L-Dopa decreases cutaneous nociceptive inhibition of motor activity in Parkinson's disease

OBJECTIVES: To estimate changes in motor inhibitory mechanisms at the spinal level in Parkinson's disease (PD) patients by measuring cutaneous silent responses to nociceptive stimuli in the course of L-Dopa therapy. MATERIALS AND METHODS: Fourteen patients with idiopathic PD (Group 1) and 13 patients with other forms of parkinsonism (Group 2) participated in the study. The cutaneous silent period (CSP) from the hand and clinical scores (UPDRS, part III) were measured "off" therapy (T0), after a single dose of L-Dopa (T1) and 3 months after the beginning of L-Dopa daily therapy (T2). RESULTS: At T0 the duration of the CSP was significantly prolonged in Group 1 and Group 2. At T1 and T2 the mean duration of the CSP significantly decreased in Group 1 (P < 0.05) and a significant correlation was found between the shortening of the CSP and the improvement of rigidity and bradikynesia in the upper limb. CONCLUSIONS: Our findings show that L-Dopa decreases the cutaneous nociceptive inhibition of motor activity in PD patients. CSP may be useful to assess L-Dopa responsiveness during the clinical course of PD.     

Pharmacokinetics and pharmacodynamics of L-Dopa after acute and 6-week tolcapone administration in patients with Parkinson's disease

Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inhibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.     

Short latency somatosensory evoked potentials and brain-stem auditory evoked potentials in coma due to CNS depressant drug poisoning. Preliminary observations

In patients in coma due to severe CNS depressant drug overdose the central somatosensory conduction time (CCT) after median nerve stimulation is prolonged and N20 is dispersed. Brain-stem auditory evoked potentials demonstrate delayed interpeak latencies (IPLs) I-III, III-V and I-V. This was observed in 4 out of 5 patients investigated after intake of an overdose of amitriptyline (2 cases), barbiturates, meprobamate and nitrazepam (one case each). Toxic levels of drug overdose were related to prolonged CCT and IPLs, whereas normal CCT and IPLs were found at therapeutic drug plasma levels. CCT, IPLs and dispersion of N20 decreased during the course of coma. All patients were successfully treated. It appeared that SSEP and BAEP investigations could make a distinction between a 'toxic' and a 'therapeutic' coma level in severe drug overdose. It further appeared that normalization of CCT and IPLs preceded clinical improvement.     

Upper airway muscles dysfunction and levodopa responsiveness in Parkinson's disease.

Pulmonary function tests were performed before and at different times after 250 mg L-Dopa in 12 patients with Parkinson's disease (PD). Six were de-novo patients, the other six patients had been taking L-Dopa over different periods. All patients had an abnormal basal flow-volume loop, which significantly improved only in de-novo patients. This improvement occurred early and was independent on improvement of neurological symptoms. The effect of L-Dopa on pulmonary function could be a useful test in differentiating PD from related extrapyramidal syndromes.     

Eye movements induced by head rotation in unresponsive patients

Eye movements induced by head rotation were studied in 6 patients in acute coma, 4 patients in a persistent vegetative state, and 6 healthy, alert control subjects. Results from control subjects suggest that the oculocephalic response in the supine position is principally a vestibulo-ocular reflex. A position-step rotation of the head produced an initial oppositely directed eye movement, followed by a drift of the eyes back toward midline with a negative exponential time course. The time constant of this drift was greater than or equal to 10 seconds in control subjects but less than or equal to 1.5 seconds in unconscious patients and less than or equal to 0.5 seconds in vegetative patients. The rapid drift back of the eyes in unresponsive patients implies dysfunction of reticular and, possibly, cerebellar connections; the rate of this drift may indicate the severity and extent of brain injury. Sinusoidal head rotation produced slow and quick phases of nystagmus in normal subjects. Quick phases were absent in patients in acute coma; although present in vegetative patients, the quick phases did not keep the eyes close to primary position, as was the case in control subjects.     

Auditory brain-stem responses in brain death.

Auditory brain-stem responses were measured by far-field recording techniques in 27 patients fulfilling the criteria of brain death. The responses were either absent or consisted of the presence of just the initial component (Wave I). Wave I, when present, was of normal amplitude but prolonged in latency. Four patients were followed over several days from a state of coma with evidence of preserved brain-stem and cerebral functions to a clinical state compatible with brain death. Auditory brain-stem responses were initially intact and then showed a decrease in amplitude and a prolongation of latency of the later components until finally Wave I was alone. Auditory brain-stem responses are an objective measure of one of the sensory pathways traversing the brain-stem and can be used to evaluate the functional states of the brain-stem in patients in whom the question of brain death has been raised.     

Effects of L-Dopa and Vitamin B6 on Electroencephalograms of Schizophrenic Patients: A Preliminary Report

1. To assess the therapeutic effect of low-dose L-Dopa therapy and associated EEG changes in chronic schizophrenia, 10 patients with a mean duration of illness of 12.4 years were treated with L-Dopa for a period of eight weeks during which the dosage was increased progressively from an initial level of 300 mg q.d. biweekly up to 600 mg q.d. The treatment was moderately effective in one case and slightly efficacious in one, produced no significant change in the conditions of seven patients while the remaining patient showed exacerbation; hence a noticeably low rate of improvement. There occurred no significant changes in the EEG pattern in the series of 10 patients on the average. The individual patients' responses, nevertheless, could be classified into three groups: one with no observable EEG changes, the second showing a slight degree of increase in alpha activity and the third exhibiting diminution of alpha activity in the EEG. The patients in the latter two groups all had durations of disease less than 10 years. 2. Observations were made primarily of changes in the EEG in 20 chronically schizophrenic patients with a mean duration of disease of 13 years receiving 60 mg of vitamin B₆ (as pyridoxa15'-phosphate) daily over a period of four weeks. Slight increase of alpha activity and decrease of theta activity in the EEG were noted on the average of the 20 cases, in response to the vitamin B₆ therapy. The increase of alpha activity was frcquently seen among patients with a duration of illness less than 10 years whose pretreatment EEG pattern had been alpha dominant (five out of 10 cases), whereas a slight ameliorative tendency of EEG was observed only in one out of 10 patients whose pretreatment EEG pattern had been slow-wave dominant. Symptomatic improvement was evident only in one of the 20 cases studied. 3. Observations were made of the therapeutic effect and associated EEG changes in eight patients receiving combined medication of 200 mg L-Dopa and 30 mg vitamin B₆ (as pyridoxal 5'-phos-phate) daily for a period of 12 weeks. Of these eight patients with a mean duration of disease of 18.3 years, two showed excellent response, three good and three fair; hence good to excellent responses attained in five out of the eight cases or 62.5%. A marked increase in alpha activity in the EEG occurred from the 2nd to 4th weeks onward in all eight cases. The EEG changes were likely to precede the symptomatic improvement. 4. To sum up the results of these three clinical trials, administration of L-Dopa alone resulted in practically no symptomatic improvement or EEG changes in patients with chronic schizophrenia whilst vitamin B₆ administered singly as pyridoxal-5'-phos-phate scarcely produced significant symptomatic improvement but brought about a slight ameliorative tendency in the EEG of such patients. Both symptomatic amelioration and EEG improvement occurred following combined medication of L-Dopa and vitamin B₆ The findings suggest that diminution of the activity of decarboxylase essential to the metabolism of L-Dopa to DA might be present in chronically schizophrenic patients.     

The problems of L-dopa therapy in the course of Parkinson syndrome

101 patients with Parkinson's disease were analyzed in a retrospective study to evaluate the influence of L-Dopa monotherapy, duration of the disease and age at onset on the clinical course of the syndrome. The effects of L-Dopa dosage adjustments after hospitalization were particularly considered. Results: patients with late onset of symptoms showed a more accelerated deterioration as compared to those with early manifestation of the disease who also were less severely affected. Patients treated with L-Dopa for more than five years had a greater neurological deficit score than patients who had not received L-Dopa. Besides a more severe course, these patients also exhibited significantly more dyskinesias and on-off-phenomena. It should be emphasized that in our study, 73% of the 101 patients had been treated inadequately prior to admission to our clinic. The extent of neurological deficit could be improved by L-Dopa dose adjustments in those cases. Only in 11% of cases, an augmentation of the dopa medication was found to be effective in improving the clinical syndrome, whereas in 43%, a substantial reduction of dosage was necessary and resulted in a marked improvement of the clinical syndrome.     

The pharmacokinetic profile of the "first ever" oral dose of levodopa in de novo patients with Parkinson's disease

To understand the delay in the clinical benefit that commonly occurs after initiation of levodopa (L-Dopa) treatment, we examined the pharmacokinetic profile of L-Dopa after the first oral dose ever taken of L-Dopa/carbidopa in untreated patients with Parkinson's disease and followed these parameters after 1 month of treatment. This was performed in correlation with the clinical therapeutic effect. Plasma levels of L-Dopa were measured with use of high-performance liquid chromatography with electrochemical detection after administration of the "first ever" 125 mg L-Dopa/12.5 mg carbidopa tablet in 15 patients with de novo Parkinson's disease (mean age, 69 +/- 11 y, mean disease duration, 1.5 +/- 0.8 years). Blood samples were drawn before administration and thereafter at various intervals for a period of 4 hours. Repeated measurements after the same oral dose were performed after 1 month of continued therapy with L-Dopa/carbidopa 125/12.5 mg three times daily. Patients were clinically evaluated by unified Parkinson's disease rating scale motor scores. There was a modest clinical improvement after 1 month of continuous L-Dopa treatment (motor scores, 13.1 +/- 11.6 vs. 17.6 +/- 11.7; p < 0.01). Peak plasma L-Dopa levels and area under the curve did not differ significantly between the first-ever dose and after 1 month of continuous treatment (0.9 +/- 0.1 vs. 1.0 +/- 0.1 microg/mL and 66.0 +/- 30.9 vs. 86.2 +/- 34.9 microg/mL, respectively; p < 0.1. There was also no change in time to peak levels between measurements. Results indicate that the first-ever dose of oral L-Dopa is well absorbed and that pharmacokinetic mechanisms such as reduced absorption of L-Dopa probably do not play a major role in the initial delay in clinical response to oral L-Dopa/carbidopa in patients with Parkinson's disease. The latter phenomena may be linked to central pharmacodynamic mechanisms.     

Characteristics of the electromyographic patterns of lower limb muscles during gait in patients with Parkinson's disease when OFF and ON L-Dopa treatment

The purpose of this study was to compare the electromyographic (EMG) behavior of the triceps surae (TS), tibialis anterior (TA), quadriceps and hamstring muscles of the lower limbs during self-initiated free gait in a group of patients (n=15) with Parkinson's disease (PD), when OFF and ON L-Dopa, with that of normal controls. When OFF L-Dopa, we observed qualitative disturbances in muscle activation patterns, such as an absence or extreme reduction in TA activations in early stance or during the early and late swing phases. Other disturbances included flatter profiles of the TS activation burst at push off, and temporal alterations that included prolonged activation of the proximal muscles during the stance phase. Statistical analysis showed that the TA was the most affected muscle in most of the patients particularly during the activation burst in late swing (p<.0004). After medication (ON L-Dopa), the amplitude and timing of distal muscle activations became more similar to normal values, with the increase in EMG amplitude being dramatic in some patients. In the proximal muscles, the effects on EMG amplitude were less marked and prolonged activation often persisted even after the administration of L-Dopa.     

Characteristics of the electromyographic patterns of lower limb muscles during gait in patients with Parkinson''s disease when OFF and ON L-Dopa treatment

The purpose of this study was to compare the electromyographic (EMG) behavior of the triceps surae (TS), tibialis anterior (TA), quadriceps and hamstring muscles of the lower limbs during self-initiated free gait in a group of patients (n=15) with Parkinson's disease (PD), when OFF and ON L-Dopa, with that of normal controls. When OFF L-Dopa, we observed qualitative disturbances in muscle activation patterns, such as an absence or extreme reduction in TA activations in early stance or during the early and late swing phases. Other disturbances included flatter profiles of the TS activation burst at push off, and temporal alterations that included prolonged activation of the proximal muscles during the stance phase. Statistical analysis showed that the TA was the most affected muscle in most of the patients particularly during the activation burst in late swing (p<.0004). After medication (ON L-Dopa), the amplitude and timing of distal muscle activations became more similar to normal values, with the increase in EMG amplitude being dramatic in some patients. In the proximal muscles, the effects on EMG amplitude were less marked and prolonged activation often persisted even after the administration of L-Dopa.This work was supported by grants from Laval University.     

A comparison between the effect of intentional modulations and the action of L-dopa on gait in Parkinson's disease.

The aims of the present study were to analyze how L-Dopa allows parkinsonian patients to increase their gait velocity and to compare these L-Dopa-induced modifications with those achieved by consciously attempting to walk as fast as possible (intentional modulations). The 'intentional modulations' of velocity were also compared with those of healthy elderly subjects. The results showed that parkinsonian patients walked more slowly, with shorter strides and shorter durations of swing phase, and longer durations of stance and double support phases, although no differences were observed for cycle duration. The mechanisms involved in increasing gait velocity were found to differ according to whether this was achieved through the action of L-Dopa, or by intentional increases in velocity. Intentional increases in velocity were greater than those caused by the effect of L-Dopa. The patients, however, used efficient strategies to increase their velocity when under the influence of L-Dopa. As L-Dopa leads to a ceiling effect on stride length, the patients can increase their velocity by modifying the cycle to such an extent that it compensates for the limitation in stride length. This strategy effectively increases velocity, despite the L-Dopa ceiling effect. The effects of L-Dopa on locomotion and, more generally, on motor control aspects are discussed.     

L-dopa-carbidopa: combined therapy for the treatment of Parkinson's disease.

It is now generally acknowledged that L-Dopa is the therapy of choice for Parkinson's Disease. However, L-Dopa has some short comings: It requires large daily dosage, the therapeutic benefits are achieved only after a delayed onset of 1-2 months, and it has a number of side effects both central and peripheral. In the last few years there has been an intense search for agents that are less toxic, more efficient and more rapidly acting that L-Dopa. The ideal agent has not yet been found. However, a combination therapy with L-Dopa and dopa decarboxylase inhibitors has shown promise. The decarboxylase inhibitors used have a large molecule which does not cross the blood brain barrier. Thus when L-Dopa and the decarboxylase inhibitor are given togehher, peripheral production of dopamine from L-Dopa is inhibited, therefore, rendering L-Dopa more readily and rapidly available for brain metabolism. In the present paper we present the results of the treatment of 50 patients on combined therapy using L-Dopa combined with Carbidopa.     

Treatment of parkinsonism with l-dopa and a decarboxylase inhibitor. An electrophysiological and clinical study.

Twelve parkinsonian patients with an unsatisfactory therapeutic result on L-Dopa alone due to nausea, vomiting and involuntary movements were treated WITH L-Dopa and decarboxylase inhibitor. The daily dose reached 800mg L-Dopa and 200 mg decarboxylase inhibitor. Single doses of each of the components were also given. Electrophysiological examination of hypokinesia, tremor and rigidity, and clinical observation revealed clear evidence of rapid improvement on small doses of L-Dopa combined with decarboxylase inhibitor. Most of the improvement occurred during the 1st week before the maximal dose was reached. A single oral dose of decarboxylase inhibitor resulted in an improvement, suggesting the presence in the organism of a small AMOUNT OF L-Dopa. This work also shows the absence of liver toxicity of the drug used. Elimination of the extracerebral side effects nausea and vomiting in our opinion is a principle advantage of the compound compared to L-Dopa alone, wheras abnormal involuntary movements, which were found in all patients, remain the limiting adverse side effect.     

Time related changes in reversible MRI findings after prolonged hypoglycemia

Diffusion weighted magnetic resonance images (DWI) in hypoglycemic coma show more definite and earlier findings than do T1-weighted images, or even fluid-attenuated inversion recovery (FLAIR). However, there has been limited information on the time related changes of such MRI images. We report here the time related changes of MRI findings after prolonged hypoglycemia in a diabetic 62-year-old man without hypoxia. We found in the patient that hyperintensities in DWI, T2-weighted and FLAIR images disappeared on the 14th day along with normalization of the apparent diffusion coefficient (ADC). Single photon emission computed tomography (SPECT) showed no low perfusion findings throughout the course. Since the day when the hyperintensities disappeared, the patient became to open his eyes in response to verbal command. This paper demonstrates serial alterations in reversible DWI findings after prolonged hypoglycemia and we need to define its mechanisms in the future.     

Brain death in secondary brain lesion

The criteria of brain death established by Japanese Society of EEG in 1974, necessitates a prerequisite; be applicable only to "acute destructive, primary gross lesion of brain". Namely, because of insufficient clinical data, secondary brain lesion such as post-anoxia, intoxication, metabolic coma and some kinds of CNS infection were excluded for the object to determine brain death. The criteria published by others also describe that etiology of coma should be clarified, and that careful measures are necessary to diagnose brain death if the cause of coma is unknown. In the present study, it was investigated that whether a clinico-pathological entity of brain death could exist universally regardless of the etiology, and by what means it could be defined clinically. The patients suffering from nondestructive, secondary brain lesions and who showed "brain death-like state" were selected for the study. ("Brain death-like state" requires coma, dilated nonreactive pupis and arrest of respiration concomitantly for more than 6 hours.) And 25 patients were collected, whose underlying diseases were post-anoxia or shock, CO intoxication, Paraquat poisoning, near-drowning or suffocation, hepatic coma, accidental hypothermia and sepsis, with or without the episode of cardiac arrest. Though all the patients died from 1 to 13 days after the insult, clinical signs of brain death-like state were not always irreversible. Isoelectric EEG was obtained on that state in 11 patients and repeated EEG revealed no return on those patients. But another 5 patients showed EEG activity when brain death was strongly suspected clinically.(ABSTRACT TRUNCATED AT 250 WORDS)     

Barbiturate therapy for patients with refractory intracranial hypertension following severe traumatic brain injury: its effects on tissue oxygenation, brain temperature and autoregulation.

The aim of this study was to explore the effects of barbiturate coma on cerebral tissue oxygen tension and cerebrovascular pressure reactivity (PRx), as an index of cerebral autoregulation in severe head injury patients. This was a prospective observational clinical study of 12 patients with severe traumatic brain injury, carried out at a tertiary-level neurosurgical intensive care unit between April 2002 and May 2005. All patients received standard neurosurgical intensive care and monitoring. Probes for intracranial pressure (ICP), brain temperature (BT) and brain tissue oxygenation (PTiO2) were inserted into (noncontused) normal-looking white matter. Cerebrovascular PRx was measured as a moving correlation between ICP and arterial blood pressure. Barbiturate coma was instituted when ICP became refractory (ICP>20 mmHg). All data from the multimodal monitoring were digitally extracted and statistically analysed. The mean ICP decreased with barbiturate coma in eight of the 12 patients (75% of the patients), but only four achieved a value below 20 mmHg. Of eight patients with prebarbiturate PTiO2 levels above 10 mmHg, six had a further improvement in oxygenation. Thus, concordant favourable changes in ICP, PRx and PTiO2 with barbiturate coma were seen in those who survived. Effective response to barbiturates can be detected by improved PTiO2 and autoregulation (PRx) in severe head injury patients.     

A case of 6-pyruvoyl-tetrahydropterin synthase deficiency demonstrates a more significant correlation of L-Dopa dosage with serum prolactin levels than CSF homovanillic acid levels

6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a tetrahydrobiopterin (BH4) deficiency that presents as hyperphenylalaninemia. Administration of the neurotransmitter precursors L-Dopa/carbidopa and 5-hydroxytryptophan (5HTP), as well as BH4, is necessary for treatment. It has been reported that serum prolactin levels are elevated in patients with PTPS deficiency indicating that inhibition of prolactin secretion by dopamine is insufficient and is negatively correlated with the CSF level of HVA. Here, we present a case of PTPS deficiency which showed a more significant correlation of dosage of L-Dopa/carbidopa with serum prolactin levels than with CSF HVA levels. Combined treatment of BH4, L-Dopa/carbidopa, and 5HTP was started as the CSF neopterin/biopterin ratio (N/B ratio 7.54, control 0.46-1.59) and serum prolactin level (36.79 ng/ml, control <15) were elevated. The dosage of L-Dopa/carbidopa was adjusted in the range of 9.08-10.5mg/kg/day. The CSF level of HVA stayed within normal limits using these dosages of L-Dopa/carbidopa, and there was no correlation between dose given and HVA level (R=0.230, p=0.71). On the other hand, even in this relatively small dosing range, the serum prolactin level showed significant negative correlation with the dosage of L-Dopa/carbidopa (R=0.645, p=0.023). The patient did not show any neurological symptoms even when the serum prolactin level was elevated. From these results, we suggest that the serum prolactin level may be a more sensitive marker than the CSF HVA level to guide the dose adjustment of L-Dopa/carbidopa in the management of patients with PTPS deficiency.     

Comparison between L-dopa and lisuride intravenous infusions: a clinical study

L-Dopa is still the most effective drug for the treatment of Parkinson's Disease, but after 5 years or more of therapy fluctuations in motor performance and abnormal involuntary movements commonly appear. Continuous intravenous infusions of L-Dopa abolish or strikingly reduce such fluctuations. Unfortunately, this is not suitable for daily treatment because of the low solubility of L-Dopa. Lisuride is a potent dopamine agonist and is very soluble in water. In this study the clinical effects of L-Dopa and lisuride continuous intravenous infusions were compared in a group of 20 fluctuating parkinsonian patients. L-Dopa controlled fluctuations in almost all the subjects, whereas only seven patients were continuously mobile while taking lisuride. Another seven patients showed a fluctuating response and the remaining six did not satisfactorily respond to lisuride. Dyskinesias were present in all patients during "on" phases, with both levodopa and lisuride treatment.     

Evaluation of sensory stimulation as a treatment for prolonged coma—seven single experimental case studies

Abstract

An earlier paper discussed the results from the four single case studies that evaluated the immediate within-session effects of sensory stimulation for the treatment of patients in prolonged coma (vegetative state). All four patients were found to show behavioural changes, which suggested increased arousal when treated with the version of the procedure known as multimodal stimulation (in which each sense was stimulated in turn in every session). The procedure known as unimodal stimulation (in which just one sense was treated in any session) did not produce any significant behavioural changes in these four patients. This paper presents even further single case experiments, which give a diversity of findings. Three of the patients showed significant behaviour changes, which suggested increased arousal to unimodal stimulation and not to multimodal stimulation, one subject showed apparent decreased arousal in response to unimodal stimulation and no response to multimodal stimulation, one subject showed apparent increased arousal to multimodal stimulation and decreased arousal to unimodal stimulation and two cases showed no significant findings whatsoever. The findings are discussed in relation to the case histories of the patients.