[Secondary superficial siderosis of the central nervous system: report of three cases]. / Sidérose superficielle secondaire du système nerveux central : à propos de trois cas et revue de la littérature.

BACKGROUND: Superficial siderosis (SS) is an under-recognized entity. It is due to repeated microhemorrhages in the subarachnoid spaces resulting in a deposit of hemosiderin at the surface of the central nervous system and/or the cranial nerves. The origin of microhemorrhages remains unknown in almost one third of cases and therefore no treatment can be recommended. Through a literature review and new observations, our goal is to detail the outcome of patients with a recognized etiology of SS and treated surgically. METHODS: Series of three cases and review of the literature. RESULTS: We present three patients with symptomatic SS for whom the origin of microhemorrhages was found. The first two patients complained of longstanding ataxia and neurosensory deafness while the third patient presented with urinary retention, vertigo, diplopia and facial paresis. Neuroradiological explorations revealed a left temporoparietal cavernoma, a fronto-orbital arterio-venous malformation and a cauda equina myxopapillary ependymoma respectively. Surgical resection of the source of hemorrhage was performed in all cases. All outcomes were good with improvement of their SS-related symptoms. These cases are discussed and the current literature is reviewed. CONCLUSION: It is important to recognize SS since the treatment of the bleeding source may prevent further deterioration and may even in some cases improve the clinical condition.

The effects of elevated blood lead levels and succimer chelation therapy on physical growth in developing rhesus monkeys.

Seventy-two female rhesus monkeys were randomly assigned to three lead exposure conditions (none, birth to 1 year, birth to 2 years). In a completely crossed design, the lead-exposed and control monkeys were randomized to placebo or chelation therapy which began at 1 year of age. Dosing was conducted daily beginning on day 8 postpartum. The lead dose levels were adjusted biweekly to gradually elevate the blood lead level of each monkey to a target of 1.69-1.93 micromol/L (35-40 microg/dL). Succimer (or placebo) was administered orally (30 mg/kg/day for 5 days and 20 mg/kg/day for 14 additional days) for a total 19-day treatment regimen. There were two separate chelation regimes at 53 and 65 weeks of age. Succimer therapy in combination with lead abatement reduced blood lead levels significantly faster than lead abatement alone; however, that advantage disappeared once succimer therapy was discontinued. Weight, crown-rump length, and head circumference were measured regularly. Growth in weight, length, and head circumference did not vary significantly as a function of blood lead levels. Succimer chelation therapy did not significantly affect weight, length, or head circumference through 2 years of age.

Oral succimer decreases the gastrointestinal absorption of lead in juvenile monkeys.

Although succimer (Chemet, meso-2,3-dimercaptosuccinic acid, DMSA) is considered to be a safe and effective chelating agent for the treatment of lead poisoning in humans, there is concern that it may increase the gastrointestinal (GI) absorption and retention of Pb from exposures suffered concurrent with treatment. This concern is justified because the availability of Pb-safe housing during outpatient treatment with oral succimer is limited. We used a juvenile nonhuman primate model of moderate childhood Pb intoxication and a sensitive double stable Pb isotope tracer methodology to determine whether oral succimer chelation affects the GI absorption and whole-body retention of Pb. Infant rhesus monkeys (n = 17) were exposed to Pb daily for 1 year postpartum to reach and maintain a target blood lead (BPb) level of 35-40 microg/dL. Animals were administered succimer (n = 9) or vehicle (n = 8) over two successive 19 day succimer treatment regimens beginning at 53 and 65 weeks of age. The present study was conducted over the second chelation regimen only. Animals received a single intravenous (iv) dose of stable (204)Pb tracer (5 microg, 24.5 nmol) followed by a single oral dose of stable (206)Pb tracer (72.6 microg, 352 nmol) immediately before chelation, in order to specifically evaluate GI Pb absorption and whole-body Pb retention with treatment. We collected complete urine and fecal samples over the first 5 days and whole blood over the first 8 days of treatment for analyses of stable Pb isotopes using magnetic sector inductively-coupled plasma mass spectrometry. Results indicate that succimer significantly reduced the GI absorption of Pb (vehicle, 64.9% +/- 5.5; succimer, 37.0% +/- 5.8; mean +/- SEM). Succimer also significantly increased the urinary excretion of endogenous Pb by approximately 4-fold over the vehicle treatment, while endogenous fecal Pb excretion was decreased by approximately 33%. Finally, although succimer reduced the whole-body retention of endogenous Pb by approximately 10% compared to vehicle, the majority (77%) of the administered internal dose of Pb tracer was retained in the body when assessed after 5 days of treatment. These data do not support the concern that succimer treatment increases GI Pb absorption.

Chronic myelocytic leukemia in a juvenile rhesus macaque (Macaca mulatta).

Myeloid neoplasia has been studied extensively in human beings but has not been reported in macaques. A 2-year-old female rhesus macaque that was experimentally exposed to lead as a neonate, was noted to have immature circulating myelocytic cells, including 1% blasts, and normocytic normochromic anemia on a blood sample obtained for monthly health monitoring. The animal was treated with hydroxyurea, blood transfusion, and recombinant human erythropoietin to reduce the leukocytosis and correct the anemia. The disease had a relatively indolent course for 3 months, when it progressed to blast crisis. After the onset of blast crisis, the animal was euthanized because of bleeding problems, anemia, and a progressive decline in her health. The animal was negative by serology, polymerase chain reaction (PCR) assays, and/or culture for simian retrovirus (SRV), simian T-lymphotropic virus type I (STLV-I), and simian immunodeficiency virus (SIV). PCR assay for the bcr-ABL chromosomal translocation using primers made for the human gene was negative. Serology for Epstein-Barr virus (EBV)-like viruses was positive for IgG directed against the viral nucleocapsid antigen, but epidemiologic factors make it unlikely that the leukemia was associated with EBV-induced viral transformation. Lead exposure has been associated with neoplasia in human beings, and the possible role of neonatal lead exposure in hematologic neoplasias deserves further scrutiny.

Exploring a partially enclosed space by lead-exposed female rhesus monkeys.

Beginning on Day 8 postpartum, lead acetate was administered to female rhesus monkeys (n=48). Their blood lead levels rose to 35-40 microg/dl (the level maintained for the duration of the study period) by 12 weeks of age. Weekly, these lead-exposed monkeys and their controls (n=23) were placed in a partially enclosed space from the second postnatal week until they escaped three times or were 26 weeks old. The lead-exposed monkeys exhibited more fear, were more likely to be agitated, and climbed more frequently during the first testing session. In subsequent sessions, they more frequently explored the periphery of the test area than the controls. The lead-exposed monkeys also tended to escape sooner although that trend did not consistently reach the.05 level of significance. The increased activity and agitation of the lead-exposed monkeys is suggestive of deficits reported in human children with high blood lead levels.

The effects of succimer chelation therapy on auditory function in rhesus monkeys.

Sixty-six female rhesus monkeys were randomly assigned to three lead exposure conditions (none, from birth to 1 year, and from birth to 2 years) by two chelation treatment (succimer and no succimer) conditions. Blood lead levels were maintained at 35-40 microg/dl beginning shortly after birth and continuing for 1 or 2 years postnatally. There were two separate chelation regimes: 53 and 65 weeks of age. Lead and lead-vehicle dosing were discontinued while succimer was administered. Succimer (or placebo) was administered orally at a dose of 30 mg/kg/day (divided into three doses per day) for 5 days and for 14 additional days at 20 mg/kg/day (divided into two doses per day) for a total 19-day treatment regimen. Auditory function was assessed in these monkeys at least 1 year after lead intake had been discontinued. The outcome measures included tympanometry to assess middle ear function, OAEs to assess cochlear function, and ABRs to assess the auditory nerve and brainstem pathways. There were no significant differences as a function of succimer treatment for any of the tympanometric variables measured. Suprathreshold and threshold distortion product otoacoustic emissions were comparable among the succimer and vehicle groups. However, there was a nonsignificant trend to smaller amplitude distortion products at the highest frequencies assessed (6.4-10.0 kHz). Finally, the auditory evoked response at levels from the auditory nerve to the cerebral cortex did not significantly differ as a function of succimer treatment.

The effects of early lead exposure on auditory function in rhesus monkeys.

Thirty-one female rhesus monkeys were randomly assigned to three lead exposure conditions (none, birth to 1 year, and birth to 2 years). Blood lead levels were maintained at 35-40 microg/dl beginning shortly after birth and continuing for 1 or 2 years postnatally. Auditory function was assessed in these monkeys at least 1 year after exposure to lead. The outcome measures included tympanometry to assess middle ear function, otoacoustic emissions (OAEs) to assess cochlear function, and auditory brainstem-evoked responses (ABRs) to assess the auditory nerve and brainstem pathways. There were no significant differences among the three experimental groups for any of the tympanometric variables measured suggesting no effect of lead exposure on middle ear function. Suprathreshold and threshold distortion product OAEs (DPOAEs) were comparable among the three groups. Finally, the auditory-evoked response at levels from the auditory nerve to the cerebral cortex did not significantly differ as a function of lead exposure. The lead exposure in this study had little effect on auditory function.

Selected secondhand smoke research: summary and comment.

Secondhand smoke is one of the more controversial public health issues. It is controversial because laws regulating secondhand smoke create conflict between the rights of smokers and non-smokers. The results of secondhand smoke research frequently focus on risk factors in four areas: heart disease, cancer, respiratory disorders, and middle ear discase. While many studies have found hazards in each of these four areas, there is some disagreement regarding the degree and extent of the threat posed by these hazards. Future research should discover more risks associated with secondhand smoke and suggest appropriate educational, medical, legal, and environmental remedies for this problem. Then society can establish prevention programs and enact laws which protect non-smokers, but at the same time infringe as little as possible on the rights of others.

Immittance and otoacoustic emissions in rhesus monkeys and humans.

The purpose of this study was to compare multifrequency tympanometry and otoacoustic emissions (OAEs) in rhesus monkeys (Macaca mulatta) and humans. Tympanometry and OAEs can be recorded efficiently in Macaca mulatta to assess peripheral auditory function with results comparable to those in humans. Differences include (1) greater admittances and conductances in humans from 226 to 630 Hz, the frequency range validly assessed; (2) larger amplitude transient evoked OAEs (TEOAEs) and noise levels in humans; (3) larger amplitude monkey 2f(1)-f(2) distortion product OAEs (DPOAES) (f(2)s>2 kHz); (4) more prominent DPOAEs other than 2f(1)-f(2) in monkeys; (5) more narrowly tuned human f(2)/f(1) X 2f(1)-f(2) amplitude functions at the lower frequencies tested; and (6) lower 2f(1)-f(2) DPOAE thresholds at f(2)=0.5 kHz and > or = 8 kHz in monkeys.

Succimer and the reduction of tissue lead in juvenile monkeys.

The extent to which succimer (2,3-dimercaptosuccinic acid, DMSA) chelation reduces target organ lead (Pb) levels, including the skeleton, relative to the cessation of Pb exposure is a primary consideration in evaluating its efficacy for reducing toxicity in children. Here, we utilized a rhesus monkey model of childhood Pb exposure and a sensitive stable (204)Pb isotope tracer methodology to determine the efficacy of succimer for reducing Pb in blood, liver, and skeletal tissues from chronic (>/=1 year) versus short-term (3-4 days) Pb exposures. Specific attention was paid to the efficacy of succimer treatment compared to the cessation of Pb exposure. Infant rhesus monkeys (n = 48) were exposed to Pb daily for 1 year or >1 year postpartum to reach and maintain a target blood Pb level of 35-40 microg/dL. Two successive 19-day succimer treatment regimens were administered at 53 and 65 weeks of age (30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days). Blood was collected over the course of treatment, and liver and bone biopsy samples were collected on days 0, 5, and 20, relative to the start of treatment (day 0). Complete 24-h urine collections were conducted over the course of treatment. Results of the first chelation indicate that a single regimen of succimer treatment led to significant reductions in blood and liver Pb levels, relative to the placebo group. However, the cessation of Pb exposure alone (i.e., placebo) also led to significant reductions in blood and liver compared to pretreatment levels. Neither succimer nor the cessation of Pb exposure had a significant impact on bone lead levels. Blood Pb levels in the succimer-treated group rebounded within 5 days after treatment ended, becoming comparable with levels in the placebo group from that point on. Results from the second chelation indicate that succimer treatment is essentially equally efficacious in reducing blood Pb at moderate (20 microg/dL) levels where exposures ended >3 months previously and more elevated (40-50 microg/dL) levels where exposures ended just prior to treatment, relative to the placebo treatment. Finally, similar overall outcomes were observed for tissue Pb from recent exposures (i.e., (204)Pb tracer levels), indicating little or no apparent difference in the chelation of Pb from recent (3-4 days) versus long-term exposures. These data demonstrate that succimer does not reduce skeletal Pb levels, and they show that the efficacy of succimer for reducing blood Pb levels does not persist beyond the completion of treatment due to posttreatment rebounds in blood Pb from endogenous sources. They also demonstrate the relative benefit of eliminating Pb exposures, which serves to underscore the importance of primary prevention of Pb exposure. The extent to which these data reflect the efficacy of succimer for reducing neurocognitive impairment is not yet known, although those data are forthcoming.

Succimer and the urinary excretion of essential elements in a primate model of childhood lead exposure.

Succimer is considered to be a safe and effective treatment for lead (Pb) poisoning, since it reduces body Pb levels without an apparent diuresis of other essential elements. However, while existing clinical data indicate that succimer does not significantly increase the excretion of non-target elements, those studies have also reported a wide range of outcomes. Therefore, we investigated whether succimer treatment measurably increased the urinary excretion of essential elements in a primate model of childhood Pb exposure. Infant rhesus monkeys (Macaca mulatta) were exposed to Pb from birth through one year of age, and presented blood Pb levels of approximately 40-50 microg/dL at the start of treatment. Subsequently, they were treated with succimer (30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days, n = 15) or vehicle (n = 14) for 19 days. Complete urine samples were collected over the first 5 days of treatment, and were analyzed for levels of calcium (Ca), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), magnesium (Mg), manganese (Mn), nickel (Ni), and zinc (Zn), using trace metal-clean techniques and magnetic sector-ICP-MS. Succimer treatment significantly (p < 0.05) reduced blood Pb levels when compared to the vehicle group over the treatment period, and concomitantly produced a significant >4-fold increase in urinary Pb excretion. Succimer treatment also significantly (p < 0.05, multivariate ANOVA) increased the urinary excretion of essential elements, but only when the cumulative total excretion over treatment days 1-5 for all elements were considered. None of these relative increases reached statistical significance for any particular element x day, although increases in Zn (day 3) excretion were only marginally non-significant (0.1 > p > 0.05). Multivariate analyses of a subset of elements (Cu, Fe, Mn, Zn) similarly indicated no significant effect of succimer treatment overall, although the urinary excretion of Mn was significantly increased on day 3 of treatment. Collectively, these data indicate that succimer does contribute to an increase in the urinary excretion of essential elements, although not significantly for any single element considered here. This may be important in Pb-exposed children, who can possess reduced trace element reserves due to nutritional deficiencies.

Lead effects on neurobehavioral development in the neonatal rhesus monkey (Macaca mulatta).

Effects of lead exposure on behavioral development during the first month of postnatal life were examined in rhesus monkeys using a multi-item assessment scale developed for the evaluation of neonatal rhesus monkeys. Lead was administered daily beginning at day 8 postpartum at levels that produced blood lead levels of about 20 microg/dl by week 4 (n = 48); controls were treated identically but given vehicle only (n = 24). All monkeys were tested once a week for the first 4 weeks postpartum. The first principal component explained a substantial portion of the variance and was relatively consistent across ages for both groups. Analyses of the individual items and of both conceptually derived and empirically defined summary scores yielded no significant effects of lead. Furthermore, there were no systematic relationships between blood lead level and performance on the test. Correlation coefficients indicated more similarity across age for control monkeys than for lead-exposed monkeys suggesting that continuity of development, as measured by this test, was disrupted by lead. The relationship between outcome on these early assessments and later behavior will be explored in subsequent studies of these monkeys.

Otoacoustic emission, evoked potential, and behavioral auditory thresholds in the rhesus monkey (Macaca mulatta).

Distortion product otoacoustic emission (DPOAE), auditory brainstem evoked response (ABR), and behavioral thresholds were recorded in a group of 15 adult rhesus monkeys with normal auditory function. DPOAE thresholds were recorded with stimulus parameters selected to maximize signal-to-noise ratio. Additional averaging at the lowest frequencies ensured comparable noise levels across frequencies. DPOAE thresholds decreased with increasing frequency (f(2)=0.5-16 kHz) and at 16 kHz were close to 0 dB SPL. ABR thresholds were best from 1 through 16 kHz (32-38 dB peSPL); higher at 0.5 (45 dB peSPL), 24 (39 dB peSPL), and 30 kHz (49 dB peSPL). At all levels including threshold, the early ABR waves (II and I) were more prominent at the high frequencies while the later waves (IV and V) were more prominent at the low frequencies. The behavioral thresholds recorded were similar to those reported by other researchers although elevated by about 10 dB presumably because of the complexity of the threshold task. DPOAE and ABR thresholds can be reliably and efficiently recorded in the rhesus monkey and provide information concerning site of processing in the auditory pathway not directly available from behavioral data.

Understanding the NIH review process: a brief guide to writing grant proposals in neurotoxicology.

During the past two years, the National Institutes of Health have made significant changes in the review process for investigator-initiated research grant applications in neurotoxicology. First, study sections that formerly dealt with toxicology and alcohol, respectively, have been merged. Neurotoxicology grant applications are now reviewed by ALTX-3, a study section in which the majority of members have expertise in the neuronal, biochemical or behavioral effects of alcohol, but usually not other neurotoxicants. Second, the NIH has instituted new review criteria, in which significance, approach, innovation, investigator expertise, and research environment must all be explicitly addressed by the reviews. In this article, past and present members of the ALTX-3 study section describe the NIH review process, with emphasis on how neurotoxicology applications are handled, and provide guidelines for preparing competitive applications.

The development of auditory event related potentials in the rhesus monkey (Macaca mulatta).

Auditory event related potentials were recorded from neonatal, 3-month, and 3-year old rhesus monkeys. Auditory brainstem evoked responses (ABRs) were reliably recorded at all ages. ABR latencies decreased with age. Age effects were greater the more centrally generated the wave. Wave I amplitude decreased with age, Wave II increased, and Wave IV remained about the same. Stimulus rate effects were greater in neonates than older monkeys. Stimulus frequency also affected the ABR, but not differentially as a function of age. Recording montage had a significant effect on the recorded waveform. Wave I tended to be larger in amplitude in horizontal recordings and front-back recordings, while the later waves were relatively more prominent in more vertical montages. Middle latency evoked responses and late potentials were less reliably recorded than the ABR. Their reproducibility improved with age. Auditory event related potentials are promising measures of auditory function for research requiring nonhuman primate models of the developing human.

Efficacy of succimer chelation for reducing brain lead in a primate model of human lead exposure.

The extent to which succimer (meso-2,3-dimercaptosuccinic acid [DMSA], Chemet) reduces brain lead (Pb) levels may be a primary consideration in evaluating its efficacy for reducing neurotoxicity. Clinical research in this area has been hampered by the need to use blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of greater relevance to cognitive outcomes. Here, a nonhuman primate model of human Pb exposure was used to determine: (1) The efficacy of oral succimer for reducing brain Pb derived from chronic or recent exposures, and (2) The extent to which blood Pb levels reflect brain Pb prior to and following chelation. Adult rhesus monkeys were chronically exposed to Pb orally for 5 weeks to reach and maintain a target blood Pb level of 35-40 microg/dL. Chelation of Pb from recent exposures was assessed using a stable (204)Pb isotope tracer administered over 4 days prior to treatment. Immediately prior to chelation, a prefrontal cortex (PFC) biopsy was collected to determine pretreatment brain Pb levels. Subsequently, monkeys were assigned to vehicle (n = 5) or succimer (n = 6, 30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days) groups. Blood and brain PFC, frontal lobe (FL), hippocampus (H), and striatum (S) were analyzed for total Pb and (204)Pb tracer concentrations by magnetic sector inductively coupled plasma-mass spectrometry. There were no measurable differences in brain Pb concentrations between the succimer and vehicle groups, indicating that succimer treatment was not efficacious in reducing brain Pb levels. In contrast, the cessation of Pb exposure significantly reduced brain (PFC) Pb ( approximately 34%) when compared to pretreatment levels (succimer and vehicle groups). Pb concentrations also varied among brain regions (PFC > FL approximately H > S). Finally, pretreatment PFC Pb concentrations were significantly correlated with the integrated blood Pb level (AUC) over the Pb exposure period, but not with the single pretreatment blood Pb collected concurrently with the PFC biopsy. Following treatment, blood Pb levels correlated only with Pb in the PFC, and not the other brain regions measured (FL, H, S). These data indicate that, under the conditions of this study, succimer treatment did not reduce brain Pb levels beyond the cessation of Pb exposure alone. Moreover, a single blood Pb measurement may be a poor predictor of brain Pb levels, reflecting limitations in the use of blood Pb level as an indicator of treatment efficacy.

Geriatric bone lead metabolism in a female nonhuman primate population.

A geriatric rhesus monkey (Macaca mulatta) population, previously exposed to lead, was investigated using 109Cd K X-ray fluorescence (K XRF) to determine whether metabolism of lead in bone was similar to that in human populations. The accumulation rate of lead into the tibia in this group of monkeys was determined to be 0.10-0.13 micrograms Pb (g bone mineral)-1 (microgram dl-1 year)-1, which compares well with human data, where the rate has been found to be 0.05-0.10 microgram Pb (g bone mineral)-1 (microgram dl-1 year)-1. In addition, bone lead changes over a 10-month time period were investigated, but no statistically significant difference was found. A halflife for lead in "bone" was calculated by fitting a single exponential model to serial blood lead data; the mean half-life of lead in bone was found to be 3.0 +/- 1.0 years. Both endogenous and exogenous lead exposure were found to be low at the present time, 10 years after cessation of lead intake. It is concluded that rhesus monkeys are an extremely good animal model of human bone lead metabolism and, in addition, that further research is needed to provide a more complete understanding of lead metabolism in geriatric populations.

The effects of lead on otoacoustic emissions and auditory evoked potentials in monkeys.

Auditory functioning was assessed in two groups of adult rhesus monkeys (11 years of age). One (n = 11) received modest exposure to lead early in life and the other (n = 8) served as controls and did not receive any lead supplementation. Two lead-exposed monkeys had abnormal distortion product otoacoustic emissions (DPEs) and smaller amplitude or absent evoked potentials. These monkeys had abnormal distortion product otoacoustic emission (DPEs) and smaller amplitude or absent evoked potentials. These monkeys had the highest blood levels recorded in their respective groups. For the remaining lead-exposed monkeys there was little difference between their DPEs and the DPEs of the control monkeys with one exception. DPE amplitudes of the control monkeys increased more rapidly as a function of stimulus level than those of the lead-exposed monkeys at most frequencies. There was also a significant but modest effect of lead exposure on the auditory brain stem evoked responses (ABRs) of these lead-exposed monkeys. There was no apparent effect on the middle latency evoked responses (MLRs), although that result could be due to the relatively greater variability of the MLR.