Yoram Finkelstein

Low-level lead-induced neurotoxicity in children : an update on central nervous system effects

The neurotoxicity of low-level long-term exposure to lead has a special relevance in children. An extensive database has provided a direct link between low-level lead exposure and deficits in the neurobehavioral-cognitive performance evidenced in childhood through adolescence. Electrophysiological studies showed that neurosensory processing may be affected by lead, with consequent decrease in auditory sensitivity and visuomotor performance. Lead disrupts the main structural components of the blood-brain barrier by primary injury to astrocytes with a secondary damage to the endothelial microvasculature. Within the brain, lead-induced damage occurs preferentially in the prefrontal cerebral cortex, hippocampus and cerebellum. Some characteristic clinical features of lead poisoning may be attributed to this specific anatomical pattern. The cellular, intracellular and molecular mechanisms of lead neurotoxicity are numerous, as lead impacts many biological activities at different levels of control: at the voltage-gated channels and on the first, second and third messenger systems. These effects could be related to leads ability to interfere with the regulatory action of calcium in cell functions. Consequently, it may be assumed that lead acts as a chemical stressor and causes breakdown of the homeostatic cellular mechanisms. This is expressed in both the anatomical site and the neurotransmitter systems which are crucial in modulating emotional response, memory and learning. There is no threshold below which lead remains without effect on the central nervous system; thus, symptoms could simply be a clinical reflection of the brain regions preferentially involved. In integrating these physiological and clinical data, it may be suggested that the different mechanisms of low level lead neurotoxicity have a final common functional pathway.

Herbal medicine and epilepsy: proconvulsive effects and interactions with antiepileptic drugs.

The use of complementary and alternative medicine is on the rise, including among patients with epilepsy. Herbal medicine, one of the most popular forms of CAM, is considered to be both safe and effective by most consumers. Yet many herbs may increase the risk for seizures, through intrinsic proconvulsant properties or contamination by heavy metals, as well as via effects on the cytochrome P450 enzymes and P‐glycoproteins, altering antiepileptic drug (AED) disposition. Herb–drug interactions may be difficult to predict, especially since the quality and quantity of active ingredients are often unknown. Since most patients do not inform their physicians that they are taking herbal medicines, health care professionals must initiate a dialogue in order to prevent complications with the combined regimen. At the same time, further research is required regarding the effect of herbs on seizure activity and interactions with AED treatment.

Selenium neurotoxicity in humans: Bridging laboratory and epidemiologic studies

Selenium is a metalloid of considerable interest in the human from both a toxicological and a nutritional perspective, with a very narrow safe range of intake. Acute selenium intoxication is followed by adverse effects on the nervous system with special clinical relevance, while the neurotoxicity of long-term overexposure is less characterized and recognized. We aimed to address this issue from a public health perspective, focusing on both laboratory studies and the few epidemiologic human studies available, with emphasis on their methodological strengths and limitations. The frequently overlooked differences in toxicity and biological activity of selenium compounds are also outlined. In addition to lethargy, dizziness, motor weakness and paresthesias, an excess risk of amyotrophic lateral sclerosis is the effect on the nervous system which has been more consistently associated with chronic low-level selenium overexposure, particularly to its inorganic compounds. Additional research efforts are needed to better elucidate the neurotoxic effects exerted by selenium overexposure.

Are environmental exposures to selenium, heavy metals, and pesticides risk factors for amyotrophic lateral sclerosis ?

Abstract The etiology of sporadic amyotrophic lateral sclerosis (ALS), the most common form of this degenerative disease of the motor neurons, is still unknown, despite extensive investigation of several genetic and environmental potential risk factors. We have reviewed laboratory and epidemiological studies assessing the role of exposure to neurotoxic chemicals (metalloid selenium; heavy metals mercury, cadmium, and lead; pesticides) in ALS etiology by summarizing the results of these investigations and examining their strengths and limitations. Despite limitations in the exposure assessment methodologies typically used in human studies, we found suggestive epidemiological evidence and biologic plausibility for an association between ALS and antecedent overexposure to environmental selenium and pesticides. The relation with mercury, cadmium, and lead appears weaker.

Progressive Parkinsonism in a Young Experimental Physicist Following Long-Term Exposure to Methanol

A case is described of an experimental physicist who developed parkinsonism, apparently as delayed toxic effect of long exposure to vapors of methanol in the laboratory. Clinical and magnetic resonance imaging (MRI) supported the diagnosis, after exclusion of hereditary diseases and primary degenerative diseases. Screening for heavy metals in urine and plasma ceruloplasmin was negative. This case illustrates the neurotoxic delayed effect of long-term exposure to methanol with no episodes of acute intoxication. The setting of a research laboratory with prolonged exposure to mixed single crystals and inhalation of methanol vapors may exist in other academic and hi-tech environments, and pose the risk of similar delayed toxic influences.

Infant with altered consciousness after cannabis passive inhalation

Cannabis is the most commonly used illicit drug worldwide (Bauman & Phongsavan, 1999). Its primary active ingredient s THC (Delta [9]-tetrahydrocannabinol) which exerts its biological effects by activating the cannabinoid receptor CB1 in the rain. Cannabis abuse has been described almost exclusively in adolescents and adults. In 2002, 50% of 18 year olds reported sing cannabis during their lifetime. Of these, 22.4% have met Diagnostic and Statistical Manual of Mental Disorders IV DSM-IV) criteria for cannabis abuse and 15.8% have met DSM-IV criteria for cannabis dependence (Cooper & Haney, 2009). In infancy, cannabis effects are merely discussed in the context of maternal prenatal exposure. These effects include eurobehavioral symptoms such as inattention, impulsivity, increased externalizing behavior and decreased cognitive erformance with memory and learning impairments (Huizink & Mulder, 2006). However, the direct exposure of infants to cannabis substances is discussed neither in clinical assessment nor in public ealth education. To the best of our knowledge and after surveying the literature using PubMed and Google search, we elieve that this is the first reported clinical case of severe toxicity after passive inhalation of cannabis smoke by an infant. he infant was admitted to hospital with severe neurological symptoms, following this toxic exposure. The significance of his topic is far beyond being the first reported case, but it also carries a significant social importance due to the increasing umber of young parents who smoke near their children and thus is probably underdiagnosed as toxicology screens are ncommon by implemented in this age group; this fact underscores the importance of our report. Since cannabis intoxication has the potential to jeopardize the lives and health of young infants, in this report we have imed to draw attention to the differential diagnosis of THC toxicity in infants with altered state of consciousness; and to

Pediatric cinnarizine overdose and toxicokinetics.

Cinnarizine, a piperazine derivative, is a widely prescribed medication for the treatment of vestibular disorders and motion sickness. Cinnarizine has antihistaminic, antiserotoninergic, antidopaminergic, and calcium channel–blocking properties. We present the first report in the English literature of cinnarizine poisoning and toxicokinetics. A 30-month-old toddler ingested 225 mg of cinnarizine, 18 times the recommended dose for older children. Four hours later, she became jittery with a wide-based gait and vomited 3 times. She was examined by her family physician, who reported stupor and twitching in both hands. On admission to the hospital, 6 hours after the ingestion, she was stuporous and had 3 short, generalized tonic-clonic convulsions that were controlled with a single dose of midazolam. Full clinical recovery was seen 10 hours after ingestion. Serum cinnarizine levels were 7407, 2629, and 711 ng/mL on admission and at 4 and 12 hours thereafter, respectively, 26.9 times higher than the therapeutic levels in adults. Elimination rate constant, calculated by linear regression of the ln concentrations of the 3 data points, was 0.19. Half-life, calculated from the equation t1/2 = 0.693/kel, where kel is the elimination rate constant, was 3.65 hours. The manufacturing company revealed that their database contains 23 reports of cinnarizine overdose (adult and children), received between 1972 and 2004. Clinically, these cases reflect mainly symptoms of alterations in consciousness ranging from somnolence to stupor and coma, vomiting, extrapyramidal symptoms, and hypotonia. In a small number of young children, convulsions developed; recovery was uneventful in 4 cases and not reported in 1. The neurologic complication may be explained by the antihistaminic effect of cinnarizine because central nervous system depression and convulsions are known complications of antihistaminic overdose. It is hypothesized that cinnarizine-induced convulsions also are related to the antidopaminergic effect of the drug. Apart from the convulsions, no other adverse effects related to calcium channel–blocking properties, such as bradycardia or hemodynamic instability, were observed. Pediatric patients with cinnarizine overdose need to be observed in a health care facility for potential neurologic complications and be treated symptomatically. The delay to onset of clinical effect should be considered in the observation period.

Protective effect of a novel peptide against methylmercury-induced toxicity in rat primary astrocytes

Methylmercury (MeHg) is an environmental neurotoxicant associated with aberrant central nervous system (CNS) functions. In this study, we examined the protective effect of a novel anti-inflammatory and cytoprotective nonapeptide, termed IIIM1, against MeHg-induced toxicity in cultured rat neonatal primary astrocytes. Astrocytes were pretreated for 66 h with 5 μg/ml IIIM1 (4.95 μM) followed by 6 h exposure to MeHg (5 μM). MeHg significantly increased F(2)-isoprostane generation, a lipid peroxidation biomarker of oxidative injury and this effect was significantly reduced upon pre-treatment with IIIM1. The MeHg-induced increase in levels of prostaglandin E(2) (PGE(2)), biomarkers of inflammatory responses, was also decreased in the peptide-treated cells. Mass spectrometry analysis revealed no chemical or binding interaction between MeHg and IIIM1, indicating that intracellular cytoprotective mechanism of action accounts for the neuroprotection rather than direct intracellular neutralization of the neurotoxicant with the peptide. These findings point to therapeutic potential for IIIM1 in a plethora of conditions associated with reactive oxygen species (ROS) generation. The implication of these findings may prove beneficial in designing new treatment modalities that efficiently suppress neurotoxicity, triggered not only by MeHg, but also by other metals and environmental agents, as well as chronic disease conditions that inherently increase reactive radical production and inflammatory signaling.

Intrathecal methotrexate neurotoxicity: clinical correlates and antidotal treatment

The neurotoxicity of methotrexate (MTX) is more severe when administered intrathecally (IT) than by the oral and intravenous (IV) routes, and has been reported even with a single administration of therapeutic doses of 12 or 15mg. Prompt recognition and treatment are essential to improve the outcome after massive IT-MTX overdose. Treatment options include CSF drainage or CSF exchange, ventriculolumbar perfusion, IT corticosteroids to reduce CSF inflammation and IV leucovorin to reduce systemic toxicity. Toxicity resulting from IT injection of leucovorin is controversial. CSF drainage and exchange are particularly effective if performed soon after the overdose. In this paper we describe a protocol of treatment for severe cases of IT-MTX overdose in excess of 100mg. The mainstay of treatment is dilution and removal from CSF of excessive methotrexate alongside with specific antidotal therapy.

Respiratory failure in a neonate after folk treatment with broom bush (Retama raetam) extract.

Objectives: To increase the awareness of intoxication by folk herbal remedies in the pediatric population. Methods: Case report of a 7-day-old baby boy admitted to a pediatric intensive care unit in a university-affiliated hospital. Results: The patient presented with respiratory failure and central nervous system depression. Specific questioning of the parents revealed consumption of folk herbal remedy by the neonate. Mechanical ventilation was used for 24 hours until normal activity level resumed. Conclusions: The possibility of intoxication in a neonate should not be overlooked. Folk herbal remedies, especially if taken in larger than recommended amounts, may be hazardous. Accessible herbal and folk medicine data bank will contribute to a better treatment of patients having side effects of these remedies.