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S Konitsiotis

Publications and source records attributed to S Konitsiotis.

At least 19 recordsLinked to original sources
PubMed2006

Akinetic mutism followed by a manic reaction on introduction of steroid replacement for Addison's disease.

Neuropsychiatric changes during exogenous corticosteroid administration are well-recognized. However, reports of neuropsychiatric reactions to corticosteroid replacement for Addison's disease are distinctively rare. We report on a patient with primary adrenocortical insufficiency, initially presenting with depressive symptoms, who developed akinetic mutism followed by acute manic illness shortly after the initiation of steroid replacement. Both disorders occurred with physiological doses of hydrocortisone and resolved spontaneously. The pathogenesis of the above neuropsychiatric reactions is discussed in the context of glucocorticoid receptor-related brain effects of glucocorticoids. In addition, this report points to the need for accurate psychiatric assessment of patients with Addison's disease upon introduction of replacement therapy.

Addison Disease↗
PubMed2006

A method for classification of transient events in EEG recordings: application to epilepsy diagnosis.

OBJECTIVES: The aim of the paper is to analyze transient events in inter-ictal EEG recordings, and classify epileptic activity into focal or generalized epilepsy using an automated method. METHODS: A two-stage approach is proposed. In the first stage the observed transient events of a single channel are classified into four categories: epileptic spike (ES), muscle activity (EMG), eye blinking activity (EOG), and sharp alpha activity (SAA). The process is based on an artificial neural network. Different artificial neural network architectures have been tried and the network having the lowest error has been selected using the hold out approach. In the second stage a knowledge-based system is used to produce diagnosis for focal or generalized epileptic activity. RESULTS: The classification of transient events reported high overall accuracy (84.48%), while the knowledge-based system for epilepsy diagnosis correctly classified nine out of ten cases. CONCLUSIONS: The proposed method is advantageous since it effectively detects and classifies the undesirable activity into appropriate categories and produces a final outcome related to the existence of epilepsy.

Action Potentials↗
PubMed2005

Astrocytoma-like multiple sclerosis.

Multiple sclerosis (MS) may sometimes mimic clinically and radiologically a brain tumor. The initial recognition of such cases is essential as it might avoid a surgical intervention and supplementary treatment. However, even in patients who underwent surgery, the appropriate preparation of the specimen is of crucial importance for the correct pathological diagnosis since tumors and non-neoplastic demyelinating lesions share some common histopathological features. We present such a case of multiple sclerosis presenting with features of an astrocytoma and was treated with surgery and additional radiotherapy.

Astrocytoma↗
PubMed2000

AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys.

OBJECTIVE: To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias. BACKGROUND: Motor fluctuations and dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA subtype. The possible role of AMPA receptors, however, has not yet been examined. METHODS: The authors compared the ability of an AMPA agonist (CX516) and a noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated parkinsonian monkeys received rising doses of each drug, first in monotherapy and then in combination with low-, medium-, and high-dose levodopa. RESULTS: CX516 alone, as well as when combined with low-dose levodopa, did not affect motor activity but induced dyskinesia. Moreover, following injection of the higher doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p < 0.05). LY300164 potentiated the motor activating effects of low-dose levodopa, increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa-induced dyskinesia by up to 40% (p < 0.05). CONCLUSIONS: AMPA receptor upregulation may contribute to the expression of levodopa-induced dyskinesia. Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or in combination with NMDA antagonists, in the treatment of PD, by enhancing the antiparkinsonian effects of levodopa without increasing and possibly even decreasing levodopa-induced dyskinesia.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

Antiparkinsonian and antidyskinetic activity of drugs targeting central glutamatergic mechanisms.

Motor dysfunction produced by the chronic non-physiological stimulation of dopaminergic receptors on striatal medium spiny neurons is associated with alterations in the sensitivity of glutamatergic receptors, including those of the N-methyl-D-aspartate (NMDA) subtype. Functional characteristics of these ionotropic receptors are regulated by their phosphorylation state. Lesioning the nigrostriatal dopamine system of rats induces parkinsonian signs and increases the phosphorylation of striatal NMDA receptor subunits on serine and tyrosine residues. The intrastriatal administration of certain inhibitors of the kinases capable of phosphorylating NMDA receptors produces a dopaminomimetic motor response in these animals. Treating parkinsonian rats twice daily with levodopa induces many of the characteristic features of the human motor complication syndrome and further increases the serine and tyrosine phosphorylation of specific NMDA receptor subunits. Again, the intrastriatal administration of selective inhibitors of certain serine and tyrosine kinases alleviates the motor complications. NMDA receptor antagonists, including some non-competitive channel blockers, act both palliatively and prophylactically in rodent and primate models to reverse these levodopa-induced response alterations. Similarly, in clinical studies dextrorphan, dextromethorphan, and amantadine have been found to be efficacious against motor complications. Recent observations in animal models further indicate that certain amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) antagonists alleviate, while others exacerbate, these complications. Thus, it appears that the denervation or intermittent stimulation of striatal dopaminergic receptors differentially activates signal transduction pathways in medium spiny neurons. These in turn modify the phosphorylation state of ionotropic glutamate receptors and consequently their sensitivity to cortical input. These striatal changes contribute to symptom production in Parkinson's disease, and their prevention or reversal could prove useful in the treatment of this disorder.

Animals↗
PubMed1999

Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study.

BACKGROUND: In a recent acute study, amantadine was found to have antidyskinetic effect against levodopa-induced motor complications in patients with Parkinson disease. The longevity of this effect was not addressed but is of interest in light of the controversy in the literature regarding the duration of amantadine's well-established antiparkinsonian action. OBJECTIVE: To determine the duration of the antidyskinetic effect of amantadine in advanced Parkinson disease. DESIGN: One year after completion of an acute, double-blind, placebo-controlled, crossover study, patients returned for re-evaluation of motor symptoms and dyskinesias using a nonrandomized, double-blind, placebo-controlled follow-up paradigm. SETTING: National Institutes of Health Clinical Center. PATIENTS: Seventeen of the original 18 patients with advanced Parkinson disease complicated by dyskinesias and motor fluctuations participated in this study; 1 was lost to follow-up. Thirteen of the 17 individuals had remained on amantadine therapy for the entire year. INTERVENTIONS: Ten days prior to the follow-up assessment, amantadine was replaced with identical capsules containing either amantadine or placebo. MAIN OUTCOME MEASURES: Parkinsonian symptoms and dyskinesia severity were scored using standard rating scales, while subjects received steady-state intravenous levodopa infusions at the same rate as 1 year earlier. RESULTS: One year after initiation of amantadine cotherapy, its antidyskinetic effect was similar in magnitude (56% reduction in dyskinesia compared with 60% 1 year earlier). Motor complications occurring with the patients' regular oral levodopa regimen also remained improved according to the Unified Parkinson's Disease Rating Scale (UPDRS-IV). CONCLUSION: The beneficial effects of amantadine on motor response complications are maintained for at least 1 year after treatment initiation.

Amantadine↗
PubMed1999

Differing effects of N-methyl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys.

The antiparkinsonian and antidyskinetic profile of two N-methyl-D-aspartate (NMDA) receptor antagonists, a competitive antagonist, (R)-4-oxo-5-phosphononorvaline (MDL 100,453), and a novel noncompetitive allosteric site antagonist, 4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piper idi ne (Co 101244/PD 174494), was assessed in six levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine-lesioned parkinsonian monkeys. The effects on motor function of these two drugs, alone and in combination with levodopa, were then correlated with NMDA subtype selectivity and apparent affinity for four diheteromeric NMDA receptor subunit combinations expressed in Xenopus oocytes. MDL 100, 453 (300 mg/kg s.c.) by itself increased global motor activity (p =. 0005 versus vehicle) and administered 15 min after a low dose of levodopa/benserazide s.c., MDL 100,453 (50, 300 mg/kg s.c.) showed dose-dependent potentiation of antiparkinsonian responses and also produced dyskinesias. Following injection of a fully effective dose of levodopa, MDL 100,453 (300 mg/kg s.c.) also produced a 25% increase in mean dyskinesia score (p =.04). In contrast, Co 101244 did not change motor activity by itself and only showed a tendency to potentiate the antiparkinsonian response when given in combination with a low dose of levodopa, which did not attain statistical significance. However, with a high dose of levodopa, Co 101244 (0.1, 1 mg/kg s.c.) displayed antidyskinetic effects (67 and 71% reduction, respectively) while sparing levodopa motor benefit. In vitro, MDL 100,453 was an NMDA glutamate-site antagonist, with approximately 5- to 10-fold selectivity for the NR1A/NR2A subtype combination (K(b) = 0.6 microM) versus NR1A in combination with 2B, 2C, or 2D. In contrast, the allosteric site antagonist Co 101244 showed approximately 10,000-fold selectivity for the NR1A/NR2B (IC(50) = 0.026 microM) versus the other three subunit combinations tested. Taken together, the data suggest that the NR2 subunit selectivity profile of NMDA receptor antagonists can play an important role in predicting behavioral outcome and offer more evidence that NR2B-selective NMDA receptor antagonists may be useful agents in the treatment of Parkinson's disease.

Animals↗
PubMed1998

Amantadine reduces levodopa-induced dyskinesias in parkinsonian monkeys.

The antidyskinetic potential of the glutamate NMDA receptor channel blocker amantadine was evaluated in four levodopa-primed parkinsonian monkeys using two different regimens (1.25 or 2.5 mg/kg administered subcutaneously twice daily for 3-6 days). When administered with a relatively low dose of levodopa, amantadine produced a near-total suppression of choreiform dyskinesias and a substantial reduction in dystonic dyskinesias at the expense of a significant reduction in antiparkinsonian response. With a high dose of levodopa, amantadine had a smaller but still significant effect on dyskinesias without altering the antiparkinsonian response. These results lend support to the view that glutamate receptor-mediated mechanisms contribute to levodopa-induced dyskinesias. They also suggest that amantadine could alleviate such complications in parkinsonian patients, especially with careful dose optimization.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Chronic exposure to MPTP as a primate model of progressive parkinsonism: a pilot study with a free radical scavenger.

The development of a validated primate model of progressive parkinsonism is a critical step in the evaluation of drugs that might halt or slow progression of Parkinson's disease. In this pilot study, we gradually exposed 14 cynomolgus monkeys to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), at a weekly dose of 0.5 mg/kg s.c. for 10 weeks, to determine their probability of not reaching a predetermined endpoint on a disability scale by Kaplan-Meier analysis. Four other MPTP-exposed animals were coadministered the potent free radical scavenger 7-hydroxy-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetylamino-2,2,4,6- tetramethylindan (OPC-14117) as a single oral daily dose of 0.6 g/kg, starting 2 weeks before MPTP initiation. The risk of reaching endpoint by week 10 was 79% and mean time before reaching endpoint was 6 weeks. Global motor activity, recorded in a subset of animals using a portable activity monitor, declined following the first MPTP dose and never recovered. Several cerebrospinal fluid indices of central monoamine metabolism collected by suboccipital puncture at 0, 5, and 10 weeks, including HVA, DOPAC, and tetrahydrobiopterin but not MHPG, were found to be "trait" markers for MPTP exposure, whereas CSF DOPAC and tetrahydrobiopterin constituted potential "state" markers for reaching endpoint. The antioxidant OPC-14117 did not protect against MPTP-induced parkinsonism. Further attempts to validate this incremental model of neurotoxin-induced parkinsonism as a predictor of patient responses to putative neuroprotective agents appear warranted.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and is manifested as a movement disorder. A positive family history is the second most important risk factor for developing the illness, after age. Both autosomal dominant and recessive forms of the illness have been described. Recently deletions in a novel gene, parkin, have been associated with the autosomal recessive form of the illness in Japanese families. In this study, we demonstrate that deletions of exons 5, 6 and 7 of the parkin gene are present in two affected individuals of a Greek pedigree with early onset Parkinson's disease. However, no deletions were identified in a different branch of the same pedigree with three affected individuals. These results suggest that deletions in the parkin gene will be found in other families besides those of Japanese origin and that there must be at least one additional locus responsible for early onset autosomal recessive Parkinson's disease.

Female↗
PubMed1998

Opposite rotation induced by dopamine agonists in rats with unilateral lesions of the globus pallidus or substantia nigra.

Normal rats with a unilateral ibotenic acid lesion of substantia nigra pars reticulata (SNR, n = 12) or globus pallidus (GP, n = 12) were challenged systemically with the mixed dopaminergic agonist apomorphine (0.5 and 1.5 mg/kg) and the indirect acting d-amphetamine (1.5 mg/kg). The low dose of apomorphine produced a weak contralateral rotation only in the SNR-lesioned group, which showed an intense ipsilateral rotation following the administration of the higher dose. GP-lesioned rats also showed ipsilateral rotation after the high dose of apomorphine. d-Amphetamine produced ipsilateral rotation in GP-lesioned rats, contrasting with a vigorous contralateral rotation in SNR-lesioned rats. The unexpected opposite rotation after apomorphine and d-amphetamine, observed only in SNR-lesioned animals, indicates that the role of SNR in basal ganglia functions is less clear and more complex than what is expected from our current model of basal ganglia circuitry and functions. On the other hand, the GP lesion resulted in a consistent and predictable ipsilateral rotation after both apomorphine and d-amphetamine, indicating a more determinant effect on the output of the basal ganglia than heretofore believed. Our results may contribute to the recently expressed views challenging the established model of basal ganglia organisation.

Animals↗
PubMed1997

Motor response to a dopamine D3 receptor preferring agonist compared to apomorphine in levodopa-primed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys.

The profile of dopamine receptor subtype activation contributing to the therapeutic efficacy and motor response complications of levodopa (nonselective pro-agonist) in Parkinson's disease remains unclear. Potent, selective, short-acting dopamine D2 receptor subfamily agonists show good antiparkinsonian efficacy but produce dyskinesias comparable to levodopa. Nonetheless, agonists displaying higher affinity for dopamine receptors other than the D2 subtype may have a better therapeutic index. To clarify this issue, we compared the nonselective dopamine D1/D2 receptor subfamilies agonist apomorphine to the dopamine D3 receptor preferring agonist [R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4 , 3-b]-1,4-oxazin-9-ol] (PD 128,907) in 6 levodopa-primed , 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian monkeys with reproducible dyskinesias. Single s.c. dosing with the lowest fully effective dose of apomorphine (averaging 27.9 +/- 4.5 microg/kg) and PD 128,907 (averaging 41.7 +/- 4.4 microg/kg) yielded equivalent antiparkinsonian efficacy on the behavioral scale and portable activity monitoring used. A comparable significant dose-dependent increase in the response magnitude and duration was seen with two higher doses. The severity of dyskinesia was also similar between the two drugs. When the lower dose for each drug was administered six times at a fixed 90-min interval, both drugs remained efficacious with no significant tolerance observed. The D3 receptor preferring antagonist U-99194A significantly reduced the motor effects of both apomorphine and PD 128,907. Thus, increased D3 receptor tone does not acutely ameliorate dyskinesias in levodopa-primed parkinsonian monkeys. Given the reported lack of affinity of PD 128,907 for central D1 receptors, our data support the concept that the pharmacological activation of D1 receptors is not mandatory for relief of parkinsonism and production of dyskinesia.

Animals↗
PubMed1996

Functional assessment of the rat sciatic nerve following intraoperative expansion: the effect of recovery duration on behavioural, neurophysiological, and morphological measures.

The purpose of this study was to investigate the feasibility of rapid intraoperative elongation of the rat sciatic nerve with the use of tissue expander and to assess its functional recovery. Out of 51 rats 43 had their right sciatic nerve expanded with a 5-ml intraoperative expander over 1 hr and 8 were sham-operated controls. The functional recovery of the nerve was assessed at intervals up to 4 months using the Sciatic Functional index (SFI), neurophysiological indices, and histology. Intraoperative expansion elongated the rat sciatic nerve by about 13%. SFI decreased on the first postoperative day and started to recover by Day 7, reaching almost preoperative values by Days 14 and 30 according to De Medinaceli and Bain-Mackinnon-Hunter formulas, respectively. Latency and motor conduction velocity demonstrated a deterioration after expansion which peaked on Day 1. Recovery started by Day 7 and reached preoperative levels by 60 days. The histological findings indicated minor aberrations immediately after expansion and maximal demyelination with minimal axonal disruption on Day 1. The reparative process started by Day 7 and continued till Day 120 when almost no histological changes were observed. In conclusion, intraoperative nerve expansion successfully elongates the rat sciatic nerve. It also causes functional and morphological abnormalities which are of low to moderate degree, have a short duration, and are reversible. Intraoperative nerve expansion might be a valuable solution in the treatment of short nerve gaps, but its clinical application still needs to be evaluated.

Animals↗
PubMed1990

Topography of dopamine D-1 and D-2 receptor-mediated rotation after intrastriatal injections of dopamine-related drugs in normosensitive rats.

Naive rats were challenged systematically with apomorphine after receiving unilateral dorsal or ventral intracaudate injections of the dopamine D-1 receptor antagonist, SCH23390, or the D-2 receptor antagonist, sulpiride. Sulpiride injections into both the dorsal and ventral striatum induced a robust ipsilateral rotation, while SCH23390 elicited a weaker ipsilateral rotation only on injection into the ventral striatum. Both drugs were ineffective in saline-treated rats, although sulpiride injections into the ventral striatum after systemic saline elicited a small ipsilateral preference. The results from this rotational model mediated by normosensitive receptors indicate that only dopamine D-1 receptors in the ventral striatum mediate rotation while D-2 receptors in both striatal regions mediate rotation. A functional dichotomy between these two neostriatal regions is thus proposed.

Analysis of Variance↗