Long-term reproductive endocrine health in young women with epilepsy during puberty.

OBJECTIVE: To evaluate the outcome of epilepsy and later reproductive endocrine health in girls who had epilepsy during puberty, using a population-based controlled study. METHODS: Sixty-nine patients (88%) and 51 control subjects (94%) of previously identified cohorts of 78 girls with epilepsy and 54 healthy control girls participated in this study (initial age 8 to 18.5 years, at follow-up 12.5 to 25.8 years). Thirty-five of the patients were initially taking valproate (VPA), 17 carbamazepine, and 17 oxcarbazepine as monotherapy. Most of the patients (61%) were off medication. All the subjects were examined clinically, the medical and menstrual histories were obtained, ovarian ultrasonography was examined, and serum reproductive hormone concentrations were analyzed. RESULTS: There were no significant differences in laboratory or clinical findings between the patients off medication and the control subjects. Postpubertal patients on medication had higher serum testosterone (1.9 nmol/L, SD 0.7 nmol/L) and androstenedione (18.8 nmol/L, SD 15.2 nmol/L) levels than patients off medication (1.4 nmol/L, SD 0.5 nmol/L, and 9.5 nmol/L, SD 2.6 nmol/L) or control subjects (1.4 nmol/L, SD 0.5 nmol/L, and 10.2 nmol/L, SD 3.2 nmol/L) (all comparisons p < 0.02). All patients still on VPA had elevated serum androstenedione levels. Polycystic ovary syndrome was more common in patients on medication (38%; in 63% on VPA, in 25% on other medication) than in patients off medication (6%) or in controls (11%) (p = 0.005). CONCLUSIONS: Epilepsy during pubertal maturation does not affect reproductive endocrine health in female subjects who discontinue the medication before adulthood. However, an increased prevalence of endocrine disorders is detected if the patients remain on antiepileptic drugs, especially VPA, until adulthood.

Brainstem size and function at term age in relation to later neurosensory disability in high-risk, preterm infants.

UNLABELLED: The aim of this study was to measure brainstem size on magnetic resonance imaging (MRI) scans of high-risk. preterm infants, to assess brainstem function by brainstem auditory-evoked potentials (BAEP) and to determine the predictive value of these measures for the neurosensory outcome. A total of 51 preterm infants (gestational age <34 wk, birthweight <1,500 g) underwent examinations at term age; neuromotor outcome and hearing were followed up until a corrected age of 18 mo. Fourteen (27%) infants had neurosensory disability. Those with a later neurosensory disability had a significantly smaller brain stem than those with a normal outcome. The preterm infants had significantly longer peak latency (L) V and interpeak latency (IPL) III-V than the full-term control infants. Most of the preterm infants with severe cerebral palsy or hearing loss had abnormal BAEP. Sensitivity of morphometric dimensions for predicting neurosensory disability was only 20-31%, but specificity was 97-100%. Abnormal L I and IPL III-V in BAEP predicted disability with a sensitivity of 93% and a specificity of 57-59%. CONCLUSION: We conclude that adverse events during the perinatal period may lead to morphofunctional changes in the brain stem in high-risk, preterm infants, and it seems that functional changes are accurate in predicting neurosensory disability in such patients.

Motor nervous pathway function is impaired after treatment of childhood acute lymphoblastic leukemia: a study with motor evoked potentials.

BACKGROUND: The objective was to evaluate whether motor nervous pathways are affected when patients are treated for childhood acute lymphoblastic leukemia (ALL). PROCEDURE: Thirty-two children with ALL were studied at the end of treatment by means of motor evoked potentials (MEPs) elicited by magnetic stimulation (MS) transcranially and peripherally and underwent a detailed neurological examination. Thirty-two healthy children matched with them for age, sex, and height served as a control group. RESULTS: The latencies of the MEPs were significantly prolonged along the entire motor nervous pathway in the patients with ALL compared with the healthy controls, indicating demyelination in the thick motor fibres. The MEP amplitudes of the distal extremities elicited by stimulation at the brachial plexus and LV spinal level were significantly lowered in the patients treated for ALL, also indicating anatomical or functional loss of descending motor fibres and/or muscle fibres. The MEP amplitudes elicited by cortical MS showed wider variation and no clear abnormalities were found. Neurological signs and symptoms were common after treatment: 41% of the patients had depressed deep tendon reflexes, 31% had fine motor difficulties and 63% gross motor difficulties, and 34% had dysdiadochokinesia. The conduction delay within the peripheral nerve was related to the post-therapeutic interval after administration of vincristine and the lesions within the CNS to the number of injections of intrathecal methotrexate. CONCLUSIONS: The present results show adverse effects of the ALL treatment on the entire motor nervous pathways. In our experience, the measurement of MEPs by MS provides an objective, painless, and practical tool for assessing the treatment-related neurotoxicity in both the CNS and the peripheral nerves. These disturbances in the motor nervous pathways at the end of treatment raise the question of the long-term effects of ALL treatment on the motor nerve tracts, and have led us to employ MEPs to study these effects in long-term survivors of ALL.

Prediction of permanent hearing loss in high-risk preterm infants at term age.

UNLABELLED: The aim of this series was to assess hearing screenings; auditory brainstem responses (ABR), transient evoked otoacoustic emissions (TEOAE) and free field auditory responses (FF) for the prediction of permanent bilateral hearing loss in high-risk preterm infants at term post-conceptional age. A total of 51 preterm infants (gestational age < 34 weeks, birth weight < 1500 g) underwent examinations at term and hearing, speech and neurological development were followed up until a corrected age of 18 months. Significant hearing defects were verified by broader ABR examinations under sedation and by clinical ward observation including responsiveness to sounds and enhancement of hearing using an amplification device. Seven bilateral fails in ABR were found, together with nine bilateral fails in TEOAE and four fails in FF screening at term age. Six preterm infants were later confirmed to have a significant permanent bilateral hearing loss, four of whom had also cerebral palsy. Bilateral failure in ABR screening predicted hearing loss with a sensitivity of 100% and a specificity of 98%, TEOAE with a sensitivity of 50% and a specificity of 84% and in the FF examination at the levels of 50% and 98%, respectively. CONCLUSION: Transient evoked otoacoustic emissions alone seem not to be so applicable to the neonatal screening of hearing in high-risk preterm infants as shown earlier in full-term infants, possibly because a hearing defect may be due to retrocochlear damage. Consequently, auditory brainstem response screening seems to be more suitable for very low birth weight preterm infants.

Magnetic resonance imaging at term and neuromotor outcome in preterm infants.

In order to evaluate the value of neonatal brain magnetic resonance imaging (MRI) for predicting neuromotor outcome in very low birthweight (VLBW) preterm infants, 51 such infants with gestational age <34 wk underwent brain MRI at term age. Myelination, parenchymal lesions (haemorrhage, leukomalacia, infarction, reduction of white matter), parenchymal lesions without subependymal haemorrhage, ventricular/brain ratios and widths of the extracerebral spaces were assessed. The MRI findings were compared with cranial ultrasound (US) performed at term. Infants' neuromotor development was followed up until 18 mo corrected age. Parenchymal lesions seen in MRI at term predicted cerebral palsy (CP) with 100% sensitivity and 79% specificity, the corresponding figures for US being 67% and 85%, respectively. Parenchymal lesions in MRI, excluding subependymal haemorrhages, predicted CP with a sensitivity of 82% and a specificity of 97%, the corresponding figures for US being 58% and 100%, respectively. Delayed myelination, ventricular/brain ratios and widths of the extracerebral spaces failed to predict CP. Term age is a good time for neuroradiological examinations in prematurely born high-risk infants. Parenchymal lesions seen in MRI are reliable predictors for CP.

Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy.

Valproate is effective for treatment of a variety of seizure types both in adults and in children with epilepsy, but it induces obesity and polycystic ovaries in a considerable proportion of adult women, particularly when the medication is started before the age of 20. In the present study we evaluated reproductive endocrine function in 41 girls, 8 to 18 years old, taking valproate for epilepsy and in 54 healthy control girls. Among the girls taking valproate, 16 were prepubertal, 11 were pubertal, and 14 were postpubertal, and the corresponding numbers were 20, 13, and 21 in the control group. The mean serum testosterone concentrations of prepubertal, pubertal, and postpubertal girls taking valproate were significantly higher than those of the control girls at the same pubertal stage. Hyperandrogenism, defined as serum testosterone levels higher than the mean + 2SD in the control girls at the same pubertal stage, was seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls taking valproate. In addition, postpubertal girls taking valproate were more obese than the controls and the mean serum insulin-like growth factor binding protein-1 concentration of pubertal and postpubertal hyperandrogenic girls taking valproate was lower than in valproate-treated girls without hyperandrogenism. Valproate may induce hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation, and the frequency of hyperandrogenism increases with pubertal development. This emphasizes the importance of careful endocrine observation of girls taking valproate for epilepsy.

Nerve lesions after therapy for childhood acute lymphoblastic leukemia.

BACKGROUND: The objective of the current study was to use somatosensory evoked potentials (SEP) to detect signs of nerve lesions in the peripheral nerve and in the central nervous system (CNS) after 3 years of treatment for childhood acute lymphoblastic leukemia (ALL). METHODS: The somatosensory potentials evoked by stimulation of the median nerve and posterior tibial nerve were recorded in 31 children with ALL after 3 years of therapy. All patients were examined clinically. The 14 standard risk patients had been treated with chemotherapy according to the Nordic regimen, and the 17 intermediate risk or high risk patients had been treated with chemotherapy and cranial irradiation according to the ALL BFM-83 protocol. RESULTS: A decrease in amplitudes was observed at the brachial plexus and spinal cord (C7) in the median SEP, and at the knee, spinal cord (Th12), and cortex in the tibial SEP, indicating axonal injury within the entire CNS in the patients with ALL compared with healthy age-, gender-, and height-matched controls. Prolongation of the SEP latencies was found within the spinal cord, indicating demyelination. These SEP changes had persisted for 2 years since the last injection/infusion of vincristine or methotrexate, which are the principal neurotoxic drugs used in chemotherapy for ALL. Clinical signs of nerve injury such as depressed deep tendon reflexes and gross or fine motor difficulties were found in approximately 33% of the patients and dysdiadochokinesia in 50%. CONCLUSIONS: Treatment of ALL in children principally with vincristine and methotrexate causes long-standing axonal injury throughout the nervous system and demyelination within the spinal cord. These changes are associated with clinical neurologic findings.

A longitudinal magnetic resonance imaging study of the brain in survivors in childhood acute lymphoblastic leukemia.

BACKGROUND: The objective of this study was to evaluate changes in magnetic resonance imaging (MRI) of the brain in children with acute lymphoblastic leukemia (ALL) during the first 5 years after the cessation of therapy and to correlate MRI abnormalities with neuropsychologic outcome. METHODS: Thirty-two children with ALL were studied at the end of treatment and 5 years later by brain MRI and the results were compared with the neuropsychologic findings. Fifteen patients had received chemotherapy alone and 17 had received chemotherapy plus cranial radiation. RESULTS: MRI of the brain was abnormal in 6 of 30 patients at the end of treatment and in 8 of 32 patients 5 years later. White matter changes (WMC) were found in 3 patients at the end of treatment and in 4 patients 5 years later. Two patients had developed new mild changes, whereas in one case WMC had normalized during the follow-up. Two patients had old hemorrhages or calcifications at each examination, with some improvement after follow-up, although one case revealed a new calcification or hemorrhage. Signs of cortical atrophy were observed in five patients at both evaluations. The patients with abnormal MRI findings did not differ significantly in their performance in the neuropsychologic tests from the patients with normal MRI findings, but the two patients with persistent WMC had a depression of verbal functions. CONCLUSIONS: Abnormalities in brain MRI were infrequent at the end of treatment for childhood ALL and 5 years later. They did not appear to correlate significantly with neuropsychologic outcome. Brain MRI is not very informative as a routine follow-up method during the first 5 years after treatment.

Brain perfusion after treatment of childhood acute lymphoblastic leukemia.

UNLABELLED: Children with acute lymphoblastic leukemia (ALL) have impairment in their neuropsychological functioning and morphological changes in their brain after cranial irradiation and chemotherapy. The aim of this study was to identify possible brain perfusion defects caused by different types of treatment and their association with abnormalities in cerebral MRI and neuropsychological and clinical neurological findings. METHODS: Twenty-five consecutive children with ALL at the cessation of chemotherapy or after 1 yr were included. All of the children were given intravenous and intrathecal methotrexate for central nervous system therapy, 13 of them received cranial radiation therapy. Brain SPECT, cerebral MRI, clinical neurological and neuropsychological evaluations were performed. RESULTS: Eleven of the 25 patients (44%) had brain perfusion defects in SPECT, eight of whom were treated with chemotherapy alone, and three received cranial irradiation. Two patients had small bilateral white matter changes on MRI; their brain SPECT scans were abnormal, although the findings were not related. Impairment of neuropsychological functioning was found in 86% of the patients tested. No significant difference between the patients with abnormal and normal SPECT were found. Those patients with abnormal SPECT were younger than those with normal SPECT and had received more frequent intravenous methotrexate infusions. CONCLUSION: Brain SPECT detected perfusion defects that had occurred after treatment for childhood ALL. These defects may be related to frequent administration of a combination of intravenous and intrathecal methotrexate and/or young age.