Long-term Phenytoin Research Articles

A rare case of phenytoin-induced cerebellar atrophy

Epilepsy is a common health problem and affects humans of any age. Phenytoin is indicated in all types of seizure except in absence epilepsy. It has a wide range of pharmacokinetic properties with a narrow therapeutic range thus often leading to toxicity. Long-term neurological side effects of phenytoin include cerebellar atrophy. Therefore, monitoring of plasma levels should be done in patients on long-term phenytoin. Here, we describe a case of cerebellar degeneration in a post-operated brain abscess patient on chronic phenytoin therapy.

Does long-term phenytoin have a place in Dravet syndrome?

Anti-seizure medications that block sodium channels are generally considered contraindicated in Dravet syndrome. There is, however, considerable debate about the sodium-channel blocker phenytoin, which is often used for status epilepticus, a frequent feature of Dravet syndrome. We describe four patients with Dravet syndrome in whom long-term phenytoin therapy reduced seizure frequency and duration. In two patients, phenytoin produced prolonged periods without status epilepticus for the first time. Attempting to wean phenytoin in all patients after 1 to 20 years of use resulted in seizure exacerbation. Reintroducing phenytoin improved seizure control, suggesting phenytoin is beneficial in some patients with Dravet syndrome.

Effect of Antiepileptic Drugs on Serum Lipid Profile among Children with Epilepsy at a Tertiary Care Hospital, Chennai, India

Introduction: An arsenal of Antiepileptic Drugs (AED) is used in the management of childhood seizure disorders. Most of them are taken long-term. These drugs have the potential to cause hyperlipidemia by inducing the P450 enzyme system. The alteration in lipid profile caused by long-term use of antiepileptic drugs in children needs to be studied to reduce the risk of future atherosclerosis. Aim: To analyse the effect of antiepileptic drugs on serum lipid profile in children with epilepsy in a tertiary care. Materials and Methods: This prospective descriptive study was conducted in the Outpatient and Inpatient Wards of the Department of Paediatrics and Neurology, Institute of Child Health and Hospital for Children, Chennai, Tamil Nadu, India, from February 2017 to September 2017. The study involved a total of 155 children, who were on monotherapy antiepileptic drugs for atleast 6 months (33 on phenytoin, 42 on phenobarbitone, 20 on levetiracetam, 20 on carbamazepine, 40 on sodium valproate). A corresponding numbers of children, who attended the General Outpatient Department for acute upper respiratory tract and were otherwise healthy, were included as controls. A blood sample (3 mL) was drawn after an overnight fast for serum glucose, liver enzymes, total cholesterol, High Density Lipoprotein-Cholesterol (HDL-C), Low Density LipoproteinCholesterol (LDL-C), Very Low Density Lipoprotein (VLDL) cholesterol and Triglycerides (TG) measurement. Chi-square test was performed to find out the significance of association and independent t-test was used to compare the mean between various groups. Results: Cytochrome P450 (CYP) enzyme inducers like carbamazepine, phenytoin and phenobarbitone significantly modified serum lipids in epileptic children when compared to healthy controls. In children on long-term phenytoin monotherapy, mean cholesterol levels were significantly higher in the cases compared to controls (156.73±31.93 mg/dL vs 105.03±8.60 mg/dL, p-value <0.0001), significantly elevated triglycerides (123.48±25.99 mg/dL vs 87.88±12.16 mg/dL, p-value <0.0001), and HDL-C level was significantly lower (44.52±10.14 mg/ dL vs 56.73±12.56 mg/dL, p-value <0.0001) than in controls. Phenobarbitone use was associated with significantly higher levels of cholesterol (164.97±34.41 mg/dL vs 107.76±9.28 mg/dL, p-value <0.0001), LDL (155.27±28.55 mg/dL vs 93.36±6.81 mg/ dL, p-value <0.0001), and triglycerides (125.55±42.19 mg/dL vs 86.30±8.12 mg/dL, p-value <0.001) and lower HDL (46.30±9.47 mg/dL vs 57.73±14.41 mg/dL, p-value <0.0001). Levetiracetam was not associated in significant alteration in both liver enzymes and lipid profile (p-value >0.05). Carbamazepine monotherapy was associated with higher levels of cholesterol (180.50±28.06 mg/dL vs 112.15±13.55 mg/dL, p-value <0.0001), LDL (138.85±22.55 mg/dL vs 82.45±12.12 mg/dL, p-value<0.0001) and triglycerides (142.80±9.48 mg/dL vs 85.40±6.29 mg/dL, p-value <0.0001) when compared to healthy controls. There was no alteration in lipid profile in valproate monotherapy. Valproate monotherapy was associated with significant increase in levels of SGOT and SGPT when compared to mean levels (40.35±11.208 (IU/L), and 40.70±8.809 (IU/L), respectively) observed in other AEDs and significant increase in SGPT levels when compared to healthy controls (36.50±10.61(IU/L) in cases vs 40.70±8.81 (IU/L) in controls). Conclusion: Levetiracetam did not produce significant changes in the serum lipid profile and liver enzymes and appears to be safe to use in children for long-term epilepsy management especially in children with baseline deranged lipid profile.

To determine the effect of long-term antiepileptic drug on the serum folate and vitamin B12 among epileptic patients

The purpose of this study was to prevent anaemia caused on long-term phenytoin treatment among Epileptic patients. Therefore, two groups were categorised based on the duration of phenytoin namely, cases and control. The duration of Phenytoin treatment for case was > 2 years while control had < 1 year. The estimation of serum Folate and Vitamin B12 was carried out and the association between the deficiency of Vitamins with the duration of treatment were evaluated using Linear Regression Analysis. The statistical results shown that the mean value of Folate (2.61 ± 1.81) and the mean value of Vitamin B12 (284.68 ± 110.12) were considered to be low as the duration of Phenytoin treatment increases (> 2 years) compare to control with the Folate concentration of (7.01 ± 4.40) which was statistically significant (p < 0.000). The experimental results have proved that a long-term phenytoin treatment significantly affects the concentration of Folate and Vitamin B12 among the Epileptic patients vigorously.

The possible protective role of selenium against long-term phenytoin administration effects on cerebellar cortex of adult male albino rats: Histological and immunohistochemical study

Background: Phenytoin is a commonly prescribed antiepileptic drug. Chronic phenytoin treatment has been documented to be associated with cerebellar degeneration. Selenium is one of the main antioxidant coenzymes of glutathione peroxidase and it is a key component of seleno-proteins that play important roles in brain development and metabolism.Aim: This work aimed to study the possible protective role of selenium against long-term phenytoin administration effects on cerebellar cortex of the adult male albino rats.Material and Methods: Forty-five adult male albino rats were used in this study, aged from 6-8 months, weighting 180 -200 gm. Rats were equally divided into three groups: Group I: rats were further equally subdivided into: group IA: kept as negative control, group IB: each rat received 1ml of distilled water /day orally for 45 days and group IC: each rat received selenium at a dose of 0.5 mg/kg BW(body weight)/day orally for 45 days. Group II: each rat received phenytoin at a dose of 20mg/ Kg BW /day orally for 45 days. Group III: each rat received phenytoin as group II in addition to selenium at a dose of 0.5 mg/kg BW/day orally for 45 days.Results: The present work revealed that long term phenytoin administration induced histological changes of rat’s cerebellar cortex in the form of decreased thickness, irregular deeply stained Purkinje cells and increased perineural space around Purkinje cells and granule cells. Selenium administration with phenytoin nearly preserved the histological structure of the cerebellar cortex.Conclusion: Long term phenytoin administration led to histoarchitectural changes of rat’s cerebellar cortex. However, Selenium administration with phenytoin greatly protected the cerebellar cortex from such changes

The Case Files

Figure: Corrected Phenytoin Concentration v. Dose of PhenytoinFigureFigureFigureFigureA 63-year-old man presented with hand tremors, dizziness, and expressive aphasia. His symptoms had started a month earlier, and this was his third visit to the ED for these symptoms, though the aphasia was a new symptom. He said his symptoms had been growing worse. The patient's symptoms had been previously attributed to alcohol intoxication. He also said he had been experiencing vomiting, dry heaving, bilateral tinnitus, and dizziness but no fever, chills, chest pain, abdominal pain, shortness of breath, vision and hearing problems, gait problems, vertigo, numbness, or loss of consciousness. He had had multiple falls due to dizziness but no head or neck trauma. He occasionally had constipation but no other symptoms. His history included right leg deep vein thrombosis, left shoulder replacement, epilepsy, anxiety disorder, panic attacks, and benzodiazepine and opiate dependence. He had been in a methadone program for 25 years for heroin abuse, but he had stopped all benzodiazepines a month before his ED visit because his primary care physician advised him not to mix them with alcohol. His medications were alprazolam, cholecalciferol, phenytoin, folic acid, meclizine, and naproxen. He reported daily alcohol and cannabis use. His temperature was 98.3°F, pulse was 75 bpm, respiration rate was 20 bpm, blood pressure was 167/108 mm Hg, and oxygen saturation was 98% on room air. The patient was alert and oriented times four but anxious and confused. His pupils were round, equal, and reactive to light with bilateral horizontal nystagmus. The patient was able to follow commands but unable to converse due to confusion. He had an ataxic gait but an otherwise unremarkable examination. His laboratory findings were a WBC of 6.7k/μL, RBC of 4.38 M/μL, Hbg of 14.5 g/dL, hematocrit of 43.4%, MCV of 99 FL, ALT of 53 IU/L, AST of 60 IU/L, albumin of 3.8 g/dL, and serum phenytoin of 36.6 mcg/mL. The patient's phenytoin was stopped, and he was admitted to monitor his drug level and breakthrough seizures. He regained cognitive and motor stability once his drug level dropped below therapeutic levels. He was discharged five days later with levetiracetam 500 mg BID.TableSerum Monitoring Phenytoin can be used nonemergently to treat complex partial and tonic-colonic seizures and emergently to treat status epilepticus. It has a narrow therapeutic serum range of 10-20 mcg/mL. (N Engl J Med 1985 18;313[3]:145; Br J Clin Pharmacol 1974;1[2]:163; http://bit.ly/2qCKcqA.) Phenytoin toxicity was more common in the past, but incidence is much lower now because other antiepileptic medications have better side-effect profiles and dose management. Many studies have reported that adverse symptoms of phenytoin depend on the serum concentration levels. (Table.) (Proc Singapore Health 2013;22[3]:198; http://bit.ly/2PgjX8a; DRUGDEX System: Truven Health Analytics; 2013; www.micromedexsolutions.com; Lexicomp. Phenytoin. https://online.lexi.com.) Phenytoin serum values are corrected based on albumin levels using the Sheiner-Tozer formula. This corrected serum concentration standardizes the value to allow for comparison between individuals. (Ann Pharmacother 1995;29[7-8]:667.) This patient's serum albumin of 3.8 g/dL and phenytoin of 36.6 mcg/mL resulted in a corrected phenytoin value of 42.56 mcg/mL, supporting the patient's symptoms of confusion, horizontal nystagmus, ataxia, slurred speech, nausea, and vomiting. The most common treatment is to replace the medication with another anticonvulsant (mostly levetiracetam), which is better tolerated and has fewer adverse effects. (Neurocritical Care 2014;21[2]:228.) Patients on long-term phenytoin require constant serum monitoring and dose corrections. (N Engl J Med 1985 18;313[3]:145.; Br J Clin Pharmacol 1974;1[2]:163; http://bit.ly/2qCKcqA.) Monitoring is necessary because of the exponential relationship between corrected phenytoin concentration v. the phenytoin dose. (Figure.) It displays that the therapeutic dose range is within ~50 mg/kg. This narrow window makes it easy to be in nontherapeutic range when under treatment. With a slight increase, it reaches toxic levels, with the patient presenting with the correlated symptoms shown in the table. Constant serum monitoring is troublesome, but follow-up is more difficult for those with a history of illicit drug and alcohol abuse, like our patient. The dose is not the only factor that can lead to elevated serum levels in the blood; a slight decrease in liver function through cirrhosis, malnutrition, or aging can also cause the drug serum concertation to rise. (Epilepsy Res 2006;68[Suppl 1]:S49; http://bit.ly/2JSp0G3.)

Phenytoin-related ataxia in patients with epilepsy: clinical and radiological characteristics

PurposePhenytoin is an effective anticonvulsant for focal epilepsy. Its use can be associated with long-term adverse effects including cerebellar ataxia. Whilst phenytoin is toxic to Purkinje cells in vitro; the clinical and radiological phenotype and mechanism of cerebellar degeneration in vivo remain unclear. We describe the prevalence, clinical and radiological characteristics of phenytoin-related ataxia. MethodsPatients with epilepsy receiving treatment with phenytoin were recruited from the Epilepsy clinics at Royal Hallamshire Hospital, Sheffield, UK. Neurological examination was performed on all patients after recruitment. Patients were categorised into those with and without ataxia. We determined the severity of ataxia clinically (SARA score) and the pattern of cerebellar involvement by neuroimaging (MRI volumetry and MR spectroscopy). ResultsForty-seven patients were recruited. Median duration of epilepsy was 24 years, median duration of phenytoin treatment was 15 years and current median phenytoin daily dose was 325 mg. Fifty-five percent of patients complained of poor balance. Clinical evidence of ataxia was seen in 40% patients. Gait, stance and heel-shin slide were the predominant features of cerebellar dysfunction. MRI demonstrated structural, volumetric and functional deficits of the cerebellum. Only one patient with ataxia had phenytoin levels above the normal range. ConclusionsCerebellar ataxia is present in 40% of patients with epilepsy and chronic exposure to phenytoin. Patients on long-term phenytoin have reduced cerebellar volume even if they have no clinical evidence of ataxia. Evidence of structural deficits on imaging suggests a predilection for vermian involvement.

CEREBELLAR ATROPHY WITH LONG-TERM PHENYTOIN (PHT) USE: CASE REPORT

Cerebellar atrophy can be found with long-term phenytoin (PHT) use or acute phenytoin intoxication. PHT may cause cerebellar symptoms, such as nystagmus, diplopia, dysarthria and ataxia. Clinical manifestations may be persistent. We report a case of a 41-year-old male who presented with cerebellar dysfunction and cerebellar atrophy after longterm phenytoin use. He had ataxic gait, preserved strength, commuting deep reflexes, dysmetria, dysdiadochocinesia, scanning speech and somnolence. Cranial computed tomography revealed enlargement of interfollicular cerebrospinal fluid spaces in cerebellum and also a slight enlargement of the fourth ventricle, suggesting signs of cerebellar volumetric reduction. PHT was withdrawn. Six months later, he presented improvement in his condition; he had atypical gait, mild dysmetria, diadochokinesia and normal speech. In conclusion, clinicians should be vigilant with patients on phenytoin. If the patient has cerebellar signs with a correspondent clinical history of phenytoin intoxication CT scan should be helpful as an initial cerebellar assessment.

Chronic phenytoin treatment reduces rat carotid body chemosensory responses to acute hypoxia

Ventilation is peripherally controlled by afferent activity arising from the peripheral chemoreceptors. In the rat, chemosensory activity is conveyed to the central nervous system through axons of neurons located in the nodose-petrosal-jugular-complex. These neurons have distinct electrophysiological properties, including a persistent Na+ current. Acute blockade of this current with phenytoin and other anti-epileptic drugs reduces normoxic chemosensory activity and responses to acute hypoxia. However, because anti-epileptic therapy is prolonged and there is no information on the effects of chronic phenytoin treatment on peripheral chemosensory activity, we studied the effects of long-lasting phenytoin treatment (~25 days) on afferent chemosensory activity, on a wide range of oxygen inspiratory fractions. Osmotic pumps containing dissolved phenytoin (166mg/mL) or vehicle (daily flow: 60µL) were implanted subcutaneously in male adult Sprague Dawley rats. At the end of the treatment, the animals were anesthetized and carotid sinus nerve activity was recorded in vivo. Afferent chemosensory activity in normoxia was not significantly different between control (71.2±2.2Hz) and phenytoin treated (95.4±2.1Hz) rats. In contrast, carotid body chemosensory responses to acute hypoxic challenges were markedly reduced in phenytoin treated rats, specifically in the lowest part of the hypoxic range (control 133.5±18.0Hz vs phenytoin treated 50.2±29.4, at 5% FIO2). Chronic phenytoin treatment severely impaired the chemosensory responses to acute hypoxia, suggesting that long-term phenytoin treatment in patients may result in a reduced peripheral respiratory drive together with a reduction in the respiratory responses to hypoxic challenges.

Dendritic, Axonal, and Spinal Pathology of the Purkinje Cells and the Neurons of the Dentate Nucleus After Long-Term Phenytoin Administration

Phenytoin is a commonly prescribed anticonvulsant drug; however, there is evidence that long-term administration is related to cerebellar ataxia, cerebellar atrophy, loss of Purkinje cells, and hyperplasia of Bergman glia cells. The aim of the present study was to detect and describe any possible alterations of the Purkinje cells, and neurons of the dentate nucleus, as those can be seen with the use of silver impregnation techniques, such as Golgi and Nauta method. The study was performed on a 7-year-old boy who was under phenytoin treatment for more than 3.5 years and had clinical manifestations of cerebellar ataxia. Golgi silver impregnation technique revealed substantial loss of dendritic spines and tertiary dendritic branches, both on the Purkinje cells and the neurons of the dentate nucleus, whereas the Nauta method demonstrated swollen and degenerated axons of Purkinje cells.

Effects of withdrawal from long-term diphenylhydantoin treatment on audiogenic and maximal electroshock-induced seizures in rats.

Rats withdrawal from long-term diphenylhydantoin treatment (DPH) were tested for their sensibility to convulsant stimuli. Animals were more sensitive to convulsions elicited by maximal electroshock and sound, respectively, at 48 and 72 h after drug removal. These results suggest that long-term DPH treatment might develop a central nervous system supersensitivity state.

Cytomegalovirus antibodies in epileptics receiving diphenylhydantoin

Cytomegalovirus (CMV) antibodies were determined by indirect haemagglutination in 53 epileptics receiving long-term diphenylhydantoin (DPH) therapy and in 53 matched controls. Absorption of serum IgG, IgA and IgM performed in 12 sera showed that the antibodies were of the IgG class. A decreased incidence of high CMV antibody titres (greater than or equal to 320) was found in epileptics (11.3%) compared with controls (34.0%) (0.02 greater than P greater than 0.01), whereas antibody titres greater than or equal to 40 were found in 37.7% of epileptics and in 45.3% of controls (n.s.). The CMV antibody incidence and titre range were similar in patients with symptomatic (37.9%) and idiopathic (37.5%) epilepsy, suggesting that the DPH treatment was responsible for the decreased antibody occurrence in patients. No correlation between CMV antibody titres and the serum immunoglobulin levels or the DPH concentration or clearance could be established in the epileptics.

Initial and maintenance dose of vitamin D2 in the treatment of anticonvulsant osteomalacia.

Bone mineral content (BMC), serum calcium and serum alkaline phosphatase levels were measured in 40 epileptics on long-term phenytoin treatment, before and during treatment with vitamin D2 Initially the patients were divided into 3 groups, who received 2000, 4000, and 8000 international units daily for 105 days. Hereafter the 27 patients on the two higher doses were subdivided into two groups, who for a further 150 days received either 1000 I.U. or 200 I.U. daily. During the whole study the biochemical parameters were unaffected by the vitamin D treatment. With all 3 doses an initial increase in BMC (corresponding to a positive calcium balance) was observed, which was highest with 4000 I.U. daily. With this dose the mean BMC value was normalized. In the following maintenance dose period an estimated calcium balance close to zero was seen with 1000 I.U. daily, whereas the patients on 200 I.U. daily showed a negative calcium balance, as their BMC values returned to the initial figures. It is a cost-benefit problem whether it is advisable to give prophylactic vita-min D treatment to epileptic patients. To elucidate this problem a controlled therapeutic trial on a large scale would be needed, so planned as to clarify the clinical benefit of such treatment.

Effects of Menatetrenone on the Bone and Serum Levels of Vitamin K2 (Menaquinone Derivatives) in Osteopenia Induced by Phenytoin in Growing Rats

Objective: We investigated the effects of phenytoin, an antiepileptic drug, and vitamin K2 (menatetrenone) on bone mineral density and the changes in the levels of menaquinone derivatives (MK-1 ∼ MK-14) in the sera and femurs of growing male rats. Methods: Levels of menaquinone derivatives were measured with high-performance liquid chromatography with an electrochemical detector. Results: Bone mineral density values decreased significantly in all parts of the femoral bones measured (diaphysis and metaphysis) in the phenytoin-treated group. When the serum and bone levels of menatetrenone and MK-6 decreased due to phenytoin administration, we observed bone loss in rats. Conversely, when bone loss was prevented by the combined administration of phenytoin and menatetrenone, serum and bone levels of menatetrenone and MK-6 increased to the levels of vehicle-treated rats. Conclusions: Long-term phenytoin exposure may inhibit bone formation concomitantly with insufficient vitamin K, which, at least in part, contributes to bone loss in rats.

Effects of long-term phenytoin or phenytoin plus ascorbic acid administration on urethane anesthetic effect in rats: A controlled study

Background: Phenytoin, a widely used anticonvulsant, interacts with many drugs. These interactions may be clinically significant. Objective: This controlled, 31-day study investigated the possible interactions of phenytoin with urethane and ascorbic acid. Methods: Groups of male rats were subjected to long-term oral phenytoin treatment with or without ascorbic acid coadministration. The responsiveness of treated animals to the anesthetic activity of urethane then was investigated by assessing their righting reflexes. Results: Long-term phenytoin treatment resulted in hyporesponsiveness to the urethane anesthetic effect, and this interaction was augmented by ascorbic acid coadministration. Conclusion: Our results indicate that phenytoin interacts with ascorbic acid and urethane in vivo, which may be of clinical and/or experimental importance.

The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement.

The cytochrome P450 enzyme CYP2C9 catalyses the metabolism of numerous therapeutic agents, including the anti-epileptic drug phenytoin. CYP2C9 is genetically polymorphic: two allelic variants are known, CYP2C9*2 and CYP2C9*3, differing from the wild-type CYP2C9*1 by a single point mutation. Both mutant alleles are associated with markedly impaired metabolic capacity for many CYP2C9 substrates compared to the wild-type, resulting in raised serum drug levels upon a given dose. Because this may be relevant in treatment with phenytoin, we studied the effect of CYP2C9 genotype on phenytoin dose requirement in a group of 60 epileptic patients on long-term phenytoin therapy. CYP2C9 genotyping was performed by polymerase chain reaction analysis, phenytoin serum concentrations were measured by high-performance liquid chromatography analysis and related to the maintenance doses. For patients carrying at least one mutant CYP2C9 allele (n = 17), the mean phenytoin dose required to achieve a therapeutic serum concentration was about 37% lower than the mean dose required by wild-type individuals (199 mg/day versus 314 mg/day; P < 0.01). A low maintenance dose (< 200 mg/day) sufficed for 47% of carriers, while 58% of normals required a high dose (> 300 mg/day) for an effective serum level. The results show that there is a strong association between CYP2C9 allelic variants and phenytoin dose requirement. Since phenytoin has a narrow therapeutic index and genotyping may be carried out rapidly and at low cost, dosage adjustment based on CYP2C9 genotype, especially at the induction of therapy, would be of value in order to lower the risk of concentration dependent drug intoxications in carriers.

Interictal cardiovascular autonomic responses in patients with epilepsy.

To evaluate the interictal autonomic nervous system function in 84 patients with epilepsy: 37 with newly diagnosed, previously untreated epilepsy, and 47 patients receiving long-term carbamazepine (CBZ), phenytoin (PHT), or valproate (VPA) monotherapy, or CBZ plus PHT, or CBZ plus VPA for their seizure disorder. We assessed autonomic control of the cardiovascular regulatory system by standardized cardiovascular reflex tests measuring changes in heart rate (HR) and blood pressure (BP) at rest and after certain stimuli. The HR and BP responses were similar to those of control subjects in patients with newly diagnosed epilepsy. However, HR variation during normal breathing and maximum systolic BP increase in isometric work were diminished in patients, who had been treated with antiepileptic drugs (AEDs) for epilepsy for a long time. Diminished HR responses to the Valsalva maneuver were noted in patients receiving CBZ as monotherapy and during deep breathing in patients receiving CBZ combined with PHT or VPA. Furthermore, patients receiving CBZ had diminished BP responses in isometric work. When analyzed in relation to epilepsy type, suppressed HR responses in normal breathing were associated with primary generalized epilepsy (PGE), whereas diminished BP responses in isometric work were associated with partial epilepsy. Two patients with recently diagnosed partial epilepsy and 1 patient receiving long-term CBZ monotherapy for partial epilepsy had two abnormal cardiovascular response test results. Our results show that cardiovascular responses mediated by both the parasympathetic and sympathetic nervous system are diminished in patients with epilepsy. However, the changes appear to be clinically significant in only a few of them and appear to be associated with CBZ medication. Further studies are needed to detect the underlying complex interactions and clinical significance of autonomic nervous system dysfunction in patients with epilepsy.

The Neuromuscular Blocking Effect of Mivacurium in Isolated Rat Phrenic-Hemidiaphragm with Long-term Phenytoin Pretreatment

The Neuromuscular Blocking Effect of Mivacurium in Isolated Rat Phrenic-Hemidiaphragm with Long-term Phenytoin Pretreatment

Cerebellar atrophy in patients with long-term phenytoin exposure and epilepsy.

Cerebellar atrophy has been noted in patients with phenytoin exposure. This finding has been attributed by some investigators to seizures, but by others to phenytoin. Previous studies included patients with mental retardation and convulsive seizures. We undertook a study in a group of nonretarded patients with partial epilepsy to better elucidate the cause of the cerebellar atrophy. Case control study. Referral population from an epilepsy center. Thirty-six patients with partial epilepsy and long-term phenytoin exposure were selected from a consecutive sample of admissions to an epilepsy center. Patients with histories of ethanol abuse, perinatal distress, anoxia, status epilepticus, or neurodegenerative disorders were excluded. Age- and sex-matched controls were selected from a pool of healthy volunteers and patients who had undergone magnetic resonance imaging for complaints of headache and dizziness. All patients and controls underwent magnetic resonance imaging. Degree of cerebellar atrophy. The magnetic resonance imaging scans were reviewed in a blind fashion. A rating was assigned to each scan based on the degree of cerebellar atrophy. Cerebellar atrophy was significantly more pronounced in patients than in controls. No correlation was found between cerebellar atrophy and variables reflective of seizure severity or degree of phenytoin exposure. Cerebellar atrophy may be seen in phenytoin-exposed patients with epilepsy in the absence of generalized tonic-clonic seizures or preexistent brain damage. Whether it is the phenytoin or the seizures that play the primary etiologic role remains unanswered. These factors may be synergistic.

Decreased sensitivity to metocurine during long-term phenytoin therapy may be attributable to protein binding and acetylcholine receptor changes.

Long-term phenytoin therapy induces resistance to the neuromuscular blocking effects of metocurine. The hypothesis that this is attributable to increased plasma protein binding of the drug (decreased free fraction) related to increased concentrations of alpha 1-acid glycoprotein (AAG) or attributable to the proliferation of acetylcholine receptors (AChR) at the muscle membrane was tested in the rat. After 14 days of phenytoin 40 mg.kg-1, administered intraperitoneally twice daily (n = 12), the neuromuscular pharmacodynamics were evaluated and compared with those of time-matched controls (n = 10). Protein binding was measured by equilibrium dialysis, AAG concentrations by radial immunodiffusion assay, and AChR by 125I-alpha-bungarotoxin binding. The effective dose for 50% inhibition of baseline twitch height (ED50) was significantly greater in the phenytoin group than in the control group (15.03 +/- 1.65 micrograms.kg-1 vs. 9.98 +/- 0.69 micrograms.kg-1, respectively). The concentrations of AAG increased gradually from 133.8 +/- 7.8 micrograms.ml-1 at day 0, to 343.1 +/- 58.0 micrograms.ml-1 at day 7, to 1,729.5 +/- 422.3 micrograms.ml-1 at day 14 in the phenytoin group. The induction of AAG concentrations in plasma was dependent on plasma phenytoin concentrations and was most prominent after 14 days of phenytoin (r = 0.77; P less than 0.01; n = 22). The free fraction of metocurine was significantly decreased in the phenytoin group compared to the control group (67.2 +/- 0.18% vs. 74.5 +/- 2.5%). There was a significant negative correlation between increased AAG concentrations and decreased free fraction (r = 0.65).(ABSTRACT TRUNCATED AT 250 WORDS)