Allergic skin reactions to anticonvulsant medications in patients receiving cranial radiation therapy

PURPOSE: Erythema multiforme and Stevens-Johnson syndrome have been associated with anticonvulsant medications (AEDs) in patients with brain tumors receiving cranial irradiation. AEDs are also known to cause mild drug rashes. The incidence of these complications has not been well studied among patients with brain tumors. We reviewed the records of patients with brain tumors treated with cranial radiation and AEDs to assess the frequency of both severe and mild skin reactions. METHODS: Retrospective review of 289 radiotherapy records of consecutively treated patients from 1988 to 1993. RESULTS: Only one of 289 patients developed erythema multiforme. Milder rashes, however, occurred in 18% of exposures to AEDs including 22% of exposures to phenytoin, compared with the expected rate of 5-10%. Most of the mild drug rashes occurred before the initiation of radiotherapy, suggesting that radiation was not the cause of these reactions. CONCLUSIONS: Severe skin rashes are rare among patients with brain tumors receiving radiation therapy and AEDs. There is, however, an increased frequency of mild drug rashes among patients with brain tumors that does not appear related to radiation.     

Prophylactic effect of phenytoin in bipolar disorder: a controlled study

Objective:  Phenytoin is an effective anticonvulsant that has not previously been studied prophylactically in bipolar (BP) patients. Thus a study of phenytoin prophylaxis was undertaken and is herein reported.
Method:  Bipolar patients were studied who had at least one episode per year in the previous 2 years despite ongoing prophylaxis. Patients were stable for a mean of 4 months (range 1–13) before entering the study. Phenytoin or placebo was added to their current therapy in a double-blind cross-over design for 6 months in each phase. Thirty observation periods of 6 months each were studied for 23 patients.
Results:  Three patients had relapse on phenytoin and nine had relapse on placebo. There was a significant prophylactic effect of phenytoin in BP disorder [Cox's F -test for comparing survival in two groups: F ( 6 , 18 ) = 3.44, p = 0.02].
Conclusions:  This study suggests prophylactic effects of add-on phenytoin in BP illness. However, the number of patients was small and confirmation is necessary.     

The changes of cerebral blood flow and metabolism of normal brain tissue after surgery, radiation, and chemotherapy in brain tumor patients: evaluated by position emission tomography

The changes of cerebral blood flow (CBF) and metabolism of normal brain tissue after surgery, radiation, and chemotherapy in brain tumor patients were measured by positron emission tomography (PET). The subjects consisted of 6 men and 3 women, and were from 11 to 62 years old. Those were four patients with glioblastomas, one patient with malignant oligodendroglioma, one patient with astrocytoma grade II, one patient with astrocytoma grade III, one patient with pontine glioma, one patient with pineal germinoma. Seven patients were operated and pathohistologically diagnosed. Two patients with pineal germinoma and pontine glioma were not operated and radiologically diagnosed. Of 7 operated patients, first PET was performed before operation in 3 patients, and from 10 to 16 days after operation in 4 patients. Following first PET, the patients were treated with irradiation (1 case), or with both irradiation and chemotherapy (8 cases). The total radiation dose for tumor was from 59 to 61 Gy distributed in a period of 6-8 weeks. Whole brain irradiation was performed up to 30 or 40 Gy, with a remaining dosimetry (20-30 Gy focused on the tumor field. Chemotherapy consisted of intravenous administration of ACNU and oral administration of FT-207. Second PET was performed 1 month after therapy (9 cases), and third PET was performed from 4 to 24 months after therapy (6 cases). Fourth PET was performed in 2 patients (22 and 35 months after therapy), and fifth PET was performed in one patient (35 months after therapy).(ABSTRACT TRUNCATED AT 250 WORDS)     

Elimination of phenytoin in toxic overdose

Phenytoin is widely used for the management of seizures. Fortunately overdosage with this drug is rare. We performed a prospective study to investigate the elimination kinetics of phenytoin in toxic overdose. All patients were only on phenytoin and not on other anticonvulsants. Phenytoin toxicity was defined by clinical features and correlated with drug levels. Daily phenytoin levels were obtained until they were less than or equal to 15 mcg/ml. Nine patients with age ranging from 20 to 66-years-old were recruited. Sex ratio was male:female, 5:4. Initial phenytoin levels ranged from 34 to 57.5 mcg/ml. Serum phenytoin levels of three patients remained relatively constant for 2-5 days before declining in a steady fashion. Phenytoin levels of the remaining patients declined in an almost linear manner. Regression analysis of all patients showed that the slope terms were highly significant (with low P-values) and corresponding R(2) values were close to 1. Different patients have different rates of metabolism; in seven of nine patients, levels declined between 4.6 and 5.9 mcg/ml per day. Knowledge of the rate of elimination assists the clinician in deciding on the best time to reinstitute phenytoin therapy.     

Management of brain metastases

Brain metastases represent a common and devastating complication of cancer. With advances in surgery, radiology, and medical and radiation oncology, the number of treatment options have greatly increased. In addition, the prognosis for patients can vary widely depending on factors such as the number of lesions, extent of extracranial disease, age, and functional status. Recently, the possible impairment of whole brain radiation therapy on neurocognitive function has been a subject of concern and debate. Thus, the use of whole brain radiation therapy in conjunction with other treatment modalities should be optimized to ensure the best outcomes with regard to tumor control and functional status. As a result, patient management has become controversial, with strong opinions often dictating “optimal” therapy. This review of the management of brain metastases focuses on whole brain radiation therapy, surgery, stereotactic radiosurgery, radiation sensitizers, and clinical trials.     

Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin

In 15 months we encountered eight patients with intracranial tumors who developed erythema multiforme (EM) or erythema multiforme bullosa (Stevens-Johnson syndrome). All occurred shortly after use of phenytoin (DPH) and brain radiation therapy (WBRT). The clinical picture differed from the classic form of EM in that the erythema began on the scalp and spread to the extremities, progressing in three cases to extensive bullous formation. There were no cases of EM among patients who received either DPH or radiotherapy alone. The combination of DPH, WBRT, and tapering of steroids seems to predispose to EM. The pathogenesis of the disorder is probably immunologic. In the absence of seizures, anticonvulsants should not be given routinely to patients with brain tumors. When anticonvulsants are necessary in patients scheduled for WBRT, DPH may not be the drug of choice.     

Cerebral necrosis after 25Gy radiotherapy in childhood followed 28 years later by 54Gy radiotherapy

The development of brain necrosis is life-long risk of repeat radiation therapy, even after a long time interval and a moderate radiation dose. We report on a 34-year-old patient who had prophylactic cranial irradiation with 25Gy and adjuvant chemotherapy in childhood for leukaemia and in adulthood, 28 years later, therapeutic radiotherapy with 54Gy for an atypical (WHO grade II) meningioma. About 2 years later he developed a contrast-enhancing lesion on MRI-scan that was indicative of a tumor according to a thallium-201 ((201)Tl) SPECT scan. Histopathology of the operated contrast-enhancing lesion showed extensive radionecrosis. Radiation necrosis is a small but serious risk after repeat radiation therapy, even after a very long-term interval, the delivery of small fractions and an average cumulative total dose. Patients undergoing repeat radiotherapy therefore need to be followed life-long for potential late radiation toxicity.     

Phenytoin enhances the phosphorylation of epidermal growth factor receptor and fibroblast growth factor receptor in the subventricular zone and promotes the proliferation of neural precursor cells and oligodendrocyte differentiation

Phenytoin is a widely used antiepileptic drug that induces cell proliferation in several tissues, such as heart, bone, skin, oral mucosa and neural precursors. Some of these effects are mediated via fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR). These receptors are strongly expressed in the adult ventricular–subventricular zone (V‐SVZ), the main neurogenic niche in the adult brain. The aim of this study was to determine the cell lineage and cell fate of V‐SVZ neural progenitors expanded by phenytoin, as well as the effects of this drug on EGFR/FGFR phosphorylation. Male BALB/C mice received 10 mg/kg phenytoin by oral cannula for 30 days. We analysed the proliferation of V‐SVZ neural progenitors by immunohistochemistry and western blot. Our findings indicate that phenytoin enhanced twofold the phosphorylation of EGFR and FGFR in the V‐SVZ, increased the number of bromodeoxyuridine (BrdU)+/Sox2+ and BrdU+/doublecortin+ cells in the V‐SVZ, and expanded the population of Olig2‐expressing cells around the lateral ventricles. After phenytoin removal, a large number of BrdU+/Receptor interacting protein (RIP)+ cells were observed in the olfactory bulb. In conclusion, phenytoin enhanced the phosphorylation of FGFR and EGFR, and promoted the expression of neural precursor markers in the V‐SVZ. In parallel, the number of oligodendrocytes increased significantly after phenytoin removal.     

Levetiracetam is Associated with Improved Cognitive Outcome for Patients with Intracranial Hemorrhage

Background  

To date, common therapy in patients with intracranial hemorrhage (ICH) includes prophylaxis of seizure using antiepileptic drugs, commonly phenytoin. Phenytoin therapy is associated with a high incidence of cognitive disturbance. Levetiracetam is known to cause less cognitive disruption and may be a suitable alternative for seizure prophylaxis. Cognitive outcomes in ICH patients receiving seizure prophylaxis with levetiracetam or phenytoin are compared.     

Pharmacological prophylaxis against the development of kindled amygdaloid seizures

The kindling of amygldaloid and cortical seizures in cats was used to study the prophylactic effects of phenobarbital, phenytoin, ethosuximide, acetazolamide, and dexamethason. Phenobarbital prevented the evolution of such seizures beyond stage 4 in all amygdaloid-kindling animals during 160 days of study. The prophylactic effect persisted on periodic challenge after the drug had been discontinued. Phenytoin, ethosuximide, acetazolamide, and dexamethasone appeared to have no prophylactic effect against the development of kindled amygdaloid seizures. With cortical kindling, both phenobarbital and phenytoin retarded the evolution of seizures without achieving true prophylaxis. The drugs appeared to act as suppressants. Prophylaxis was not an "all-or-none" phenomenon but rather a limitation of the stage of seizure evolution.     

Moyamoya syndrome after cranial irradiation for bone marrow transplantation in a patient with acute leukemia

It is well known that radiation-induced vasculopathy and arteritis are two of the complications of whole brain radiation therapy. Moyamoya syndromes after cranial irradiation among patients with brain tumors were previously reported. However, we could find only three cases of prophylactic cranial irradiation for hematological disorders and no case of cranial irradiation before bone marrow transplantation in patients with acute leukemia. We recently treated a boy who developed moyamoya vessels 1.5 years after cranial irradiation for bone marrow transplantation for acute leukemia. This is the first report of moyamoya syndrome after cranial irradiation for bone marrow transplantation. The mechanism and incidence of vasculopathy after cranial irradiation are unclear. It would be useful to accumulate data and reveal the etiology of moyamoya vessels formation after cranial irradiation.     

Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy

Intractable seizures are the most common manifestation in severe cases of tuberous sclerosis. Multidrug resistance type 1 (MDR1) gene expression is directly linked to the resistance of tumor cells to chemotherapy as the major cause of treatment failure, but it has not been reported in tuberous sclerosis cells nor has the relationship between the MDR1 gene and antiepileptic drugs been described. A 4-month-old female is described with poorly controlled seizures secondary to tuberous sclerosis. The patient was treated with antiepileptic drugs, including phenytoin, phenobarbital, and lorazepam, without improvement of symptoms. Phenytoin blood levels were invariably subtherapeutic and ranged from 0.45 to 3.55 microg/mL, despite several consecutive intravenous loading doses. Surgical treatment with total resection of the brain lesions was performed as a last resort. Immunohistochemical analysis of the resected tissues revealed high levels of P-glycoprotein 170 expression, the product of the MDR1 gene. Both MDR1 gene expression and persistently low phenytoin levels likely share a common pathway liable to induce drug-resistant epilepsy.     

Intracranial hemorrhage associated with congenital organic disease in neonates

We report on two patients with intracranial hemorrhage associated with primary organic lesions who underwent surgery within 24 h after birth. The primary lesions in the two cases were an arteriovenous malformation (AVM) and a brain tumor. The patient with AVM has exhibited normal growth without neurological deficits during follow-up over 18 years, but the patient with brain tumor has exhibited various degrees of neurological deficits and developmental retardation. Timely diagnosis and aggressive surgery may be required for the management of neonatal AVMs with intracerebral hemorrhage.     

Endocrine complications of pediatric brain tumors: case series and literature review

The survival rate for childhood cancer, including brain tumors, is increasing. As a result, long-term sequelae of chemotherapy and radiotherapy are also increasing. The purpose of this study was to determine the frequency of endocrine complications of therapy for brain tumors in pediatric patients. Endocrinopathy was observed in 19 of 20 (95%) of patients with supratentorial midline tumors. Fifty-seven patients with nonmidline tumors (22 supratentorial, 35 posterior fossa) were followed for a mean of 4.6 +/- 2.4 years. Twenty-two endocrinopathies occurred in 16 patients treated as follows: one of 23 patients (0.4%) had surgery alone, zero of four (0%) had chemotherapy alone, eight of 18 (44%) had radiotherapy alone, and seven of 12 (58%) had both radiotherapy and chemotherapy. Endocrine disturbance was particularly common after craniospinal radiation (10 of 18 [55%]). Growth failure occurred in none of 23 patients who had surgery alone, in one of four patients who had chemotherapy (25%), in 11 of 18 patients who had radiotherapy (61%), in seven of 12 patients who received both radiotherapy and chemotherapy (58%), and in 12 of 18 patients who had craniospinal radiation (67%). In conclusion, endocrine and growth disturbances are uncommon with surgery alone, although they occurred in 53 and 60%, respectively, of patients treated with cranial irradiation for a brain tumor. This finding underscores the importance of routine endocrinology follow-up for all brain tumor patients receiving cranial irradiation. Literature review and endocrine surveillance recommendations are included.     

Phenytoin Toxicity Due to Genetic Polymorphism

Introduction  Patients with traumatic brain injury commonly receive phenytoin for seizure prophylaxis. Due to the non-linear pharmacokinetics of phenytoin and narrow therapeutic window, phenytoin concentrations are monitored to ensure efficacy and prevent toxicity. Because phenytoin is hepatically metabolized, polymorphisms within cytochrome P450 enzymes can affect phenytoin concentrations. Methods  We report a case of a 53-year-old Asian female admitted to the neuroscience intensive care unit after suffering a traumatic brain injury. Phenytoin was subsequently administered for seizure prophylaxis. Results  Four days after being initiated on phenytoin, the patient remained lethargic, and phenytoin toxicity was suspected. Lab values revealed a free phenytoin concentration of 4.4 mg/l, and phenytoin was discontinued. Upon further investigation, it was found that the patient was a cytochrome P450 2C9 poor metabolizer. Causes of the patient’s toxic phenytoin concentration such as drug interactions, decreased albumin, and lab error were excluded. The cause of her elevated phenytoin concentration was determined to be hepatic polymorphism. Conclusion  This case reveals the clinical significance of genetic polymorphisms and the effect on phenytoin dosage requirements. Because pharmacogenomic testing is expensive and not readily available, routine monitoring of phenytoin concentrations is warranted. Further, established polymorphisms should be documented to prevent toxicity of drugs metabolized by similar pathways.     

Treating brain metastases: current approaches and future directions

Brain metastases frequently present with neurologic signs or symptoms in a patient with a history of cancer. The finding of a brain metastasis is usually associated with terminal disease. However, patients with brain metastases are a heterogeneous group. Therefore, the treatment of brain metastases must be tailored to each individual patient. In this article, which patients with brain metastases benefit from surgical resection, radiosurgery and whole-brain radiation therapy are reviewed. Reports of treating patients with brain metastases with chemotherapy are also reviewed and data that supports prophylactic treatment of the brain for select patients is discussed. This review aims to provide a framework for treating patients with different presentations of brain metastases and to highlight important avenues for future research.     

Phenytoin inhibits isolation-induced aggression specifically in rats with low serotonin

Phenytoin is a widely used anticonvulsant drug that also reduces aggressive behavior. Aggression in humans and animals is often associated with low serotonin levels. This study examined the anti-aggressive properties of phenytoin in rodent isolation-induced aggression using a resident-intruder test to quantify aggression. Chronic treatment with p-chlorophenyl-alanine (PCPA), a competitive inhibitor of serotonin synthesis, significantly enhanced resident attack behavior compared to saline-treated control rats. Phenytoin dose-dependently reduced aggressive behavior specifically in PCPA-treated rats, but had no anti-aggressive properties in saline-treated rats. These data suggest that aggressive behavior in this model may be related to neuronal hyperexcitability that is sensitive to the anticonvulsant effects of phenytoin. Further, these data suggest isolation-induced aggression in PCPA-treated rats may be a useful model to investigate aggression associated with low serotonin in the brain.     

Brain metastasis from extramammary Paget’s disease of the scrotum

We present to our knowledge the first patient with histopathologically proven brain metastasis from extramammary Paget’s disease (EMPD) and discuss the effect of brain radiation therapy for this condition. A 68-year-old man presented to our hospital with headache and gait disturbance. Brain MRI showed multiple enhancing mass lesions, and two large cystic lesions in the left cerebellum. The patient had been diagnosed with scrotal Paget’s disease 3 months previously but no further management had been performed due to his refusal. The patient underwent stereotactic aspiration and biopsy of the two large cystic lesions. A histopathological examination revealed that the tumor was a metastatic adenocarcinoma. Immunohistochemical staining revealed that the tumor cells were strongly positive for cytokeratin 7 and moderately positive for carcinoembryonic antigen and gross cystic disease fluid protein 15. These findings were similar to those of his scrotal skin lesions and were consistent with metastatic EMPD. The patient underwent brain radiation therapy with a total radiation dose of 30 Gy in 10 fractions. The patient improved neurologically so as to be self-ambulatory, and a mild improvement in the metastatic tumors was found on follow-up MRI. We had planned systemic chemotherapy, but the patient died of acute respiratory failure 2 months after radiation therapy.     

Positron emission tomographic measurement of blood-to-brain and blood-to-tumor transport of 82Rb: the effect of dexamethasone and whole-brain radiation therapy

Unidirectional blood-to-brain and blood-to-tumor transport rate constants for rubidium 82 were determined using dynamic positron emission tomography in patients with primary or metastatic brain tumors. Regional influx rate constants (K1) and plasma water volume (Vp) were estimated from the time course of blood and brain radioactivity following a bolus injection of tracer. Eight patients were studied before and 24 to 72 hours after treatment using pharmacological doses of dexamethasone, and 6 additional patients with metastatic brain tumors were studied before and within 60 to 90 minutes after 200- to 600-rad whole-brain radiation therapy. Steroid treatment was associated with a 9 to 48% decrease in tumor K1 and a 21% mean decrease in tumor Vp. No consistent changes in K1 or Vp were observed in control brain regions. Tumor K1 and Vp did not increase in patients undergoing whole-brain radiation therapy, all of whom were taking dexamethasone at the time of study. These data suggest that corticosteroids decrease the permeability of tumor capillaries to small hydrophilic molecules (including those of some chemotherapeutic agents) and that steroid pretreatment prevents acute, and potentially dangerous, increases in tumor capillary permeability following cranial irradiation.     

Phenytoin-induced improvement in muscle cramping and insulin action in three patients with the syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy

Phenytoin sodium has been used to treat muscle cramps of diverse causes, and is known to increase insulin sensitivity during long-term use. We have previously described a syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy with continual muscle cramping. The effect of 300 mg/d of phenytoin (Dilantin) on muscle cramping and carbohydrate economy was studied in three affected patients and four control subjects. Oral glucose tolerance tests, euglycemic insulin infusion studies, and monocyte insulin binding tests were conducted before and after phenytoin administration. All three patients had notable improvement in muscle cramps. In response to phenytoin, metabolic improvements were variable, with improvement characteristically better in patients with less severe baseline metabolic abnormalities. Patient 1, with the mildest degree of glucose intolerance, had decreased fasting insulin and blood glucose levels, improved glucose tolerance, and insulin-mediated glucose disposal, associated with an increase in monocyte insulin receptors. Patient 2 had reduced fasting plasma glucose and insulin levels and improved oral glucose tolerance, suggesting a beneficial effect on carbohydrate metabolism. Patient 3, with the most severely impaired carbohydrate economy, showed no metabolic improvement despite marked lessening of muscle pain. These clinical characteristics were unaffected in control subjects. We conclude that phenytoin is of value in the therapy of muscle cramps and glucose intolerance in patients with this syndrome.