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Object The goal of this study was to compare clinical outcomes following decompressive craniectomy performed for intracranial hypertension in children with nonaccidental, blunt cranial trauma with outcomes of decompressive craniectomy in children injured by other mechanisms. Methods All children in a prospectively acquired database of trauma admissions who underwent decompressive craniectomy over a 9-year span, beginning January 1, 2000, are the basis for this study. Clinical records and neuroimaging studies were systematically reviewed. Results Thirty-seven children met the inclusion criteria. Nonaccidental head trauma was the most common mechanism of injury (38%). The mortality rate in patients with abusive brain injury (35.7%) was significantly higher (p < 0.05) than in patients with other causes of traumatic brain injury (4.3%). Children with inflicted head injuries had a 12-fold increase in the odds of death and 3-fold increase in the odds of a poor outcome (King's Outcome Scale for Closed Head Injury score of 1, 2, or 3). Conclusions Children with nonaccidental blunt cranial trauma have significantly higher mortality following decompressive craniectomy than do children with other mechanisms of injury. This understanding can be interpreted to mean either that the threshold for decompression should be lower in children with nonaccidental closed head injury or that decompression is unlikely to alter the path to a fatal outcome. If decompressive craniectomy is to be effective in reducing mortality in the setting of nonaccidental blunt cranial trauma, it should be done quite early.

Object The interhemispheric transcallosal approach offers an excellent surgical corridor for the treatment of deep-seated midline lesions. The approach typically requires the sacrifice of one or more middle-third superior sagittal sinus (SSS) cortical bridging veins, which introduces the risk of venous infarction and associated neurological injury. The authors studied the incidence of venous infarcts following this operative approach in a pediatric population. Methods The authors performed a retrospective review of surgical cases involving pediatric patients treated at the Children's Hospital Los Angeles between 1990 and 2007, in which an interhemispheric transcallosal operative procedure was performed and one or more middle-third SSS cortical bridging veins were occluded. Postoperative MR imaging studies done 1–3 days following the procedure were analyzed and compared with preoperative studies. Results Sixty-three patients met the inclusion criteria. No patient developed MR imaging evidence of venous infarction. Conclusions The occlusion of one or more middle-third SSS cortical bridging veins related to the interhemispheric transcallosal approach resulted in no incidence of cerebral venous infarction in this pediatric population.

Object The incidence, type, and severity of pediatric cervical spine injuries (CSIs) are related to age and mechanism of injury. In this study, the authors assessed the prevalence of CSIs in infants with head trauma treated in their institution. Methods The authors reviewed the medical records of children younger than 1 year of age who presented to The Children's Hospital with head injuries between January 1993 and December 2007. They excluded infants with head injuries resulting from motor vehicle accidents and known falls from heights greater than 10 ft. For each patient, collected data included age, cause of injury, diagnosis, discharge disposition, and outcome. Relevant imaging data were reviewed, and when appropriate, autopsy reports were also reviewed. Results Nine hundred five infants with head trauma and without a major mechanism/cause were identified. Their mean age was 4.3 months. Of the 905 patients, only 2 cases of CSI were detected, giving a prevalence of 0.2%. The mechanism of injury in these 2 patients was nonaccidental trauma (NAT). Conclusions The study revealed a very low prevalence of CSIs in infants with head trauma (0.2%). Routine cervical spine imaging in these infants, therefore, appears to have low diagnostic yield. The mechanism of head injury was NAT in the 2 patients who sustained an associated CSI. This supports the need for more stringent cervical spine imaging criteria for the infant with suspected NAT.

Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive pediatric brain tumors characterized by the presence of rhabdoid cells and negative immunostaining for INI1 (BAF47). Histogenesis is unknown and diagnosis can be challenging because of their extreme morphological and immunophenotypic heterogeneity. Currently no signature markers other than INI1 loss have been identified. To search for possible candidate proteins of interest in AT/RTs, Affymetrix GeneChip® microarrays were utilized to investigate nine AT/RTs vs. 124 other tumor samples. The most distinctive gene identified was claudin 6 (CLDN6), a key component of tight junctions. CLDN6 showed moderate or higher mRNA expression in eight of nine AT/RTs, with little to no expression in 114 of 115 other tumors. Average expression was 38-fold higher in AT/RTs vs. other samples. Immunohistochemical (IHC) staining of 33 tumor specimens found positive membrane staining in seven of seven AT/RTs, and was negative in 26 of 27 other brain tumor samples. Notably, none of the 16 medulloblastomas/primitive neuroectodermal tumors showed IHC staining for CLDN6. IHC staining results closely matched the level of mRNA expression detected by microarray. CLDN6 may be a useful positive marker to help further identify AT/RTs for diagnostic and treatment purposes.

Objective Rathke cleft cysts (RCCs) are cystic epithelial lesions in the sellar and suprasellar regions that are often discovered incidentally. They require surgical fenestration and drainage in a small proportion of patients who develop symptoms or demonstrate progressive enlargement. Our aim was to review our experience with pediatric patients treated surgically for RCCs. Methods A retrospective review was conducted of all patients treated surgically for RCCs at Childrens Hospital Los Angeles between 1999 and 2007 after approval by the institutional review board. Clinical notes, operative reports, radiological studies, and pathology reports were reviewed. The median follow-up period was 34 months. Results Ten patients undergoing surgical treatment of an RCC were identified, making up 20% of the 51 patients with RCCs followed clinically over the same time period. The mean age was 13 years (age range, 2-17 years). There were 6 females and 4 males. Patients requiring surgery presented with the following clinical symptoms: headache (8 patients, 80%), endocrine insufficiency (6 patients, 60%), meningitis followed by visual loss (1 patient, 10%), and incidental finding (1 patient, 10%). The mean cyst diameter was 13.6 mm (range, 8-18 mm). Four patients had strictly sellar lesions, 4 patients had suprasellar extension of an RCC, and 2 patients had primarily suprasellar RCCs. Nine of 10 patients underwent transsphenoidal surgery, and 1 patient underwent a pterional craniotomy. Complete cyst drainage on radiography was noted in 9 of 10 patients (90%), all of whom underwent transsphenoidal surgery. One patient experienced a symptomatic recurrence 6 years after complete surgical drainage. Headaches improved in 7 of 8 patients after surgery. Two patients had complete resolution of a hormonal axis deficit, whereas 3 patients developed new anterior pituitary axis deficits. Two patients developed persistent diabetes insipidus after surgery. Conclusion RCCs are an infrequent cause of symptoms in pediatric patients. The transsphenoidal approach offers an effective means of achieving complete cyst drainage for lesions requiring surgery. Fenestration and aspiration of the cyst are usually sufficient to achieve total resolution of symptoms and signs caused by RCCs. Clinical symptoms such as headaches improved in the majority of patients, whereas hormonal disturbances typically persisted. Patient selection remains of paramount importance when considering surgery for pediatric patients with RCCs.

Background/Purpose: Symptomatic ventriculoperitoneal shunt (VPS) malfunction can occur without progressive ventricular dilatation on imaging studies. A review of VPS revisions performed during an 18-month period was conducted to better characterize this cohort. The incidence of VPS malfunction without ventricular dilatation and the clinical features that may predispose to its occurrence have not been previously described. Methods: A retrospective review was conducted of all patients under the age of 18 who underwent VPS revision due to shunt malfunction from June 2001 to December 2002. The incidence of various factors that might correlate with the development of low compliance ventricles was examined. Results: One hundred and seventy-seven patients underwent a total of 287 VPS revisions during the study period; 16 patients (9%) had signs of raised intracranial pressure and showed no radiographic evidence of progressive ventricular dilatation. History of prior shunt-related ventriculitis positively correlated with the development of low compliance ventricles (Fisher’s exact test, p = 0.043). Conclusion: Nine percent of pediatric patients with symptomatic VPS malfunctions lack radiographic evidence of progressive ventricular dilatation on imaging studies. Patients with prior shunt infections are particularly at risk, necessitating increased vigilance when clinical signs and symptoms are apparent.

Objective: The authors present the first report evaluating neonates with chronic hydrocephalus using proton magnetic resonance spectroscopy (1H MRS). The goals of the study were (1) to determine absolute brain metabolite concentrations in premature infants and neonates with hydrocephalus and age-matched controls, (2) conduct an initial survey of potential biochemical abnormalities of the newborn hydrocephalic brain, and (3) determine whether 1H MRS can be used for outcome prediction in this population. Methods: Thirteen infants with chronic hydrocephalus were imaged with magnetic resonance imaging (MRI) and 1H MRS during an 18-month interval. Absolute metabolite concentrations were tabulated and compared with those of 26 age-matched controls. Metabolite abnormalities were evaluated for correlation with clinical outcome at last follow-up. Results: Mean lactate (Lac), glutamine (Gln) and alanine (Ala) concentrations in hydrocephalic patients were significantly elevated. These metabolite elevations did not correlate significantly with outcome. There was no evidence of altered neuronal maturation in patients with congenital hydrocephalus. Two patients with dramatically reduced N-acetyl-aspartate and elevated Lac had poor neurologic outcome and were found to have neurologic disease that had not been identified with prior diagnostic tests. Conclusions: Premature infants and neonates with hydrocephalus have elevated Lac, Gln and Ala compared with age-matched controls. Further investigation and follow-up is required to assess the significance of these findings. In general, 1H MRS is of limited value in predicting outcome in infants with hydrocephalus. However, 1H MRS may be useful in identifying subsets of hydrocephalic neonates that, in fact, have severe neurologic disease and poor prognosis.

OBJECTIVE: We identify radiographic imaging similarities found on head computed tomographic (CT) scans of patients with through-and-through gunshot wounds to the head with fatal outcomes. METHODS: A retrospective analysis was conducted over an 18-month period from June 2001 through December 2002. Two hundred seventeen gunshot wound patients were evaluated. Exclusion criteria included any patient with cardiopulmonary injury and instability, airway compromise, or extracranial injuries affecting prognosis. Thirty-seven patients with isolated gunshot wounds to the head were included, 10 of which were fatal. Vital signs, examination results, Glasgow coma scale (GCS) score, intracranial pressure monitoring, surgical data, days in the intensive care unit, and CT scan appearance were collected. A Cartesian xyz coordinate system was created centered on the dorsum sella. Bullet pathways on CT scans were plotted and graphed onto a standardized magnetic resonance imaging scan. RESULTS: Ten patients progressed to brain death. GCS score and pupil irregularity were associated with fatal outcome (P < 0.0001). CT scans showed that brain shift was more common in survivors. Seventy percent of nonsurvivors had minimal brain shift. A tram-track sign on CT scans correlated with fatal outcome (P = 0.005). Vector analysis of nonsurvivors showed an area of the brain approximately 4 cm above the dorsum sella that, when penetrated through the midline, led to brain death (P = 0.0006). This zone was coined the zona fatalis. CONCLUSION: We confirm that GCS score and diabetes insipidus correlated with fatal outcome. In the setting of low-velocity gunshot wounds, fatal outcome and low GCS score were associated with a tram-track sign on CT scans. Bullet passage through a particular supra-dorsum sellar transventricular zone was associated with fatal outcome.

The goal of this study was to compare clinical outcomes following decompressive craniectomy performed for intracranial hypertension in children with nonaccidental, blunt cranial trauma with outcomes of decompressive craniectomy in children injured by other mechanisms.All children in a prospectively acquired database of trauma admissions who underwent decompressive craniectomy over a 9-year span, beginning January 1, 2000, are the basis for this study. Clinical records and neuroimaging studies were systematically reviewed.Thirty-seven children met the inclusion criteria. Nonaccidental head trauma was the most common mechanism of injury (38%). The mortality rate in patients with abusive brain injury (35.7%) was significantly higher (p0.05) than in patients with other causes of traumatic brain injury (4.3%). Children with inflicted head injuries had a 12-fold increase in the odds of death and 3-fold increase in the odds of a poor outcome (King's Outcome Scale for Closed Head Injury score of 1, 2, or 3).Children with nonaccidental blunt cranial trauma have significantly higher mortality following decompressive craniectomy than do children with other mechanisms of injury. This understanding can be interpreted to mean either that the threshold for decompression should be lower in children with nonaccidental closed head injury or that decompression is unlikely to alter the path to a fatal outcome. If decompressive craniectomy is to be effective in reducing mortality in the setting of nonaccidental blunt cranial trauma, it should be done quite early.

The interhemispheric transcallosal approach offers an excellent surgical corridor for the treatment of deep-seated midline lesions. The approach typically requires the sacrifice of one or more middle-third superior sagittal sinus (SSS) cortical bridging veins, which introduces the risk of venous infarction and associated neurological injury. The authors studied the incidence of venous infarcts following this operative approach in a pediatric population.The authors performed a retrospective review of surgical cases involving pediatric patients treated at the Children's Hospital Los Angeles between 1990 and 2007, in which an interhemispheric transcallosal operative procedure was performed and one or more middle-third SSS cortical bridging veins were occluded. Postoperative MR imaging studies done 1-3 days following the procedure were analyzed and compared with preoperative studies.Sixty-three patients met the inclusion criteria. No patient developed MR imaging evidence of venous infarction.The occlusion of one or more middle-third SSS cortical bridging veins related to the interhemispheric transcallosal approach resulted in no incidence of cerebral venous infarction in this pediatric population.

Outcomes for average-risk medulloblastoma are excellent with 5-year event-free survival and overall survival>80%. Treatment failures include radiation-induced glioblastomas (RIG), which are often diagnosed solely on imaging. Recent studies suggest that RIGs differ from spontaneous glioblastoma multiforme (GBM), based on microarray gene-expression profiling. Retrospective review of children with average-risk medulloblastoma treated from 1996 to 2003 included 16 patients with 5 treatment failures. One died of disease progression, 1 died as a result of radiation necrosis, and 3 children died of pathology-confirmed GBM. Of these 3 GBMs, one was studied with electron microscopy, cytogenetics, and gene-expression microarray analysis. This tumor had focal medulloblastoma and similarity by gene-expression microarray with other RIGs. With both components in the recurrent tumor, we suggest it was in the process of transitioning from medulloblastoma to RIG, that is, "catching the tumor in the act." Some radiation-induced nervous system tumors may develop as a direct result of severe oncologic changes within the original tumor cells, with the tumor evolving into a different phenotypic tumor type. We recommend biopsy for tissue confirmation and genetic expression profile to shed light on the etiology of radiation-induced neoplasms.

Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive pediatric brain tumors characterized by the presence of rhabdoid cells and negative immunostaining for INI1 (BAF47). Histogenesis is unknown and diagnosis can be challenging because of their extreme morphological and immunophenotypic heterogeneity. Currently no signature markers other than INI1 loss have been identified. To search for possible candidate proteins of interest in AT/RTs, Affymetrix GeneChip® microarrays were utilized to investigate nine AT/RTs vs. 124 other tumor samples. The most distinctive gene identified was claudin 6 (CLDN6), a key component of tight junctions. CLDN6 showed moderate or higher mRNA expression in eight of nine AT/RTs, with little to no expression in 114 of 115 other tumors. Average expression was 38‐fold higher in AT/RTs vs. other samples. Immunohistochemical (IHC) staining of 33 tumor specimens found positive membrane staining in seven of seven AT/RTs, and was negative in 26 of 27 other brain tumor samples. Notably, none of the 16 medulloblastomas/primitive neuroectodermal tumors showed IHC staining for CLDN6. IHC staining results closely matched the level of mRNA expression detected by microarray. CLDN6 may be a useful positive marker to help further identify AT/RTs for diagnostic and treatment purposes.

Background Craniopharyngioma is a benign brain tumor that can be treated with some combination of surgery, intracystic chemotherapy and radiation therapy. Treatment for craniopharyngioma, especially radiation therapy, is associated with a variety of long-term toxicities including vascular abnormalities. We report on the incidence of vascular abnormalities seen in the children with craniopharyngioma who received radiation therapy at our institution. Procedure We reviewed our experience with craniopharyngioma patients who received radiation therapy from 1995 to 2008. We reviewed clinical data including surgery, chemotherapy, radiation therapy and imaging for vasculopathy. Results Twenty of the 22 children with craniopharyngioma who received radiation therapy had imaging available. Six of the 20 were found to have some type of vasculopathy. One had bilateral temporal cavernomas, one had moyamoya syndrome, one had an aneurysm of the internal carotid artery and three children had decreases in the caliber of the carotid or cerebral arteries, but were asymptomatic. Two of the six children with abnormalities also received intracystic bleomycin prior to radiation therapy. Conclusions We report a high incidence of vascular abnormalities in children with craniopharyngioma. The data suggest that intracystic bleomycin may contribute to radiation-related vasculopathy. We now include magnetic resonance angiography as part of our routine follow up in these children. Pediatr Blood Cancer 2009;52:227–230. © 2008 Wiley-Liss, Inc.

Background Intraventricular oligodendroglioma remains a rare diagnosis, with high-grade/anaplastic IVO being an even rarer subtype. These lesions vary in regard to tumor grading and clinical presentation, as compared with their intraparenchymal counterparts. A case report and review of the previous literature regarding IVO and tumor grading were conducted. Case description A case report of a patient with an anaplastic oligodendroglioma confined entirely within the ventricular system is presented. The patient underwent gross total surgical resection with perioperative shunt placement, yet developed aggressive recurrence of disease. The literature regarding the clinical presentation, methodology of diagnosis, and treatment of IVO was reviewed. Thirty-three studies reporting 70 patients with IVO were identified in the literature. Only 2 previous case reports of high-grade/anaplastic IVO were identified. Accurate diagnosis of these lesions, including immunohistochemistry, electron microscopy, and molecular/chromosomal subtyping, is imperative. Surgical resection with frequent perioperative shunting, as well as chemotherapy, remains the mainstay of therapy. Adjuvant therapies may differ significantly according to the tumor grade and molecular subtype. Conclusions Intraventricular oligodendroglioma remains an infrequently encountered lesion, yet is usually found to be low grade at the time of surgery. Anaplastic IVO is an exceedingly rare lesion, with only 3 case reports in the literature. Future therapy for these aggressive lesions may be based on susceptibility to various chemotherapeutic agents according to molecular subtyping.

Arachnoid cysts can cause a variety of clinical signs and symptoms in infants. The authors sought to determine whether the clinical presentation of pediatric patients younger than 2 years old and harboring arachnoid cysts influenced the type of intervention that would be required.A retrospective chart review was conducted for all patients younger than 2 years of age who had undergone craniotomy for fenestration of an arachnoid cyst at the Children's Hospital Los Angeles between 1995 and 2006. Forty-two patients were included in the study. The mean age was 10.4 months. The median follow-up time was 33 months. Clinical presentations were as follows: macrocephaly without ventriculomegaly (21 patients, 50%), hydrocephalus (six patients, 14%), and other symptoms (15 patients, 36%). After fenestration of the arachnoid cyst, 12 of 21 patients (57%) presenting with nonspecific macrocephaly required placement of a cystoperitoneal or ventriculoperitoneal shunt, compared with 1 of 15 patients (7%) presenting with other symptoms (p value = 0.0039). Five of six patients with hydrocephalus (83%) were shunt dependent following fenestration. Overall, 18 of 42 patients (43%) were shunt dependent after fenestration. Ten of these patients (55%) required revisions during the follow-up period.Patients younger than 2 years of age and harboring an arachnoid cyst commonly present with macrocephaly. These patients are more likely to require shunts than are those presenting with other findings, such as seizures or incidental lesions. The development and expansion of arachnoid cysts may be related to aberrant cerebrospinalfluid dynamics, and these lesions may be a form fruste of hydrocephalus. Arachnoid cysts should be treatedwith craniotomy and cyst fenestration, taking into account the likelihood of perioperative shunt dependency.

We identify radiographic imaging similarities found on head computed tomographic (CT) scans of patients with through-and-through gunshot wounds to the head with fatal outcomes.A retrospective analysis was conducted over an 18-month period from June 2001 through December 2002. Two hundred seventeen gunshot wound patients were evaluated. Exclusion criteria included any patient with cardiopulmonary injury and instability, airway compromise, or extracranial injuries affecting prognosis. Thirty-seven patients with isolated gunshot wounds to the head were included, 10 of which were fatal. Vital signs, examination results, Glasgow coma scale (GCS) score, intracranial pressure monitoring, surgical data, days in the intensive care unit, and CT scan appearance were collected. A Cartesian xyz coordinate system was created centered on the dorsum sella. Bullet pathways on CT scans were plotted and graphed onto a standardized magnetic resonance imaging scan.Ten patients progressed to brain death. GCS score and pupil irregularity were associated with fatal outcome (P0.0001). CT scans showed that brain shift was more common in survivors. Seventy percent of nonsurvivors had minimal brain shift. A tram-track sign on CT scans correlated with fatal outcome (P = 0.005). Vector analysis of nonsurvivors showed an area of the brain approximately 4 cm above the dorsum sella that, when penetrated through the midline, led to brain death (P = 0.0006). This zone was coined the zona fatalis.We confirm that GCS score and diabetes insipidus correlated with fatal outcome. In the setting of low-velocity gunshot wounds, fatal outcome and low GCS score were associated with a tram-track sign on CT scans. Bullet passage through a particular supra-dorsum sellar transventricular zone was associated with fatal outcome.

OBJECTIVE: The purpose of this study was to assess outcomes in patients treated with gamma knife radiosurgery for trigeminal neuralgia. METHODS: From 1997 to 2003, a total of 49 patients with trigeminal neuralgia underwent gamma knife radiosurgery. The trigeminal root entry zone immediately adjacent to the pons was targeted by use of a 4-mm collimator to deliver 40 Gy to the 50% isodose line (maximum dose, 80 Gy). Special care was taken to limit radiation dose to the adjacent pons to 12 Gy. Of the 49 study patients, all had undergone previous medical therapy, 8 (16%) had undergone microvascular decompression, 8 (16%) had undergone percutaneous rhizotomy, 2 (4%) had undergone linear accelerator-based radiosurgery, and 5 (10%) presented with multiple sclerosis. The median duration of symptoms was 6 years. There were 29 female patients (59%) and 20 male patients (41%). Facial pain outcomes were assessed by use of the Barrow Neurological Institute pain score. Other outcomes assessed included recurrence of symptoms and treatment toxicity. The median follow-up period was 49 months. RESULTS: At last evaluation, a total of 27 patients (61%) with idiopathic trigeminal neuralgia reported pain relief (scores of IIIb or less). This included 14 patients (32%) who reported complete pain relief when not receiving medications. Significant recurrence of pain after an initial interval of relief was reported by 10 patients (23%). Mean time to pain recurrence was 9.6 months (range, 2–36 mo). Mild to moderate facial numbness was experienced by 13 patients (29%), whereas 8 (18%) reported mild dysesthesias. CONCLUSION: Gamma knife radiosurgery established durable pain relief in 61% of patients with medically refractory idiopathic trigeminal neuralgia. A longer follow-up period is necessary to fully assess the incidence of late complications and recurrences.

Reactive metabolites of AP bind to hepatic and renal DNA and hepatotoxic doses initiate oligonucleosomal fragmentation of nuclear DNA. Despite generation of the reactive metabolites of AP primarily in the endoplasmic reticulum, alterations of mitochondrial proteins by reactive metabolites of AP also have been observed; however, the effects of AP metabolites on mitochondrial DNA have not been investigated. Fasted male ICR mice were given 400 mg/kg of AP or equal volumes of saline, killed at 2 h, mitochondria isolated, and DNA extracted. The mitochondrial DNA was amplified by polymerase chain reaction, using sets of primers that collectively span the entire mitochondrial genome and which were selected to amplify the common deletions that have been identified in studies of aging and degenerative diseases as critical targets for damage to mitochondrial DNA. Our studies to date do not indicate that significant increases in common deletions of mitochondrial DNA are associated with acutely hepatotoxic doses of AP, although results indicative of altered PCR amplification of the mitochondrial DNA in the AP-treated mice suggest other forms of damage to the DNA, such as alkylation. The correlation between cumulative ingestion of AP and incidence of end stage renal disease in humans [NEJM 1675, 1994] suggests a chronic injury, which may include DNA damage and mitochondrial dysfunction. Therefore, the investigations of alterations of mitochondrial DNA in relevant models of chronic exposure to AP are needed. Supported by GM44263 and a summer research fellowship (to SAM) from the Society for Pediatric Research.

The mechanisms responsible for AMPH-induced renal injury are not known. Because oxidant stresses appear to cause or exacerbate other examples of renal injury, we investigated oxidative mechanisms in AMPH nephrotoxicity. Fischer-344 (F344) rats are more suceptible to oxidant-induced injury than are Sprague-Dawley rats, and we found F344 rats to be slightly more sensitive to AMPH nephrotoxicity. Female F344 rats given single doses of 20 mg/kg of AMPH, i.p., developed elevated plasma BUN and Cr concentrations (59.7±0.6 and 1.03±0.05 mg/dl, respectively; vehicle-treated controls, 13.8±0.7 and 0.46±0.03) that peaked by 48 h, declining to baseline values by day 6 post dose. Tubular injury and progress through initial stages of tissue repair were observed by histology. Plasma and tissue levels of AMPH were measured by HPLC. Plasma concentrations showed an initial decline, with an apparent half-life of 23 h, through day 4, but no further decrease was observed through day 7 (peak 0.27; days 4-7 0.03 μg/ml). The concentrations of AMPH in renal and hepatic tissues were not closely correlated with plasma levels or tissue injury. Despite a 10-fold greater concentration of AMPH in liver (range of days 1-5: 16.9-59.4 μg/g tissue) than in kidney (1.11-3.53), plasma ALT activities did not increase. Biochemical and histologic evidence of recovery of renal injury was observed, even in animals with persistently high renal concentrations of AMPH. The redox status of renal proteins was assessed by fluorescence labeling with the thiol-specific reagent monobromobimane, followed by separation by SDS-PAGE. No substantive changes in total or in any individual protein thiol was observed, even in animals that showed marked renal damage. Further, biliary efflux of total glutathione did not increase as would be expected during an oxidant stress. Conclusions: 1) Hepatic vs renal injury do not correlate with tissue AMPH concentrations; 2) Recovery of renal function is observed despite the continued presence of AMPH; 4) Protein thiol status and biliary glutathione efflux do not support oxidant stress as the primary mechanism of AMPH nephrotoxicity.