporating its elements within standard recommendations for drug use in publications in the United States (Physicians’ Desk Reference³⁰) and Canada (Compendium of Pharmaceuticals and Specialties¹⁷). For many clinicians, such reference sources have defined the medicolegal “standard of practice.” In contrast, scientific criteria based on available evidence fail to support routine monitoring; such archival data rarely predict the occurrence of serious drug reactions. Although habits and practice vary both within the United States and in other countries, routine assessment of biochemical and hematologic function should at least be obtained at baseline.²⁸

When a drug is selected for use, the physician must review relative risks with the patient, and this discussion must be documented in the patient’s record. This process of review and information exchange forms the basis for establishing informal informed consent. Patients must understand the goals of treatment, criteria that will be used to measure success, the process of trial and error in drug selection, and how drugs will be changed, if that becomes necessary. Common dose-related side effects are useful as an aid to management, but they also interfere with treatment. The process is one of negotiation. Patients must also know the nature of side effects, what may have to be tolerated, and how the physician will use side effects in the titration process. Serious, life-threatening, idiosyncratic effects of a selected drug should be reviewed clearly but within the context of rarity. Although patients must participate in an informed way in this therapeutic alliance and understand the need to report promptly should symptoms develop, it is the responsibility of physicians to identify those without advocates or with impaired ability to communicate. For these special patients, a specific monitoring strategy may have to be formulated, something that is not needed by most patients with epilepsy.

Packaging information refers to various side effects. Frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in <1/1,000 patients. Events of major clinical importance are described in the Warnings and Precautions sections.

Efficacy and adverse effects of drugs are important considerations in making treatment decisions, and legal actions from adverse effects have had important consequences on treatment, monitoring, and documentation of patient care.⁴⁶ Several classic legal cases involving AEDs have involved determinations of medical negligence in dosing and drug selection and questions about informed consent. The drug regulation process is described further in Chapters 142 and 143 on the roles of the U.S. Food and Drug Administration and European regulatory agencies, respectively.

Standards of care in the United States are derived from expert opinion, source publications, or referreed articles that form the basis for evidence-based medicine. Textbooks of medicine and published practice guidelines are another source for such information. In the United States, both the American Academy of Neurology and the Office of Quality Assurance and Medical Review of the American Medical Association publish treatment guidelines.

In medical malpractice or medical negligence cases, determining the standard of care for a particular treatment is of utmost importance.⁴⁶ Standard of care extends not only to treatment, but also to the methods used to obtain informed consent. In litigation, the standard of care is usually established by expert testimony using source publications or articles from refereed publications. One such reference source is the Physician’s Desk Reference (PDR).^3,30

As with any area of law in which states are given authority, there can be differences from state to state in the exact
manner by which standard of care is determined. These differences are particularly evident with regard to the evidentiary force of the medication package insert and printed information contained in the PDR. States tend to use the PDR and package inserts in one of three ways. Although the differences are not categorical, it is nonetheless useful for educational and discussion purposes to consider them separately. In the first group are states that consider the PDR and package insert as establishing the standard of care [Haught v. Maceluch, 681 F.2d 291, reh’ing denied, 685 F.2d 1385 (5th Cir. 1985)].³ In the second group are states in which the package insert and PDR are considered evidence of standard of care and deviation from the prescribed directions may establish a prima facia case for negligence. In such cases, however, a physician may generally introduce evidence to support his or her basis for using a medication in ways that deviate from the detailed description presented in the PDR and package insert (Mulder rule and echo of Mulder; see following discussion) [Thompson v. Carter, 518 So. 2d 609, 613 (Miss. 1987)]. In Mulder v. Parke Davis and Co [181 N.W. 2d 882 (Minn 1970)], the court held that any deviation in drug use from that specified in the PDR requires a physician to explain the reason for that deviation. This requirement is now known as the Mulder rule. In light of this, it would seem prudent for the physician who plans to use a drug in ways that vary from recommendations in the PDR or package inserts to record the reasons for doing so and the relevant plan for management in the medical record. In the third group of states, the PDR and package insert as such are given little credence and, in some jurisdictions, are inadmissible without supporting expert testimony. This is known as the “echo” of the Mulder rule. [Spensieri v. Lasky, 723 N.E. 2d 544 (NY 1999)].³

Legal action has also involved issues of informed consent. In Serigne v. Ivker, a plaintiff alleged that informed consent had not been obtained because of lack of disclosure of teratogenicity. The court found that the plaintiff had failed to establish a connection between malformations and phenytoin and that informed consent did exist [Serigne v. Ivker, 808 So. 2d 783 (La. App. 4 Cir. 2002)]. In the case of Spano v. Bertocci [299 A.D. 2d 335, 749 N.Y.S. 2d 275 (N.Y.A.D. 2002)], the plaintiff claimed lack of informed consent based on failure to disclose the teratogenic effects of valproic acid. Trial and appellate courts found that informed consent had been obtained because of the plaintiff’s previous knowledge regarding the dangers involved in using valproate during pregnancy.⁴⁶

One landmark decision illustrates the diligence required to provide information for patients with child-bearing potential is well illustrated. In Harbeson v. Parke-Davis, claims of failure of informed consent causing wrongful birth and wrongful life were the cause for action when a woman delivered children with fetal hydantoin syndrome. In this case, the court stated that the physicians had a duty to “exercise reasonable care in disclosing ‘grave risks’ of (any) treatment” that they were advocating. Apparently, the physician had failed to do a literature search that would have uncovered the dangers of using phenytoin during pregnancy, and had this been done, it would have allowed the physician to inform the patient [Harbeson v. Parke-Davis, 656 P. 2d 483 (1983)].⁴⁶

Serious skin reactions, including Stevens-Johnson syndrome, have also raised issues of informed consent. In Shinn v. St. James Mercy Hospital, the plaintiff claimed that disclosure of serious skin reactions to phenytoin had not been provided. In this case, the court stated that it is not necessary to disclose all adverse effects to a patient, but rather only the most common ones. The court also found that given the patient’s particular medical circumstance, the patient would not reasonably have declined treatment even if adverse effects had been delineated. [Shinn v. St. James Mercy Hospital, 675 F.Supp 94 (W.D.N.Y. 1987)]. Similarly, in Williams v. Ciba-Geigy Corporation, the court found that the warnings in the PDR and package insert diminished the “danger-in-fact” of the medication. The court stated “no reasonable trier of fact could conclude that this …medicine is unreasonably dangerous per se” [Williams v. Ciba-Geigy Corporation, 686 F. Supp 573 (W.D.La. 1988)].⁴⁶

Documentation is critical. In Fritz v. Parke Davis & Co. a patient treated with phenytoin developed hepatic failure. At trial, the court originally found for the plaintiff. On appeal, that decision was reversed. The appellate court stated, “Viewing the record …the skill and care exhibited by defendant’s physicians’ diagnosis and treatment were marked by devoted diligence and attention and were wholly consistent with the professional skill …employed by other physicians in treating and controlling …the complex disease of epilepsy” [Fritz v. Parke Davis & Co., 152 N.W. 2d 129 (1967)].⁴⁶

Errors in the use of AEDs that amount to negligence have been the basis of litigation. In Hendricks v. Charity Hospital of New Orleans, a patient was to receive Dilantin 500 mg/d, but a prescription was written for 500 mg three times a day. Judgment was for the plaintiff. [Hendricks v. Charity Hospital of New Orleans 519 So. 2d 163 (La. App. 4th Cir. 1987)]. High plasma levels of Dilantin were associated with a patient’s death, and judgment for the plaintiff occurred in this case as well [Martin v. Life Care Centers of America Inc. (No. 95-4124-B, 117th Judicial Dist. Ct. Nueces County, TX, April 1998)]. One court found for the plaintiff in a case of failure to diagnosis pancreatitis associated with the use of valproate [Pester v. Graduate Hospital (No. 87-05-00357, Court of Common Pleas, Philadelphia, PA Oct 1992)].⁴⁶

There can be no question that therapeutic drug monitoring has been a major advance in helping to determine compliance, compensating for physiologic (age, pregnancy) or disease-related (uremia, hepatic failure) alterations in drug pharmacokinetics, and avoiding undesirable drug interactions (see Chapter 103). In general, however, routine blood level determinations are performed too frequently and often without a specific question in mind. It is important to remember that drug levels must be interpreted in light of a patient’s clinical progress. In the clinical setting, therapeutic effectiveness is best judged by two measures: (a) seizure frequency and (b) the appearance of adverse effects. All too often, however, the blood level, rather than the patient, becomes the goal of treatment: therapy must be optimal if a drug’s blood concentration is in the “therapeutic range.” This oversimplified view can have undesirable consequences. For example, it is not uncommon for low or “therapeutic” blood levels to be cited as evidence against a patient’s complaint of side effects. Conversely, drug dose is frequently reduced because of a “toxic” level, even if there has been good seizure control and no indication of adverse reactions. Finally, meaningful interpretation of blood levels requires knowledge about the timing of a blood sample, the dosing schedule, the interval since the last dosing change, and the clinical situation with
regard to complaints about possible side effects and seizure frequency.