Recurrent falls and mortality in Parkinson's disease: a prospective two-year follow-up study.

OBJECTIVES: To evaluate the risk factors for recurrent falling and mortality in Parkinson's disease (PD) in a prospective study design. MATERIALS AND METHODS: One hundred and twenty-five PD patients were included in the study. Baseline medical data were collected, and patients were clinically tested for mobility and balance. Falls were prospectively recorded for 2 years. Mortality was documented 4 years after the baseline. RESULTS: Seventy-nine patients reported altogether 3125 falls during the follow-up, and 59 patients were classified as recurrent fallers. Altogether 126 fall injuries including six fractures were reported. Eighteen patients had died by the time of the hospital chart review. History of falling (OR 3.02, 95% CI 1.23-7.44) and the Unified Parkinson's Disease Rating Scale activities of daily living score (OR 1.13, 95% CI 1.04-1.22) were independent risk factors for recurrent falling in PD, whereas slow walking speed (OR 16.28, 95% CI 1.85-142.97) was an independent risk factor for mortality in PD. CONCLUSIONS: History of falling and disease severity indicate increased risk of recurrent falls in PD, while patients with slow walking speed may have an increased risk of mortality. Recurrent falling was not associated with increased risk of mortality in PD in this study.

Mobility and balance in Parkinson's disease: a population-based study.

BACKGROUND AND PURPOSE: To assess the clinical correlates of mobility and balance, and to identify the risk factors for falls in Parkinson's disease (PD). METHODS: One-hundred and nineteen PD patients underwent clinical examination and tests for mobility and balance using the Timed Up & Go (TUG) test, walking speed, and the measurement of postural sway. RESULTS: The fallers (35% of the subjects) performed significantly worse in the TUG test than the non-fallers, and they also had a slower walking speed (P = 0.037 and P = 0.006, respectively). The total Unified Parkinson's Disease Rating Scale (UPDRS) score and age were positively associated with the TUG-test score. The severity of the disease and the use of walking aids correlated negatively with the walking speed, whereas the use of dopamine agonists was positively associated with the walking speed. The UPDRS total score [odds ratio (OR) 1.04, 95% confidence intervals (CI) 1.01-1.07] and increased postural sway (OR 1.25, 95% CI 1.02-1.54) were independent risk factors for falling in PD. CONCLUSION: Advanced age and severity of the disease are related to impaired mobility and balance in PD patients. The severity of the disease and increased postural sway seem to be the most important independent risk factors for falling in PD.

Sweating impairment in patients with multiple sclerosis.

OBJECTIVES: To measure sweating in patients with multiple sclerosis (MS). MATERIALS AND METHODS: Sweating was measured by an evaporimeter after a heating stimulus in 29 MS patients and in 15 healthy control subjects. RESULTS: The MS patients sweated markedly less than the controls. After 10 min of heating the sweating was significantly lower in the forehead (P = 0.034), feet (right, P = 0.033; left, P = 0.037) and legs (right, P = 0.043; left, P = 0.029) of the MS patients than in those of the controls. After 15 min of heating the difference was statistically significant only in the feet (right, P = 0.043; left, P = 0.029). The Expanded Disability Status Scale score correlated inversely with sweating at 15 min of heating in the left hand (r = 0.42, P < 0.05), and in the left (r = 0.36, P < 0.05) and right foot (r = 0.37, P < 0.05). CONCLUSIONS: MS is associated with an impairment in thermoregulatory sweating which seems to be related to the disease severity.

Sympathetic skin responses in multiple sclerosis.

OBJECTIVES: This study assessed the sympathetic skin responses (SSRs) and their correlation with brain lesion volumes in patients with multiple sclerosis (MS). MATERIALS AND METHODS: The SSRs were measured in 27 patients with MS and 27 healthy controls. The volumes of the proton density-weighted MS lesions in the brain were measured using MRI. RESULTS: The SSRs were abnormal in 52% of the patients with MS, but absent only in clinically severe MS. The total lesion volume in the whole brain correlated significantly with both the severity of MS expressed by the EDSS score (P < 0.001) and the decreased SSR amplitudes in the feet (P < 0.01). Focal lesion volumes in the temporal lobe (P < 0.01), in the pons (P < 0.01) and in the cerebellum (P < 0.01) were also separately associated with abnormal SSR reflexes. CONCLUSIONS: Sudomotor regulation failure in MS is associated with certain focal MS lesions.

Blood pressure and heart rate in parkinsonian patients with and without wearing-off.

Our study aimed to investigate the cardiovascular autonomic regulation related to the wearing-off phenomenon in Parkinson's disease (PD). We measured blood pressure (BP) and heart rate (HR) at rest and during orthostatic test in 16 patients with PD with wearing-off and in 15 patients with PD without wearing-off both before (baseline) and repetitively at 1-h intervals for up to 4 h after the morning PD medication dose. The patients with wearing-off had fluctuation of BP during the observation period, BP increasing when the motor performance worsened and vice versa. The mean supine BP was at its highest at the baseline measurement (patients with wearing-off, 145 +/- 18 mmHg; patients without wearing-off, 138 +/- 17 mmHg), fell during the first hour (patients with wearing-off, 119 +/- 17 mmHg; patients without wearing-off, 126 +/- 18 mmHg), and then rose again toward the end of the observation period (patients with wearing-off, 136 +/- 15 mmHg; patients without wearing-off, 138 +/- 18 mmHg). This BP change was statistically significant only in PD patients with wearing-off (P < 0.001). In conclusion, BP seems to fluctuate with motor impairment in PD patients with wearing-off. This fluctuation may represent autonomic dysfunction caused by the PD process itself, the effect of PD medication, or both.

A disorder of collagen biosynthesis in patients with cerebral artery aneurysm.

12 patients with subarachnoid hemorrhage due to rupture of a cerebral aneurysm were examined clinically for symptoms and signs of a connective tissue disorder and biochemically for details of the biosynthesis of collagen. No uniform clinical pattern of any connective tissue disorder was seen in these patients, although selected signs were observed. Skin fibroblast cultures were then established. The rate of procollagen production in two cell lines was reduced by 40% and 50%, respectively, and the intracellular accumulation of hydroxy[14C]proline (as a percentage of total hydroxy[14C]proline) was increased by 70% in each relative to eight control cell lines. No difference was found in the degree of intracellular degradation of procollagen. After pulse-labelling, however, the radioactive procollagen was secreted into the medium in 1 h in the control cells, but required at least 3 h in the two aneurysm patient cell lines. The results, thus, suggest that delayed secretion of procollagen rather than increased intracellular degradation led to the reduction in the rate of procollagen synthesis in these two fibroblast lines from patients with cerebral artery aneurysm.

Synthesis of structurally unstable type III procollagen in patients with cerebral artery aneurysm.

The biosynthesis of collagen was studied in skin fibroblast cultures established from 11 patients with cerebral artery aneurysms. Six patients had familial subarachnoid hemorrhage (SAH), while five patients were considered as sporadic cases. The structural stability of the triple-helical medium procollagen was studied by measuring the thermal denaturation temperature (Tm) of type I and type III procollagen molecules. Structural instability of type III procollagen was demonstrated in two patients with familial SAH. The Tm of type III procollagen was 39.0 degrees C and 39.5 degrees C in two of the cell lines, while the control value was 40.3 degrees C. The stability of type I procollagen did not differ from that of the controls, and the main features of the biosynthesis of collagen were similar in the aneurysm patient cell lines and in the controls. The results suggest that a structural defect of type III procollagen may serve as an etiological factor in the formation of cerebral artery aneurysms.

Natriuretic peptides and mortality after stroke.

BACKGROUND AND PURPOSE: Measurement of natriuretic peptides provides prognostic information in various patient populations. The prognostic value of natriuretic peptides among patients with acute stroke is not known, although elevated peptide levels have been observed. METHODS: A series of 51 patients (mean age, 68+/-11 years) with first-ever ischemic stroke underwent a comprehensive clinical examination and measurements of plasma atrial natriuretic peptides (N-ANP) and brain natriuretic peptides (N-BNP) in the acute phase of stroke. The patients were followed-up for 44+/-21 months. Risk factors for all-cause mortality were assessed. Control populations, matched for gender and age, consisted of 51 patients with acute myocardial infarction (AMI) and 25 healthy subjects. RESULTS: Plasma concentrations of N-ANP (mean+/-SD, 988+/-993 pmol/L) and N-BNP (751+/-1608 pmol/L) in the stroke patients were at the same level as those in the AMI patients (NS for both), but significantly higher than those of the healthy subjects (358+/-103 pmol/L, P<0.001 and 54+/-26 pmol/L, P<0.01, respectively). Elevated levels of N-ANP and N-BNP predicted mortality after stroke (risk ratio [RR] 4.3, P<0.01 and RR 3.9, P<0.01, respectively) and after AMI (P<0.05), and remained independent predictors of death after stroke even after adjustment for age, diabetes, coronary artery disease, and medication (RR 3.9, P<0.05 and RR 3.7, P<0.05, respectively). CONCLUSIONS: Plasma levels of natriuretic peptides are elevated in the acute phase of stroke and predict poststroke mortality.

Selegiline as primary treatment in early phase Parkinson's disease--an interim report.

We are carrying out a double-blind parallel trial comparing the effect of selegiline monotherapy and placebo in de novo parkinsonian patients. Fifty-six patients (28 in both groups) are included in the trial. This interim analysis reports the results of the first 52 evaluable patients who have had at least one follow-up visit after entering the trial. The efficacy of treatment was assessed using the Columbia University Rating Scale, the North-Western University Disability Scale and the Webster Rating Scale and followed until the addition of levodopa therapy became necessary. The data were analysed at follow-up times of up to twelve months (34 patients evaluable at the end of the period). The overall disability scores of all the rating scales used were significantly smaller in the selegiline group than in the placebo group. Levodopa treatment had become necessary in 12 patients (46%) in the selegiline group and in 14 patients (54%) in the placebo group. The side-effects were mild and similar in both treatment groups. According to the present results selegiline monotherapy seems to have therapeutic efficacy in the early phase of Parkinson's disease. Whether selegiline is able to slow down the progression of Parkinson's disease needs further clarification.

Selegiline as a primary treatment of Parkinson's disease.

In order to investigate the efficacy of selegiline as a primary treatment in Parkinson's disease (PD), we carried out a placebo controlled, double-blind prospective trial. Fifty-four de novo patients with PD were randomized to receive either selegiline (10 mg/day) or matching placebo. We continued the monotherapy until the initiation of levodopa therapy became necessary. The disability of the patients was evaluated with three different rating scales at baseline, after 3 weeks, 2, 4, 8, and 12 months, and every 4 months thereafter. Fifty-two patients were eligible for the final analysis: 27 in the selegiline group and 25 in the placebo group. The median duration of time without levodopa was 545 +/- 90 days in the selegiline treated patients and 372 +/- 28 days in the placebo treated ones (p = 0.03). The disability of the patients was significantly milder in the selegiline than in the placebo group up to 12 months. More patients showed symptomatic improvement in the selegiline than in the placebo group. However, the symptomatic effect alone did not explain the prolongation of the time without levodopa in the selegiline treated patients. Selegiline was well tolerated and no severe side effects were encountered.

Pharmacokinetics and metabolism of selegiline.

Selegiline is readily absorbed from the gastrointestinal tract. It is distributed rapidly into the tissues, including the brain. It is the L-form of selegiline that is an active MAO-B inhibitor, the D-(+)-form being 25 times less active. Selegiline is metabolised into L-(-)-desmethylselegiline (DES), L-(-)-amphetamine (A) and L-(-)-methamphetamine (MA), mainly in the liver. We measured the steady state concentrations of the metabolites in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's or Alzheimer's diseases who were on continuous selegiline therapy. The mean concentrations in serum and CSF were similar, and were not affected by the addition of levodopa. The mean concentrations of patients with Alzheimer's or Parkinson's disease were 6.5 +/- 2.5 ng/ml for A, 14.7 +/- 6.5 ng/ml for MA and 0.9 +/- 0.7 ng/ml for DES. The metabolites of selegiline were excreted in urine, and the recovery as metabolites was 87%. Due to the stereospecificity and the low CSF concentrations of the (-)amphetamine metabolites during the therapy with 10 mg selegiline, these metabolites do not seem to contribute significantly to the clinical efficacy of selegiline.

Serum lipid levels during carbamazepine medication. A prospective study.

OBJECTIVE: The aim of the study was to evaluate serum lipid levels during carbamazepine medication. DESIGN: A 5-year prospective follow-up study. SETTING: Outpatient department, University Central Hospital of Oulu (Finland). PATIENTS: Thirty-six consecutive untreated patients with recently diagnosed idiopathic epilepsy. All patients completed the 1-year follow-up, and 19 patients completed the 5-year follow-up. INTERVENTIONS: The patients were treated with carbamazepine for their newly diagnosed seizure disorder. MAIN OUTCOME MEASURES: Serum lipid levels were followed up during the medication use. RESULTS: Serum total cholesterol and high-density lipoprotein cholesterol concentrations increased after 2 months of treatment with carbamazepine and remained high after 1 and 5 years. Furthermore, concentrations of serum low-density lipoprotein cholesterol and triglycerides increased transiently during the first year of medication. The increase in serum total cholesterol levels correlated with an increase in serum gamma-glutamyltransferase concentrations. CONCLUSIONS: Serum lipid levels change during carbamazepine medication; the increase in serum concentrations of total cholesterol and high-density lipoprotein cholesterol seems permanent, but the increase in serum low-density lipoprotein cholesterol and triglyceride levels is transient. The change in lipid metabolism may be associated with induction of the liver enzymes during carbamazepine medication. The increase in serum cholesterol and high-density lipoprotein cholesterol levels may have clinical relevance with regard to the incidence of atherosclerosis and coronary heart disease in patients with epilepsy receiving carbamazepine medication.

Thyroid function in epileptic patients treated with carbamazepine.

The effects of carbamazepine monotherapy on thyroid function were evaluated in patients with epilepsy. A prospective follow-up of 40 patients with recently diagnosed epilepsy was carried out to evaluate the short-term effects. Thirty-three patients receiving long-term carbamazepine therapy (average duration, 4.2 years) and 34 healthy control subjects were studied. Levels of serum thyroxine, free thyroxine, and thyroxine binding globulin were decreased after both 2 and 12 months of therapy with carbamazepine. Low serum thyroxine and free thyroxine concentrations were also found after long-term monotherapy with carbamazepine. Baseline thyrotropin did not change during carbamazepine therapy, but thyrotropin responses to thyrotropin-releasing hormone rose slightly. No correlation was found between serum carbamazepine and hormone concentrations. The results not only support previous suggestions that carbamazepine induces the hepatic clearance of thyroid hormones but also suggest that carbamazepine may have an inhibitory effect at the hypothalamic level.

Changes in collagen metabolism in diseased muscle. II. Immunohistochemical studies.

Immunofluorescence studies using specific antibodies against collagen of types I, III, IV, and V were carried out on muscle biopsy specimens from 22 patients with various neuromuscular disorders and seven controls. Increased staining with all antibodies was seen in the patients with polymyositis and muscular dystrophy. Increased staining with types I and III antibodies was found in the samples from the patients with amyotrophic lateral sclerosis in cases with an elevated concentration of muscular hydroxyproline. Two patients with amyotrophic lateral sclerosis showed no accumulation of collagen, and this was similarly true of the polyneuropathy cases. An accumulation of types IV and V collagen was typical for the myotonia congenita samples. The immunohistochemical results were in good agreement with the biochemical findings from the same patients.

Changes in collagen metabolism in diseased muscle. I. Biochemical studies.

Possible changes in collagen biosynthesis were studied in 50 patients with neuromuscular disorders and 14 controls. Type III procollagen aminoterminal propeptide concentrations and galactosylhydroxylysyl glucosyltransferase (GGT) activities were assayed in serum, and prolyl 4-hydroxylase and GGT activities were assayed in muscle biopsy specimens. All four assays showed significantly elevated values in cases of polymyositis, adult forms of muscular dystrophy, and amyotrophic lateral sclerosis, the concentration of muscular collagen also being significantly increased in the last two conditions. Some abnormalities were also seen in polyneuropathy, myotonia congenita, and undefined myopathy. High correlations were found among the values for the four assays, but no marked correlations with muscular collagen concentration or enzyme activities characteristic of neuromuscular disorders were found. The four assays may reflect changes in actual collagen synthesis in the diseased muscle.

Muscle-specific carbonic anhydrase III is a more sensitive marker of muscle damage than creatine kinase in neuromuscular disorders.

Serum concentration of carbonic anhydrase III (S-CA III), a novel marker of type I skeletal muscle cells was measured in 37 patients with neuromuscular diseases (polymyositis, muscular dystrophies, amyotrophic lateral sclerosis, and other neurogenic diseases) and in 24 control patients. Significant elevation in S-CA III was observed in all patient groups. Serum concentration of carbonic anhydrase III correlated positively with serum-creatine kinase. Serum concentration of carbonic anhydrase III was observed to be a more sensitive skeletal muscle marker both in myogenic and in neurogenic muscle affecting diseases than serum creatine kinase.

Lysosomal and nonlysosomal hydrolases of skeletal muscle in neuromuscular diseases.

The activities of four lysosomal and two nonlysosomal hydrolases were studied in skeletal muscle biopsy samples from patients with neuromuscular diseases and from controls. beta-Glucosaminidase activity was increased in polymyositis. beta-Glucuronidase and alkaline protease activities were elevated in muscular dystrophy in adults, whereas cathepsin D activity was increased in amyotrophic lateral sclerosis. There were significant correlations between the activities of lysosomal and nonlysosomal hydrolases. The activity of beta-glucuronidase, beta-glucosaminidase, alkaline protease, and dipeptidyl aminopeptidase IV showed a positive correlation with the severity of muscular atrophy. The activities of these hydrolases and the activity of dipeptidyl aminopeptidase I correlated positively with the activities of muscular galactosylhydroxylysyl glucosyltransferase and with the serum concentration of type III procollagen aminoterminal propeptide. The results suggest that in neuromuscular diseases the lysosomal and nonlysosomal pathways for muscle degradation are affected concomitantly with collagen biosynthesis.

Serum hormones in male epileptic patients receiving anticonvulsant medication.

Circulating sex and thyroid hormones, as well as the pituitary function, were assessed in 63 male patients with epilepsy receiving either a single medication of carbamazepine, phenytoin, or valproate or a combination of carbamazepine plus phenytoin or carbamazepine plus valproate. All therapeutic regimens, including carbamazepine and/or phenytoin were associated with low levels of circulating thyroxine (T4), free thyroxine (FT4), and dehydroepiandrosterone sulfate, and with low values for the free androgen index, and phenytoin and carbamazepine plus phenytoin were associated with high serum concentrations of sex hormone-binding globulin. These hormone parameters were unaffected by valproate monotherapy. It seems probable that accelerated hormone metabolism is responsible for the hormonal changes found in patients treated with carbamazepine and/or phenytoin. However, every drug regimen studied also had depressant and/or stimulatory effects on the function of the hypothalamic-pituitary axis. The diverse endocrine effects of different antiepileptic drug regimens should be considered when starting antiepileptic drug therapy.

Asymmetric sweating in stroke: a prospective quantitative study of patients with hemispheral brain infarction.

We performed a prospective study of sweating in 40 patients with hemispheral brain infarction and 40 healthy controls to elucidate the clinical significance and prognostic value of sweating dysfunction in conjunction with brain infarction. We measured hidrosis quantitatively at six sites on each side of the body before and after a heating stimulus in the acute phase, at 1 month, and at 6 months after infarction. Excessive evaporation on the paretic side when compared with the nonparetic side was already found at baseline, but after the heating stimulus, this asymmetry reached statistical significance on the forehead, chest, forearm, and hand during the whole 6-month follow-up. Significant asymmetry in sweating occurred in 29 of the 40 patients (73%) in the acute phase of infarction, in 18 of 32 (56%) after 1 month, and in 28 of 33 (85%) after 6 months. Hyperhidrosis correlated with the severity of paresis and the presence of pyramidal tract signs. We conclude that sweating asymmetry seems to be an essential, long-lasting consequence of autonomic failure occurring in the majority of patients with hemispheral brain infarction.

Selegiline diminishes cardiovascular autonomic responses in Parkinson's disease.

Selegiline (L-deprenyl), a selective inhibitor of monoamine oxidase type B, is an established adjuvant to levodopa therapy in Parkinson's disease (PD). To evaluate whether selegiline also effects the severity and progression of autonomic nervous system dysfunction in PD, we studied autonomic functions by measuring cardiovascular responses to normal breathing, deep breathing, the Valsalva maneuver, the tilting test, and the isometric contraction test prospectively in 52 PD patients receiving either selegiline (n = 27) or placebo (n = 25) in randomized order in a double-blind parallel trial. The study also continued double-blind after the introduction of levodopa. Recordings of cardiovascular responses were carried out annually, with the median follow-up period being 6 years. Cardiovascular autonomic reflexes were diminished in the patient groups compared with those of healthy control subjects (n = 45). There was no progression (except age-related) in dysautonomia in patients on placebo, but there was a decrease in cardiovascular responses in the selegiline group. The heart rate variability in normal breathing, in the Valsalva maneuver, and in the tilting test was clearly diminished during the selegiline treatment. In addition, in the tilting test, the fall in diastolic blood pressure immediately after tilting and in systolic blood pressure 2 minutes after standing up was more pronounced in the selegiline group than in the placebo group. Levodopa treatment had no effect on the measured autonomic responses. In the isometric contraction test, the two treatment groups showed no difference. We conclude that selegiline treatment diminishes autonomic responses, especially those of the sympathetic division. This sympatholytic effect may signal an increased risk of orthostatic hypotension.