Clinical Neuroscience


VUTSKITS László1,2, GASCON Eduardo2,3, KISS Zoltán József2

MARCH 20, 2007

Clinical Neuroscience - 2007;60(03-04)

[Ketamine is a widely used drug in pediatric anesthesia practice, acting primarily through the blockade of the Nmethyl- D-aspartate (NMDA) type of glutamate receptors. A growing body of laboratory evidence, accumulated during the past few years, suggests that this drug could have potential adverse effects on the developing central nervous system. The goal of this short review is to give a brief synopsis of experimental work indicating ketamine-induced developmental neurotoxicity as well as to discuss potential limitations concerning extrapolation of these studies to clinical practice.]


  1. Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, Geneva
  2. Department of Neuroscience, University of Geneva Medical School, Geneva
  3. Institut de Biologie du Développement de Marseille-Luminy, Marseille



Further articles in this publication

Clinical Neuroscience



[Based on data accumulated regarding the neuroprotective action of Proline-Rich-Peptide-1 (PRP-1, a fragment of neurophysin vasopressin associated hypothalamic glycoprotein consisting of 15 amino acid residues) on neurons survival and axons regeneration and taking into the account that LVV-Hemorphin-7 (LVV-H7, an opioid peptide, widely distributed in different cell types of various tissues of intact rats, including those of the nervous and immune systems) derived from the proteolitic processing of hemoglobin in response to adverse environmental and physiological conditions, possesses the anti-stressor properties, we used histochemistry, immunohistochemistry and electrophysiology to investigate the putative neuroprotective action of Central Asian Cobra Naja naja oxiana snake venom (NOX) on trauma-injured rats. ABC immunohistochemical method and histochemical method on detection of Ca2+- dependent acid phosphatase activity were used for the morpho-functional study. By recording the electrical activity of the signals from the single neurons in and below the SC injury place, NOX venom has been shown to result in the complete restoration of hypothalamic-spinal projections originated from ipsi- and contra-lateral PVN and SON to neurons of SC lumbar part. NOX prevented the scar formation, well observed two months after SC injury in the control rats, resulted in the regeneration of nerve fibers growing through the trauma region, survival of the PRP-1- and LVV-H7-immunoreactive (Ir) neurons, and increase of the PRP-1- and LVV-H7-Ir nerve fibers and astrocytes in the SC lesion region. NOX was suggested to exert the neuroprotective effect, involving the PRP-1 and LVV-H7 in the underlying mechanism of neuronal recovery.]

Clinical Neuroscience


BAHNER Udo, GEIGER Helmut, PALKOVITS Miklós, LENKEI Zsolt, LUFT C. Friedrich, HEIDLAND August

[To test the effect of dehydration on brain atrial natriuretic peptide (ANP) concentrations in areas important to salt appetite, water balance and cardiovascular regulation, we subjected rats to dehydration and rehydration and measured ANP concentration in 18 brain areas, as well as all relevant peripheral parameters. Water deprivation decreased body weight, blood pressure, urine volume, and plasma ANP, while it increased urine and plasma osmolality, angiotensin II, and vasopressin. ANP greatly increased in 17 and 18 brain areas (all cut cerebral cortex) by 24 h. Rehydration for 12 h corrected all changes evoked by dehydration, including elevated ANP levels in brain. We conclude that chronic dehydration results in increased ANP in brain areas important to salt appetite and water balance. These results support a role for ANP as a neuroregulatory substance that participates in salt and water balance.]

Clinical Neuroscience


BALI Balázs, NAGY Zoltán, KOVÁCS J. Krisztina

[Introduction - (-)Deprenyl is an irreversible inhibitor of type B monoamine oxidase (MAO-B), which is now used for treatment of Parkinson’s or Alzheimer’s diseases. Evidence suggests that the neuroprotective effect of deprenyl may not be related exclusively to the inhibition of the enzyme MAO-B. Methods - To test the impact of deprenyl on ischemiainduced changes in vitro, we followed the time course of propidium iodide (PI) uptake as an indicator of neuronal cell death as well as the expression of apoptotic factors in organotypic hippocampal slice cultures exposed to oxygen- glucose deprivation (OGD) for 45 min. Results - The first signs of neuronal death were detected 2 hours after OGD and were extended to all subfields of the hippocampus by 24 hours post-injury. Presence of deprenyl (10-9 M) significantly delayed the cell death induced by the insult. Exposure of control cultures to deprenyl significantly increased the abundance of Bcl-2 and Bcl-xl mRNAs as revealed by RT-PCR. OGD resulted in an elevation of anti-apoptotic factors, while the expression of pro-apoptotic bax remained unchanged. Conclusion - These data suggest that deprenyl is neuroprotective in an in vitro model of ischemia. Although deprenyl upregulates the expression of Bcl-2 under basal conditions, its effect on anti-apoptotic factors is not significantly manifested during OGD.]

Clinical Neuroscience


BODNÁR Ibolya, HECHTL Dániel, SZÉKÁCS Dániel, OLÁH Márk, NAGY M. György

[Background and purpose - Hypothalamic dopamine (DA), the physiological regulator of pituitary prolactin (PRL) secretion, is synthesized in the neuroendocrine DAergic neurons that projects to the median eminence and the neurointermediate lobe of the pituitary gland. The rate-limiting step of DA biosynthesis is catalyzed by the phosphorylated, therefore activated, tyrosine hydroxylase (TH) that produces L-3,4-dihydroxy- phenylalanine from tyrosine. The aims of our present study were to investigate 1. the effect of local inhibition of the DA biosynthesis in the hypothalamic arcuate nucleus on PRL release, and to get 2. some information whether the phosphorylated TH is the target of enzyme inhibition or not. Methods - A TH inhibitor, α-methyl-p-tyrosine was injected either intracerebro-ventricularly or into the arcuate nucleus of freely moving rats and plasma PRL concentration was measured. Immunohistochemistry, using antibodies raised against to native as well as phosphorylated TH were used to compare their distributions in the arcuate nucleus-median eminence region. Results - Intracerebro-ventricular administration of α-methyl-p-tyrosine has no effect, unlike the intra-arcuatus injection of enzyme inhibitor resulted in a slight but significant elevation in plasma PRL. Parallel with this, the level of DA and DOPAC were reduced in the neurointermediate lobe while no change in norepinephrine concentration can be detected indicating a reduced biosynthesis of dopamine following TH inhibition. On the other hand, systematic application of the α-methyl-p-tyrosine that inhibits TH activity located in DA terminals of the median eminence and the neurointermediate lobe, resulted in the most significant elevation of PRL. Conclusion - Our results suggest that α-methyl-p-tyrosine administered close to the neuroendocrine DAergic neurons was able to inhibit only a small proportion of the TH. Moreover, it also indicate that the majority of the activated TH can be found in the axon terminals of DAergic neurons, therefore, the DA released into the pituitary portal circulation is synthesized at this site.]

Clinical Neuroscience



[Bone marrow derived stem cells (BMDSCs) have been reported to form neurons and supportive cells in the brain. We describe a technique that combines the simplicity of in vitro studies with many of the advantages of in vivo experiments. We cultured mouse brain slices, deposited GFPtagged BMDSCs evenly distributed on their surfaces, and then added test factors to the culture medium. Addition of both SDF-1 and EGF resulted in morphological changes of BMDSC and in the induction of islet-1, a marker of neuroepithelial progenitors. We conclude that organotypic tissue culture (OTC) may allow us to detect the effects of exogenous factors on the differentiation of BMDSCs (or any other type of stem cells) in an environment that may resemble the CNS after brain injury. Once such factors have been identified they could be evaluated for tissue regeneration in more complex, whole animal models.]

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Clinical Neuroscience

A case with reversible neurotoxicity induced by metronidazole

EREN Fulya, ALDAN Ali Mehmet, DOGAN Burcu Vasfiye, GUL Gunay, SELCUK Hatem Hakan, SOYSAL Aysun

Background - Metronidazole is a synthetic antibiotic, which has been commonly used for protozoal and anaerobic infections. It rarely causes dose - and duration - unrelated reversible neurotoxicity. It can induce hyperintense T2/FLAIR MRI lesions in several areas of the brain. Although the clinical status is catastrophic, it is completely reversible after discontinuation of the medicine. Case report - 36-year-old female patient who had recent brain abscess history was under treatment of metronidazole for 40 days. She admitted to Emergency Department with newly onset myalgia, nausea, vomiting, blurred vision and cerebellar signs. She had nystagmus in all directions of gaze, ataxia and incompetence in tandem walk. Bilateral hyperintense lesions in splenium of corpus callosum, mesencephalon and dentate nuclei were detected in T2/FLAIR MRI. Although lumbar puncture analysis was normal, her lesions were thought to be related to activation of the brain abscess and metronidazole was started to be given by intravenous way instead of oral. As lesions got bigger and clinical status got worse, metronidazole was stopped. After discontinuation of metronidazole, we detected a dramatic improvement in patient’s clinical status and MRI lesions reduced. Conclusion - Although metronidazole induced neurotoxicity is a very rare complication of the treatment, clinicians should be aware of this entity because its adverse effects are completely reversible after discontinuation of the treatment.

Clinical Neuroscience

[Ketamine administration in case of severe, therapy resistant depressed patient, case report]

MORVAI Szabolcs, NAGY Attila István, BÁLINT-SZÖLLŐSI Adrienn, MÓRÉ E Csaba, BERECZ Roland, FRECSKA Ede

[Objective - In our case report we present the treatment of a female patient suffering from therapy resistant depression. This procedure is not in practice in Hungary at present, the aim of our work to reproduce the findigs of international studies in domestic circumstances. Matter - Major depression is a common, chronic and severe mental disorder, with 16.2% lifetime prevalence. Many international randomized, placebo controlled trials found administration of ketamine infusion effective in depressed patients. Methods - Since ketamine is an anesthetic agent, its administration was performed in the post-operative monitoring room of our hospital operating-room, supervised by an anesthesiologist. According to formerly published data, a dose of 0.5 mg/kg of body weight was administered intravenously in 40 minutes by perfusor. The drug was administered in a same manner fifteen days later. Subject - The patient was admitted to our inpatient ward with severe depression. During two months of combined antidepressant therapy her condition has not improved significantly. Approval for off label drug indication was granted with urgency by the National Institute of Quality and Organizational Development in Healthcare and Medicines. Results - During the two treatments the Hamilton Depression Rating Scale 21 items rating scale score was reduced to 8 from the baseline 28, the Hamilton Anxiety Rating Scale score was reduced to 6 from 25, Beck Depression Inventory was reduced to 9 from 20. Upon administration of the drug no severe adverse event was detected, the mild dissociative state related to ketamine was ceased in a short period of time. Discussion - With administration of 0.5 mg/kg ketamine the authors managed to achieve rapid improvement in a therapy resistant depressed patient, without permanent side effects. Our future plan is to repeat the use of the drug within a double-blind, placebo controlled trial in order to prove its efficacy in hospital settings. ]

Lege Artis Medicinae

[Therapy of high-intensity cancer pain]


[Although cancer pain is usually a chronic one, in certain cases it needs emergency treatment due to its intensity. By the temporal appearance of pain the author discusses separately the possibilities of treatment of the continuous and the episodic (breakthrough) pain and refers particularly to the neuropathic pain. It is stressed that opiate-responsive continuous severe pain can be diminished most quickly by giving morphine intravenously and a recommendation is drafted how to perform it rapidly but safely. Finally, it is emphasized that the absence of pain analysis and appropriate drug therapy is the most important factor of inadequate pain relief up to now.]

Lege Artis Medicinae

[Tuberculous meningoencephalitis in a toddler child]

REISZ Zita, GÁL Péter, TAJTI Zsanett, TERHES Gabriella, URBÁN Edit, KISS Ildikó, BARZÓ Pál, KIS Dávid, SENONER Zsuzsanna, SZABÓ Nóra, SZAPPANOS Norbert, TISZLAVICZ László

[INTRODUCTION - Central nervous system complications occur in 1% of patients with Mycobacterium tuberculosis infection, but the mortality is very high, about 50 percent. CASE REPORT - A 1-year-old child in tenebrous condition was admitted to the hospital with suspicion of meningitis. MRI detected disseminated encephalitis and dilated ventricles. Examination of the serum and cerebrospinal fluid didn’t bring any results. The microscopic examination of the brain biopsy raised the possibility of tuberculous meningoencephalitis, and the culture and PCR from the brain tissue revealed meningoencephalitis caused by Mycobacterium tuberculosis Beijing. DISCUSSION - Tuberculous meningitis is a very rare, but severe consequence of extrapulmonary tuberculosis. Due to the high mortality, early diagnosis and whenever suspected, the use of empiric antituberculotic therapy are the only chances of recovery.]

Hungarian Immunology

[Regional cues and phenotypic responses during the ontogeny and postnatal development of splenic vasculatur]


[Among structured peripheral lymphoid tissues in man and rodents, the spleen demonstrates the most extensive flexibility in functional activities, which is coupled with considerable tissue architecture adjustments during ontogeny and immune reactions. The sequential conversion of a primary lymphohemopoietic tissue into a major peripheral lymphoid organ (while participating in the post-myeloid period of primary B-lymphopoiesis and retaining the potential for myelopoiesis) is accompanied with the ordered segregation involving various non-hemopoietic components of architecture, including the endothelia of blood vessels. In this report we will survey the functional and structural aspects of heterogeneous endothelial cells lining the various splenic vascular beds, comprising the complex circulatory network of the spleen. These features will be correlated with the characteristics of those regulatory mechanisms that have recently been demonstrated to be responsible for the establishment and maintenance of the endothelial divergence during splenic vascular development, including crucial transcription factors, morphogenic regulatory ligands and receptors of the tumor necrosis factor/lymphotoxin (TNF/LT) family and others. The influence of these regulatory elements in mice appears to be highly restricted in terms of regional involvement of the vasculature, with cellular alterations of the marginal sinus representing the most frequently affected region. This complexity highlights the importance of this tissue region in both the formation of splenic vasculature and a possible source for white pulp stromal elements as well as its function as a major gateway for lymphocyte traffic.]