A 13-Year-Old With an Acute Change in Mental Status

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1 A 13-Year-Old With an Acute Change in Mental Status Barry E. Gidal, Jeffrey N. Seltz, and Paul Rutecki A 13-year-old boy with Lennox-Gastaut syndrome characterized by absence, myoclonic, complex-partial, and secondarily generalized tonic-clonic seizures, presents with progressive obtundation and loss of motor and verbal skills over a 2-day period. Initial evaluation revealed therapeutic phenytoin serum concentrations. This article discusses the differential diagnosis and management approach used in this setting, as well as the appropriate interpretation of antiepiieptic drug serum concentrations. Copyright by W.B. Saunders Company CASE A 13-year-old, developmentally disabled boy presents with obtundation, lethargy, prolonged episodes of starting, and substantially decreased interaction with caregivers that has developed over the past 48 hours. Medical history was significant for a static encephalopathy of uncertain etiology that was associated with some loss of his language function. Birth and family history were unremarkable. Developmentally, the child had some initial slow cognitive and motor skill development that became relatively static after the age of 2 years. Seizures were first noted at 18 months of age and were characterized by head drops. He has a pharmacoresistant, mixed seizure disorder characterized by atypical absence, myoclonic, complex-partial seizures, and rare secondary generalized tonic-clonic seizures. In the past, he has had episodes of serial convulsions that have required hospitalizations. The child was a resident in a center for the developmentally disabled. On examination, he was awake with eyes open, but displayed only minimal interaction with the examiner and could not attend. Brief myoclonic segmental twitches, both of the thorax, arms, and fingers were noted. At times, head drops and dilated pupils were noted on examination. He had excessive salivation. He was afebrile, weighed 50 kg, blood pressure was 114/58, pulse 96, and respirations were 20 per minute. His pupils were dilated and sluggishly reactive to light. Extraocular movements were intact, and there was no facial asymmetry. Muscle tone and bulk were normal. Reflexes were 2+ bilaterally and plantar responses were flexor bilaterally. Examination of coordination and gait could not be tested. Laboratory examination revealed a white blood cell count /gL, red blood cell count /gL, hemoglobin 12.4 g/dl, hematocrit 39%, Na me@, K meq/l, CI 108 meq/l, CO2 29, glucose 105 mg/dl, blood urea nitrogen 7 mg/dl, Scr 0.4 mg/dl, PO4 4.6 mg/dl, Ca mg/dl, serum albumin 4.5 g/dl. Urine analysis and chest radiograph were normal. Medications included phenytoin 425 mg orally, four times a day (8.5 mg/kg/day), gabapentin 200 mg orally, three times a day (12 mg/kg/day), lamotrigine 25 mg orally, three times a day (1.5 mg/kg/day). Serum antiepileptic drug concentrations were: From the School of Pharmacy and Department of Neurology, University of Wisconsin; and the Central Wisconsin Center for Developmentally Disabled, Madison, WI. Address reprint requests to Paul Rutecki, MD, Department of Neurology, University of Wisconsin, H4/616, 600 Highland Ave, Madison, W Copyright by W.B. Saunders Company /99/ /0 phenytoin 18 ~tg/ml (total), gabapentin 1.1 ~tg/ml, lamotrigine 0.3 ~g/ml. Several months before admission, a phen;?toin serum concentration of 28.7/ag/mL had been noted. Although the child did not display clinical signs of phenytoin intoxication, there was concern that this potentially represented a toxic serum concentration. Repeat measurements were subsequently obtained over time and were 22.1 and 29 ~tg/ml. Based on these laboratory findings, phenytoin daily dosages were progressively reduced. An electroencephalogram performed on admission to the neurology service revealed diffuse bihemispheric slowing with high voltage 2 to 3 Hz frontal slowing. Intermixed multifocal sharp waves and spikes were noted that were maximally expressed in the frontal regions. Brief episodes of generalized tonic motor activity were associated with a decremental EEG pattern that consisted of and low voltage, rhythmic 10 to 12 Hz sharp activity that last less than 10 seconds (Fig 1). DISCUSSION Presentation and Evaluation of Nonconvulsive Status This boy has a clinical picture of atypical absence status epilepticus punctuated by brief tonic seizures. He fulfills the clinical criteria for the Lennox-Gastaut syndrome, although a clear etiology had not been defined~ Status epilepticus is common in the Lennox-Gastaut syndrome with estimates ranging from 54% to 97% of all individuals developing status at some point in their clinical course),2 A confusional state with brief myoclonic jerks may gradually develop and escalate to a point of continued unresponsiveness as in this patient. 2,3 Brief tonic seizures may also develop as noted once the patient was hospitalized. The diagnosis may be difficult in children already intellectually compromised and sedated by medication. The diagnosis is made on a clinical basis and confirmed by EEG. An EEG will help to define subtle seizures that may be only well defined electrographically. The EEG will also help differentiate between complex partial status and generalized nonconvulsive status epilepticus. Generalized nonconvulsive status includes absence status and atypical absence status. The differentiation between the two is made more from the clinical context with absence status as- 146 Seminars in Pediatric Neurology, VoI 6, No 3 (September), 1999: pp

2 ACUTE CHANGE IN MENTAL STATUS ~V ls Fig 1. EEG sample from period of stupor with a background high-voltage frontocentral rhythmic delta with activity interrupted abruptly by a lower voltage central 10 to 12 Hz rhythmic activity associated witha brief period of axial muscle tonic contracture. This EEG was obtained before treatment initiation. sociated with normal intelligence as opposed to atypical absence status in individuals with Lennox Gastaut syndrome. Atypical absence status also is more likely to have brief myoclonic or tonic seizures as note din this case. The treatment of nonconvulsive and tonic-status epilepticus in the context of the Lennox-Gastaut syndrome can be difficult. Aggressive therapy with sedative antiepileptic drugs, such as benzodiazepines given intravenously, may even intensify tonic seizures. 4,5 Occasionally, a stuporous, twilight state can last for days despite adequate antiepileptic treatment. With increased sedation, more obtundation and confusion make the clinical picture less clear. The barbiturates and benzodiazepines treatment may lead to more sedation and may not clearly improve the EEG pattern. Nonsedating antiepileptic drugs, such as phenytoin or valproate, may be more effective in controlling seizures. Some have advocated ACTH or prednisone therapy in more resistant cases. Therapeutic Monitoring of Antiepileptic Drugs Therapeutic drug monitoring can provide valuable information to clinicians and may aid in the individualization and optimization of antiepileptic drug regimens. For many of the "older" antiepileptic drugs, such as phenytoin, there is a generally accepted therapeutic range. This therapeutic range must be interpreted in the context of the individual patient and clinical circumstance. Therapeutic ranges are perhaps more appropriately viewed as probability statements, in that values falling within this range are more likely to achieve optimal response while minimizing toxicity. However, it is important to understand that this may not apply to individual patients. Individual patients may require serum drug concentrations that are perhaps greater or lessor than the conventionally accepted ranges, depending on the severity and type of seizure disorder. 6 Therapeutic drug monitoring should therefore serve as a guide to optimizing antiepileptic drug therapy, not as an outcome in and of itself. 7 In addition, other pharmacokinetic factors, such as protein binding, can complicate the interpretation of serum drug concentration data. s For example, phenytoin is extensively and reversibly bound to plasma proteins. In humans, binding of phenytoin to serum albumin is generally accepted to be, on average, 90%, although ranges of 69% to 96% have been reported in humans. 9 Phenytoin binding to albumin is concentration

3 148 GIDAL, SELTZ, AND RUTECKI independent. 9 Phenytoin serum concentrations are frequently used as a guide to therapy. Most commonly, total (bound + unbound) serum concentrations are determined, with a proposed therapeutic range of 10 to 20 tag/me Based on the average unbound fraction of phenytoin being 10%, a corresponding unbound "therapeutic" range for phenytoin would be 1 to 2 lag/me For most patients, this relationship between total and unbound phenytoin is consistent and predictable. Understanding the relationship between total and unbound drug concentrations as well as the pharmacokinetic principles underpinning this relationship is essential in properly interpreting phenytoin serum concentration data. Phenytoin is extensively, hepatically metabolized, with less than 5% of total dose excreted unchanged in the urine. Phenytoin is a low extraction ratio drug. As such, the total systemic clearance (Clt) of this agent depends on its unbound fraction (fu) and its intrinsic metabolic clearance (Clint). This relationship can be described by Equation 1. Clt = fu Clint (1) As the unbound fraction increases (as would happen with hypoalbuminemia, or following the addition of a protein binding site displacer), there is an initial increase in unbound drug concentration. However, unbound drug is now able to redistribute into body tissues. In addition, Clt will increase since more drug is also now available to be metabolized (Equation 2). The net result will therefore be a decrease in total serum drug concentrations. Css = F Dose/T Clt (2) Where Cs~ is total drug concentration, F is bioavailability and T is dosage interval. However, pharmacological effect depends on unbound serum concentration, in that only unbound drug is available to interact with receptors. As can be seen in Equations 3 and 4, unbound drug concentration at steady-state depends on intrinsic clearance, dose, dose interval, and bioavailability. As phenytoin unbound fractions increase, total serum concentrations will decrease; however, the pharmacologically relevant unbound concentration will remain the same. 10 C~s = F dose/t Clint (3) Css = fu Css (4) In Equations 3 and 4, C'ss is the unbound drug concentration at steady state. In this child, although total phenytoin concentrations were clearly at the high end of the therapeutic range, unbound fractions were markedly lower than would be expected. Evaluations of both total and unbound drug concentrations obtained before hospital admission were 28.7/1.8 ~tg/ml and 22.1/1.5 lag/ml, yielding unbound fractions of 6.3% and 6.8%, respectively. Reliance on total phenytoin serum concentrations may lead to an underestimation, or perhaps overestimation, of the pharmacologically relevant unbound concentrations in patients who may have an alteration in protein binding or under circumstances where binding capacity deviates somewhat from the "average." In this setting, inspection of total phenytoin concentrations led to the conclusion that drug concentrations were "toxic" and that administration of additional phenytoin would not be appropriate. However, further evaluation of unbound phenytoin concentrations were, in fact, relatively low and subtherapeutic for this individual patient. Recognizing this pharmacokinetic relationship ted to a re-interpretation of the serum drug concentratiort data, and the decision was made to administer additional phenytoin (as intravenous fosphenytoin). Hospital Course Following hospital admission, the patient was given 450 mg (PE) (8.5 mg/kg) fosphenytoin at an infusion rate of 50 mg/minute. A repeat EEG performed following fosphenytoin administration demonstrated some improvement, although clinically, brief (5 to 10 second) motor seizures were still noted. An EEG performed on hospital day 2 showed continued multifocal spike and wave discharges and diffuse background slowing. Electrographic and clinical seizures were noted as on admission. A repeat bolus infusion of fosphenytoin 500 mg (PE) was given with marked clinical improvement noted. At this time, valproic acid (VPA) 250 mg orally three times a day was added to his antiepileptic drug regimen. Based on his clinical improvement, the child was discharged from the hospital and transferred back to the center for the developmentally disabled. Follow-up On examination 1 month later, the child remained seizure free, with cognition, alertness, and

4 ACUTE CHANGE IN MENTAL STATUS 149 activities of daily living having returned to baseline levels. Antiepileptic drug concentrations determined at that time were: phenytoin total/unbound = 22.1/2.0 ~tg/ml and VPA 39 ~tg/ml. Interestingly, these measurements provide further suggestions of unexpectedly high phenytoinalbumin binding. VPA is extensively and saturably bound to albumin and is known to displace phenytoin from albumin binding sites in a concentration dependent manner. In other words, as VPA serum concentration is increased, so is phenytoin unbound fraction. VPA can also inhibit phenytoin intrinsic clearance. In this setting, one would predict an unbound phenytoin concentration 2.96 ~tg/ml versus the 2.0 ~tg/ml actually measured. 11 In summary, this 13-year-old boy illustrates a frequently seen problem in patients with Lennox- Gastaut syndrome. He became less responsive and developed an episode of nonconvulsive status epilepticus that gradually escalated to periods of brief tonic seizures. Increasing his phenytoin level led to control of his seizures, without adverse effects. Reliance on total serum phenytoin concentration data may have confounded efforts to optimize therapy in this patient, in that he did not display usual or average phenytoin protein binding. His status resolved only when phenytoin concentrations were returned to his therapeutic range. Although routine monitoring of unbound phenytoin serum concentrations is not warranted; they may prove helpful in Circumstances where alterations in protein binding are suspected or, as in the case of this child, where unusually high total phenytoin concentrations are required to maintain seizure control. Nonconvulsive status epilepticus is difficult to recognize and treat in patients with Lennox- Gastaut syndrome and should be considered in children with this condition who have a change in cognition or behavioral state. 1. Status epilepticus in the Lennox-Gastaut syndrome, in Niedermeyer E, Degen R (eds): The Lennox-Gastaut Syndrome. New York, Alan R. Liss, 1988, pp Farrell K: Symptomatic generalized epilepsy and Lennox- Gastaut Syndrome, in Wylie E (ed): The Treatment of Epilepsy: Principles and Practices (ed 2). 1997, pp Shorvon S: Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, Cambridge University Press, 1994, pp Tassinari CA, Dravet C, Roger J, et al: Tonic status epilepticus precipated by intravenous benzodiazepines in five patients with Lennox-Gastaut syndrome. Epilepsia 13: , Dimario FJ, Clancy RR: Paridoxical precipitation of tonic seizures by lorazepam in a child with typical absence seizures. Pediatr Neurol 4: , Johannessen SI: Laboratory monitoring of antiepileptic drugs, in Levy RH, Mattson RH, Meldrum BS, (eds): Antiepileptic Drugs (ed 4). New York, Raven Press, 1995, pp REFERENCES 7. Commission onantiepileptic Drugs: Guidelines for therapeutic monitoring of antiepileptic drugs. Epilepsia 34: , Cloyd JC: Pharmacokinetic pitfalls of present antiepileptic medications. Epilepsia 32:S53-$65, 1992 (suppl 5) 9. Treiman DM, Woodbury DM: Phenytoin: Absorption, distribution and excretion, in, Levy RH, Mattson RH, Meldrum BS, (eds): Antiepileptic Drugs (ed 4). New York, Raven Press, 1995, pp Mackichan JL: Influence of protein binding and use of unbound (free) drug concentrations, in Evans WJ, Schentag JJ, Jusko WJ (eds): Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring. Applied Therapeutics. Vancouver, WA, 1992, pp Haidukewych D, Rodin EA, Zielinsld JJ: Derivation and evaluation of an equation for prediction of free phenytoin concentration in patients co-medicated with valproic acid. Ther Drug Monit 11: , 1989 In addition to being highly refractory to treatment, the Lennox-Gastaut syndrome is characterized by (1) wide spontaneous fluctuations in seizure frequency, (2) periods of seizure exacerbations including prolonged spike-wave stupor, and (3) susceptibility to paradoxical reactions to antiepileptic drugs. The distinction between nonconvulsive status, drug toxicity, or paradoxical drug effect can be particularly perplexing in these patients. This is illustrated very clearly by the present report of a boy wl~o was in atypical absence status, or spike- COMMENTARY wave stupor, with repetitive tonic seizures. The patient had been hospitalized more than once previously for serial seizures, which is typical of Lennox-Gastaut syndrome. Status epilepticus was suggested by subtle observations on physical examination, such as myoclonic twitching, head drops, and episodes of pupillary dilatation. The EEG unequivocally confirmed the diagnosis. Patients in spike-wave stupor at times are still ambulatory but conspicuously ataxic (pseudo-ataxia). The described event in this patient may have been a

5 150 GIDAL, SELTZ, AND RUTECKI spontaneous occurrence. It is certainly unlikely that it was precipitated by either gabapentin or lamotrigine whose blood levels were very low. The recent reduction in the phenytoin dose might be considered as a precipitating factor. However, phenytoin is generally not considered to be an effective drug in the treatment of atypical absence status, and it is somewhat unusual that the reported patient improved after the administration of additional phenytoin. Carbamazepine, which shares a similar spectrum of activity with phenytoin, has been associated with seizure exacerbations in patients with Lennox- Gastaut syndrome. 1 Not using a benzodiazepine was a wise decision by those involved in the patient's care because of the well-established risk of precipitating or exacerbating tonic status epilepticus. In addition to the diagnostic dilemma, the second point illustrated by this case report is the importance of considering free levels of phenytoin. The unusual feature in the present case was that the free fraction of phenytoin was at the low end of the normal range, 6.3% and 6.8% as opposed to an average of about i0%. As a consequence, the patient's pharmacodynamically relevant free level of phenytoin was actually lower than suspected from the total level. This situation is the opposite of the usual pitfall with free phenytoin levels. More often, patients have a higher than average free fraction and may present clinical toxicity despite total phenytoin levels not usually associated with clinical toxicity. Had this unusually low free fraction of phenytoin not been recognized, the patient would probably not have received additional phenytoin. An additional feature of this patient is that he appears to be a fast metabolizer for phenytoin. This can be suspected on the basis of the ratio between his daily dose of 425 mg for a weight of 50 kg and the serum phenytoin level. The total level of 18 is relatively low for the dose of 8.5 mg/kg/day, but with an average free fraction of 6.5%, the patient's calculated free phenytoin level of 1.17 is even lower. This free level would correspond to a total level of 11.7 in a patient with an average free fraction of 10%. A pharmacokinetic analysis can be used to assess the patient's phenytoin metabolism quantitatively. Phenytoin elimination is assessed by the two Michaelis-Menten parameters, Vm, (mg/kg/day), and Km(mg/L) according to the following equations: Vmax Css D - (1) Km + C~ D m C~s = V,~,x - D (2) where D is daily dose in mg/kg/day and Css is the average steady-state concentration. Population values are about 6.0 mg/l for K m or 0.6 mg/l for the free Km. Vm~x values are about 8.0 mg/kg/day for adults and higher for younger children. 2,3 Average Vmax values for the patient's age of 13 years are similar to values in adults. 2,3 The patient's Vmax (assuming an average free Km value of 0.6 rag/l) can be calculated by solving Equation 1 for Vm~x and using a fi'ee C~s of 1.17 mg/l and the patient's dose of 8.5 mg/kg/day, resulting in a Vm~x value of 12.9 mg/kg/day. This is an unusually high value. However, one might also assume that the patient's Vmax value is age appropriate and that his rapid phenytoin metabolism is due to a low K m value. Using a Vmax value of 10 mg/kg/day, Equation 2 can be solved for Kin, resulting in a free Km value of 0.21 mg/l, as opposed to the population average of. 0.6 mg/l. These calculations indicate that the patient must indeed be a rapid metabolizer of pheuytoin, either due to a high Vm, value, or to a low K~ value, or to a combination of both. With only one pair of dose/level values, one cannot calculate both Vm~x and Km for this patient. Another reason for the relatively low.phenytoin levels could certainly be decreased bioavailability~ Poor compliance is another possibility, but this is less likely in an institutionalized patient. Blaise F.D. Bourgeois, MD Division of Epilepsy and Clinical Neurophysiology Department of Neurology Children's Hospital Harvard Medical School Boston, MA REFERENCES 1. Snead OC, Hosey LC: Exacerbation of seizures in children by carbamazepine. N Engl J Meal 313: , Dodson WE: The nonlinear kinetics of phenytoin in children. Neurology 32:42-48, Bauer LA, Blouin RA: Phenytoin Michaelis-Menten pharmacokinetics in Caucasian paediatfic patients. Clin Pharmacokine 8: , 1983