Manganese-induced parkinsonism in methcathinone abusers: bio-markers of exposure and follow-up.

BACKGROUND AND PURPOSE: Methcathinone abuse is a new cause of manganism. The psychostimulant is prepared from pseudoephedrine using potassium permanganate as an oxidant. We describe the clinical, biological, neuroimaging characteristics and follow-up results in a large Estonian cohort of intravenous methcathinone users. METHODS: During 2006-2012 we studied 38 methcathinone abusers with a mean age of 33 years. Subjects were rated by the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (HY), and Schwab and England (SE) rating scales. Twenty-four cases were reassessed 9-70 (20 ±â€…15) months after the initial evaluation. Manganese (Mn) in plasma and hair was analysed by inductively coupled plasma-atom emission spectrometry. Magnetic resonance imaging (MRI) was performed in 11, and single-photon emission computed tomography (SPECT) with iodobenzamide (IBZM) in eight subjects. RESULTS: The average total UPDRS score was 43 ±â€…21. The most severely affected domains in UPDRS Part III were speech and postural stability, the least affected domain was resting tremor. At follow-up there was worsening of HY and SE rating scales. Subjects had a higher mean level of Mn in hair (2.9 ±â€…3.8 ppm) than controls (0.82 ±â€…1.02 ppm), P = 0.02. Plasma Mn concentrations were higher (11.5 ±â€…6.2 ppb) in active than in former users (5.6 ±â€…1.8 ppb), P = 0.006. Active methcathinone users had increased MRI T1-signal intensity in the globus pallidus, substantia nigra and periaquaductal gray matter. IBZM-SPECT showed normal symmetric tracer uptake in striatum. CONCLUSION: Methcathinone abusers develop a distinctive hypokinetic syndrome. Though the biomarkers of Mn exposure are characteristic only of recent abuse, the syndrome is not reversible.

Frequent administration of levodopa/carbidopa microtablets vs levodopa/carbidopa/entacapone in healthy volunteers.

OBJECTIVES: An oral dispersible microtablet formulation of levodopa/carbidopa 5/1.25 mg (LC-5) was developed for individualized repeated dosing. The aim was to compare pharmacokinetic profiles of LC-5 and levodopa/carbidopa/entacapone (LCE). MATERIALS AND METHODS: A randomized, crossover study was carried out in 11 healthy subjects. Plasma concentrations of levodopa, carbidopa and 3-O-methyldopa were determined after intake of 300 mg levodopa during the day, either as three intakes of 100/25/200 mg LCE or as a morning dose of 75/18.25 mg followed by five repeated doses of 45/11.25 mg LC-5. RESULTS: Repeated dosing (2.4-hourly) with LC-5 microtablets compared to LCE (6-hourly) avoided long periods with low plasma levodopa levels. Time to maximum plasma concentrations was significantly shorter for LC-5. LC-5 showed lower fluctuation index (FI) in plasma compared to LCE (ANOVA P = 0.0028). FI for dose 2-5 was on average 1.26 for levodopa in LC-5, and 2.23 for dose 1-2 of LCE. The ratio between the two mean FI:s is 0.565; that is, LC-5 gave nearly half the FI as compared to LCE. CONCLUSIONS: Fractionation of levodopa with LC-5 into small, frequent administrations as compared to standard administrations of LCE decreased the FI in plasma for both levodopa and carbidopa by nearly half.

Clinical, neuroimaging and neurophysiological features in addicts with manganese-ephedrone exposure.

OBJECTIVE: To identify biomarkers supporting the clinical diagnosis of manganism in patients several years after exposure to manganese (Mn). METHODS: Neurophysiological examinations, magnetic resonance imaging (MRI), single-photon emission computed tomography and fluorodeoxyglycose (FDG) positron emission tomography were performed in four former ephedrone addicts with extrapyramidal symptoms. RESULTS: Peripheral nervous system was not affected. No patients had reduced uptake of (123)I Ioflupane in the striatum. MRI signal intensities were slightly changed in the basal ganglia. All patients showed a widespread, but not uniform, pathological pattern of FDG uptake with changes mainly located to the central part of the brain including the basal ganglia and the surrounding white matter. CONCLUSIONS: Presynaptic neurons in the nigrostriatal pathway are intact in Mn-induced parkinsonism after prolonged abstinence from ephedrone. The diagnosis is principally based on clinical signs and the history of drug abuse.

Impact of dystonia on quality of life and health in a Swedish population.

OBJECTIVES: Dystonia is often disabling and disfiguring. The aim of the study was to identify factors influencing the impact of dystonia on self-reported quality of life and health. MATERIAL AND METHODS: Members of the Swedish Dystonia Patient Association participated in a survey covering demographic variables, satisfaction with treatment, physiotherapy and physical activity. Quality of life and health were assessed by the Craniocervical Dystonia Questionnaire and the Cervical Dystonia Impact Profile, respectively. Of 378 questionnaires, 76% were analysed. Multiple linear regression analyses were performed to evaluate associations of the above variables with quality of life and health. RESULTS: Level of physical activity and satisfaction with treatment showed the highest association with quality of life and health. No significant relationship was found between form of dystonia and quality of life. CONCLUSIONS: The study indicates a need for health care professionals to encourage physical activity and to question dystonia patients about satisfaction with treatment. Further investigations with prospective controlled trials are necessary to evaluate the value of physiotherapy and physical activity in patients with dystonia.

Irreversible motor impairment in young addicts--ephedrone, manganism or both?

BACKGROUND: Parkinsonian syndrome related to intravenous use of a "designer" psychostimulant, derived from pseudoephedrine using potassium permanganate as the oxidant, has been observed in drug addicts in Estonia. OBJECTIVE: To describe the symptomatology of four young patients, history of drug administration and chemical analysis of a drug batch. METHODS: Mental and motor function and quality of life were scored and ephedrone was analyzed using electrospray mass spectrometry. Manganese content of the final synthetic mixture was analyzed using Inductively Coupled Plasma-Atomic Emission Spectrometry. RESULTS: None of the four cases scored below the dementia threshold in MMSE, while other ratings (UPDRS, H&Y, PDQ-39) corresponded to disabilities seen in relatively advanced Parkinson's disease. The ephedrone yield of the reaction was approximately 44% and the mixture was found to contain 0.6 g/l of manganese. CONCLUSIONS: The cases were exposed to extreme manganese load. Their symptomatology is probably identical to manganism. The role of ephedrone is presently unknown. Physicians must be aware of early signs of manganism in patients within social risk groups.

Objective assessment of cervical dystonia: a pilot study.

OBJECTIVES: The aims were to characterize the movements in cervical dystonia (CD) by using an estimate of the mechanical power and work involved in the movements and to describe this through a movement energy index (MEI). MATERIALS AND METHODS: The subjects (patients n = 6, controls n = 6) were seated in front of a screen with a laser pointer attached to a headband while they performed standardized movements. A three-dimensional motion capture system was used and a test-retest was performed. RESULTS: The mean value of MEI was significantly higher for the patients than for the controls. There was no significant difference between MEI from test to retest for the patients but there was a significant difference between MEI from test to retest for the controls. CONCLUSION: This study suggests that MEI could be a useful measure for the quantification of movement dysfunction in CD and thus an objective outcome measure in comparison of different therapies.

Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease.

OBJECTIVES: To compare daytime intraduodenal levodopa/carbidopa infusion as monotherapy with individually optimized conventional combination therapies in patients with advanced Parkinson disease (PD) for motor fluctuations and quality of life (QoL). METHODS: Twenty-four patients with motor fluctuations and dyskinesia were studied in a randomized crossover design to compare individualized conventional treatment and intraduodenal infusion of a levodopa/carbidopa gel for 3 + 3 weeks. Video scoring of motor function was assessed by blinded assessors on a global Treatment Response Scale from -3 to 0 to +3 (from severe "off" to "on" to "on" with severe dyskinesia). Patient self-assessment of motor performance and QoL was done using an electronic diary. RESULTS: Median percentage of ratings in a functional "on" interval (-1 to +1) was increased from 81 to 100% by infusion therapy (p < 0.01). This improvement was accompanied by a decrease in "off" state (p < 0.01) and no increase in dyskinesia. Median Unified Parkinson's Disease Rating Scale score decreased from 53 to 35 in favor of infusion (p < 0.05). QoL was improved, using the two instruments: Parkinson's Disease Questionnaire-39 and 15D Quality of Life Instrument (p < 0.01). Adverse events were similar for both treatment strategies. CONCLUSIONS: Continuous intraduodenal infusion of the levodopa/carbidopa enteral gel as monotherapy is safe and clinically superior to a number of individually optimized combinations of conventional oral and subcutaneous medications in patients with motor fluctuations. Intraduodenal infusion of levodopa offers an important alternative in treating patients with advanced Parkinson disease.

Increased red blood cell polyamines in ALS and Parkinson's disease.

The polyamines spermidine (SPD) and spermine (SPM) are implicated in nerve cell degeneration and regeneration. Over 70% of circulating polyamines are associated with red blood cells (RBC). Against this background we have analysed RBC polyamines in two neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Twenty patients with the sporadic form of ALS, 20 patients with PD, and 20 healthy controls were studied. The highest levels of SPD and SPM were found in the PD group where the mean values were 134 and 115%, respectively, above those of the controls. The patients with PD also presented the lowest levels of the SPD precursor, putrescine (PUTR). In the patients suffering from ALS the SPD and SPM mean levels were increased by 46 and 112%, respectively. The RBC SPD/SPM ratio in the patients suffering from PD was significantly elevated in comparison with that of ALS patient group, suggesting a different involvement of the polyamine system in these disorders. It is at present unknown if raised polyamine levels may contribute to induce the degeneration of susceptible neurons or if the increase represents a compensatory protective reaction, or simply an unspecific epiphenomenon.

Amyotrophic lateral sclerosis: evidence for intact hepatocyte growth factor/met signalling axis.

Hepatocyte growth factor (HGF) is a secreted cytokine which is expressed in the central nervous system (CNS) together with its specific receptor MET. Since HGF exerts strong neurotrophic activity including motoneurons, we have further analysed whether the HGF/MET axis is defective in patients with amyotrophic lateral sclerosis (ALS). Intrathecal HGF-secretion was measured in cerebrospinal fluid (CSF) from patients with amyotrophic lateral sclerosis and in controls without neurological diseases using a specific sandwich immunoassay (ELISA). MET-expression was analysed by immunohistology in spinal cord cross-sections of ALS patients and unaffected controls. The HGF concentrations in CSF were moderately but significantly increased in ALS patients compared to healthy controls (580 pg/ml vs 348 pg/ml). MET-protein was detectable in spinal cord motoneurons of patients with ALS as well as unaffected controls. The data demonstrate that ALS does not show a lack of the trophic signalling axis, HGF/MET, suggesting that the signalling system itself is not affected. The moderate increase in HGF-secretion may represent a compensatory effect.

High 3H-vesamicol binding in ALS motor neurons--autoradiographic visulalization of hyperactivities?

OBJECTIVES: To evaluate if increased metabolic demand in remaining motor neurons in ALS spinal cord sections can be visualized by 3H-vesamicol binding. MATERIAL AND METHODS: As a presumed marker of the vesicular acetylcholine transporter, 3H-vesamicol was applied in quantitative autoradiography in cervical spinal cord sections from 11 ALS patients and 4 control cases. The regional binding was compared to that of the muscarinic ligand 3H-QNB. RESULTS: Our results demonstrate the same magnitude of H-vesamicol binding in the ventral horn of ALS spinal cord as compared to controls, despite the profound loss of motor neurons in that specific area in ALS. The specificity of 3H-vesamicol binding for the cholinergic transporter is high in the motor neuron area, and sigma-sites constitute a minor proportion. CONCLUSION: The lack of decrease in 3H-vesamicol binding in postmortem ALS spinal cord sections probably reflects an upregulated synthesis of vesicular membranes in remaining and hyperactive motor neurons in vivo.

Duodenal levodopa infusion in Parkinson's disease--long-term experience.

Motor fluctuations in parkinsonian patients can be reduced by intraduodenal infusion of levodopa. Between 1991 and 1998 continuous daytime administration of levodopa through a transabdominal port has been used in 28 very advanced patients over a total period of 1045 months. A stable suspension of levodopa and carbidopa (Duodopa) has been developed. Patients were characterized by early onset, long history of disease and levodopa therapy. The reason for infusion was in all cases related to on-off fluctuations. All patients experienced a general improvement after the introduction of continuous treatment. There have been no severe complications. Six patients have taken the decision to curtail their treatment. The mean daily levodopa consumption has been slightly reduced on infusion as compared to oral therapy. Nine of the first group of patients participating in the new therapy have been regularly evaluated by means of rating scales and movement analyses. Short-term results have already been published and a follow-up showing continued positive effect after 4-7 years of continuous duodenal infusion is presented.

Gender differences in Parkinson's disease symptom profile.

Gender symptom differences were studied in 948 subjects with Parkinson's disease (PD) using a questionnaire covering the most common symptoms associated with PD at debut (SP-1) and at present (SP-2). The symptoms most frequently reported by both genders were: tremor, fumblingness, writing problems, rigidity and fatigue. At SP-1 females reported neck-pain and low back pain more frequently than males. At SP-2 subjects reported an increased number of symptoms. The following symptoms were more frequent among males than females: writing difficulties, fumblingness, gait problems, speech problems, increased flow of saliva, lack of initiative. Sleep problems were common in both sexes with inability to turn in bed and calf muscle cramps in a high percentage. A majority of female subjects find their symptoms (e.g. depression) constantly distressing. Although depression is not one of primary reported symptoms (36%) attention is called for, due to the problem with compliance to treatment regimes. About 30% do not report having tremor and rigidity. This study indicates the usefulness of a symptom profile instrument capable of capturing the many symptoms involved in PD. Such an instrument could be used to detect apparent mistakes in medication and thereby increase the function and quality of life for the individual.

A comparative study of methionine adenosyltransferase activity and regional distribution in mammalian spinal cord.

To provide a background for future studies on neurodegenerative changes in the spinal cord, the present study analysed the distribution of the activity of methionine adenosyltransferase (ATP:L-methionine S-adenosyltransferase, EC 2.5.1.6, MAT), an enzyme that catalyses the synthesis of the biological methyl group donor S-adenosylmethionine (AdoMet), in spinal cords from bovine and pig, and compared the results with those from human spinal cord. The enzyme activity was estimated by a radiochemical method measuring the rate of formation of [(3)H]AdoMet from L-[methyl-(3)H]methionine and ATP. The MAT activity (V(max)) was quite homogeneously distributed between spinal regions and species investigated (19-50 pmol [(3)H]AdoMet/mg protein/minute), with the highest level found in the male bovine group. The bovine group (both males and females) also presented a 20% higher enzymatic activity in the dorsal horn as compared to the ventral horn and white matter areas. In the pig spinal cord, the highest level of activity was found in the white matter. The lowest affinity for methionine (highest K(m)) was found in the human spinal cord. Whole spinal cords of one cat and one rhesus monkey were also analysed and the levels of MAT activity were similar to that of humans and bovine females, respectively. Studies of MAT stability in the rat spinal cord (post-mortem time 0-72 hr) showed a significant decrease in enzyme activity during the interval of 0-8 hr (23 degrees ). From this time point on and up to 72 hr (4 degrees ), the significant decrease in the activity remained at 60% of the initial value.

Palmar and axillary hyperhidrosis treated with botulinum toxin: one-year clinical follow-up.

Focal hyperhidrosis is a common and sometimes handicapping condition for which the presently most effective treatment, sympathectomy, often leads to irreversible side-effects. We aimed to study effectiveness and tolerability of an alternative treatment with botulinum toxin injections over a period of one year for this condition. Twenty-eight patients with palmar (n = 19) and/or axillary (n = 13) hyperhidrosis were treated with intracutaneous injections of botulinum toxin (Botox(R)) 2 U/4 cm2. Sweat function was studied clinically and by objective measurements after treatment of one side. Treated and untreated sides, and pre- and post-treatment skin areas were compared. Subjective evaluation was performed after treatment of one side and 2-5 months after treatment of both sides. Duration of effect was controlled by a one-year follow-up. Sweating disappeared in eight out of 13 patients with axillary and in five out of 19 with palmar hyperhidrosis, and was reduced markedly in another five out of 13 and 10 out of 19 patients. Two-thirds of those treated for hand sweat noticed a slight and transient reduction of power of finger grip. No side-effects were noticed after treatment of axillary hyperhidrosis. We find intracutaneous injections of botulinum toxin with this technique safe and effective, and due to the relatively long duration of effect the treatment should be recommended before sympathectomy for focal hyperhidrosis.

Upregulation of Bax protein and increased DNA degradation in ALS spinal cord motor neurons.

OBJECTIVES: To investigate if degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is related to altered levels of the apoptosis regulating proteins Bcl-2 and Bax. In addition, immunoreactivity of the cysteine protease ICH-IL and detection of motor neurons with DNA fragmentation, indicative of apoptosis, was also studied. MATERIAL AND METHODS: The immunoreactivity of Bcl-2, Bax and ICH-1L were compared in ALS and control spinal cord motor neurons by immunohistochemical analysis and motor neurons with DNA fragmentation were identified by the TUNEL-method. RESULTS: The results demonstrate an increased expression of Bax in the ALS material as compared to controls but no change in Bcl-2 and ICH-1L expressions. Moreover, a larger proportion of motor neurons stained positive for TUNEL in ALS spinal cords. CONCLUSION: Present study suggest an upregulation of the cell death promoting protein Bax and increased DNA degradation, indicative of apoptosis, in spinal motor neurons of ALS patients.

Methionine adenosyltransferase activity in erythrocytes and spinal cord of patients with sporadic amyotrophic lateral sclerosis.

The role of transmethylation mechanisms in the etiology of amyotrophic lateral sclerosis (ALS) is hitherto unexplored. The activity of L-methionine S-adenosyltransferase (MAT), a regulatory enzyme of S-adenosylmethionine biosynthesis, was investigated in erythrocytes of 21 patients with ALS, spinal cord specimens of 7 ALS patients, and matched controls. In ALS patients the activity of MAT in erythrocytes was sex-dependent. In comparison with controls, the male group presented a 33% higher V(max) (P < 0.05) and a 41% decrease in the affinity of MAT for methionine (K(m), P < 0.05). The type of ALS onset (limb or bulbar), age, or duration of the disease did not influence erythrocyte MAT activity. In the spinal cord, the activity of MAT was homogeneously distributed through dorsal horn, ventral horn, and white matter. Comparisons between data from controls and ALS patients and analysis of sex effect showed no significant differences. The kinetic difference of erythrocyte MAT in the male group of ALS patients might be interesting to explore since it is well known that there is a male predominance of 1.5 to 2. 5:1 in ALS.

Increased expression of glial cell line-derived neurotrophic factor mRNA in muscle biopsies from patients with amyotrophic lateral sclerosis.

The expression of glial cell line-derived neurotrophic factor (GDNF) mRNA and brain-derived neurotrophic factor (BDNF) mRNA were studied in muscle biopsies from five patients with amyotrophic lateral sclerosis (ALS), six patients with other neuromuscular diseases and eight healthy control persons. All five patients with ALS had higher GDNF mRNA expressions in their biopsies than the healthy control group (almost a three fold increase). Among the other patients only one, who had a rapidly progressing toxic polyneuropathy, showed a GDNF mRNA expression above those of the controls. The BDNF mRNA expressions in the biopsies from the ALS patients were in the same range as those from the healthy controls, although the mean value of the ALS patients was higher. The only biopsy that showed a markedly higher BDNF mRNA expression was taken from one patient with progressive muscular atrophy. These results suggest that increased GDNF mRNA expression in muscle is an unspecific response to ongoing denervation and that this response is maintained in ALS, at least temporarily. If increased GDNF mRNA in muscle proves to be a constant finding in ALS the rationale for the use of GDNF as a therapeutic agent in ALS must be questioned.

Absorption of L-DOPA from the proximal small intestine studied in the rhesus monkey by positron emission tomography.

Positron emission tomography (PET) seems to be a valuable method for the understanding of intestinal absorption mechanisms, for simultaneous quantitation of absorption rate and distribution kinetics to the tissues of interest after oral drug delivery. PET was evaluated in three Rhesus monkeys for quantitation of the absorption rate from the gastrointestinal tract and the distribution kinetics into different organs. To obtain optimal standardized conditions for the measurement of absorption the drug was administered via a naso-duodenal catheter directly to the absorption site in the proximal small intestine. l-DOPA was used as study drug given in a suspension together with carbidopa and the radiomarker l-[beta-11C]DOPA. The l-DOPA suspension was given into the duodenum without and after administration of a suspension of six l-amino acids (120 mM) in order to investigate any interaction on the intestinal absorption and distribution of l-DOPA into the liver and brain tissue. Intestinal absorption was in general minor during the first study period and higher together with administered l-amino acids. The somewhat contradictory result with increased absorption when amino acids were present in the intestinal lumen, may be a consequence of increased intestinal motility initiated by the nutrient load.