Randomized trial of 4-aminopyridine in patients with chronic incomplete spinal cord injury.

OBJECTIVE: To test the efficacy of 4-aminopyridine (4-AP) on functional status, walking speed and vibration perception in patients with chronic, incomplete spinal cord injury. METHODS: Twenty SCI patients were randomized in a trial with a double-blind, crossover design to receive four weeks of orally administered 4-AP, followed by a two-week wash-out period and four weeks of placebo, or vice versa. The total daily dose of 4-AP during the four weeks of treatment was systematically increased to a maximum of 0.5 mg/kg body weight. Evaluation of (side-)effects took place at the beginning, after one week, and at the end of each four-week study period. RESULTS: No significant benefit was found on functional status (COOP-WONCA). A statistically significant treatment effect was found on the vibration perception threshold (VPT) in the left fingers, during the first study period. On average, patients receiving 4-AP treatment responded less favourably (mean increase in VPT of 0.29 (0.31) microm) than patients receiving placebo (mean decrease in VPT of 0.05 (0.35) microm) (p=0.04). Neither comfortable nor maximum walking speed altered significantly following 4-AP treatment. CONCLUSIONS: No statistically significant, functional benefit from 4-AP was found for patients in the present study. Furthermore, no support was found for the possibility that an a priory selection of responsive patients would have yielded more favourable results.

Glucose tolerance and other determinants of cardiovascular autonomic function: the Hoorn Study.

AIMS/HYPOTHESIS: Currently, three categories of measures are used to assess cardiovascular autonomic dysfunction: measures of the Ewing-test, measures of heart-rate variability, and measures of baroreflex sensitivity. We studied the determinants of these measures obtained from cardiovascular autonomic function tests in the Hoorn Study. METHODS: The study group (n = 631) consisted of a glucose-tolerance-stratified sample from a 50- to 75-year-old group of people. Cardiac cycle duration (RR interval) and continuous finger arterial pressure were measured under three conditions: during (a) spontaneous breathing, (b) six deep breaths over one minute, and (c) an active change in position from lying to standing. From these readings, ten measures of autonomic function were assessed (three Ewing, six heart-rate variability and one baroreflex sensitivity). As possible determinants we considered age, sex, glucose tolerance, cardiovascular disease, use of anti-hypertensive drugs, anthropometric factors, metabolic factors and lifestyle factors. RESULTS: Multivariate analysis showed that eight of ten cardiovascular autonomic function measures were most strongly associated with glucose tolerance. Furthermore, measures were moderately associated with age, sex, waist-to-hip ratio, use of anti-hypertensive drugs, and insulin. The measures were weakly associated with coronary artery disease but not with lipids. The strongest determinants seemed to differ between subjects with and without diabetes: in the non-diabetic subjects the most strongly associated were age and use of anti-hypertensive drugs and in subjects with diabetes, insulin. No consistent differences in association between the three categories of measures were observed. CONCLUSION/INTERPRETATION: The strongest determinants of autonomic function were age, presence of diabetes and use of anti-hypertensive drugs.

Methods for assessing diabetic polyneuropathy: validity and reproducibility of the measurement of sensory symptom severity and nerve function tests.

The usefulness of sensory symptoms in the assessment of diabetic polyneuropathy is unclear. In the present study, we studied the hypothesis that pain is associated with small nerve fibre function, and that sensory alteration is associated with large nerve fibre function. In addition, we assessed the reproducibility and the ability to detect changes in clinical status over time of the nerve function tests currently used in clinical trials. Patients (78) with stable diabetic polyneuropathy were examined on three separate occasions with a test-retest interval of 17 and 52 weeks. Small nerve fibre function was measured using temperature discrimination thresholds for warmth (TDTwarmth) and cold (TDTcold). Large nerve fibre function was measured by testing sensory and motor nerve conduction velocities (SNCV and MNCV) and vibration perception thresholds (VPT). Neuropathic pain was only significantly associated with TDTcold, and with the MNCV of the tibial nerve. Sensory alteration was associated with almost all nerve function tests except the SNCV and MNCV of the ulnar nerve. The measurements of symptom severity and the nerve function tests all proved to be sufficiently reproducible. The standardized smallest detectable difference on group level (SDD) of the measurement of sensory alteration and neuropathic pain were almost the same (9% and 12%, respectively). Among the nerve function tests, the SNCV and MNCV had the smallest SDD (3-4%), and were, therefore, potentially the most responsive instruments. The SDD of the TDT was greater than the VPT (9-14% vs 21-28%, respectively). In conclusion, neuropathic pain was not associated with small nerve fibre function, and sensory alteration was associated with both large and small fibre function. In addition, the standardized measurement of symptom severity, the SNCV and MNCV tests, and the VPT test appear to be useful for monitoring the course of polyneuropathy in clinical trials.

Hyperhomocysteinaemia is not related to risk of distal somatic polyneuropathy: the Hoorn Study.

OBJECTIVE: Distal somatic polyneuropathy is a major contributing factor in the pathogenesis of chronic foot infections and ulcers, and may lead to lower limb amputations. Both metabolic and vascular abnormalities may contribute to the development of impaired nerve function. We therefore assessed the association between hyperhomocysteinaemia, a risk factor for cardiovascular disease, and polyneuropathy. DESIGN, SETTING AND SUBJECTS: We studied an age-, sex- and glucose-tolerance-stratified random sample of a 50- to 75-year-old general Caucasian population in the Hoorn Study (N = 629). Any polyneuropathy (N = 95) was defined as the absence of at least two of the three following sensory modalities or reflexes of either foot: light touch sense, ankle reflex and vibration sensation. Definite polyneuropathy (N = 25) was present if, in addition, the vibration perception threshold of the right big toe was abnormal. RESULTS: The prevalence of any polyneuropathy was 12.4% (33 of 266) in subjects with normal glucose tolerance (NGT), 12.6% (21 of 167) in those with impaired glucose tolerance (IGT), and 25.3% (41 of 162) in those with type 2 diabetes. The prevalence of definite polyneuropathy was 2.6% (7 of 266) in subjects with NGT, 2.4% (4 of 167) in those with IGT and 8.7% (14 of 161) in type 2 diabetic subjects. Polyneuropathy was associated with known risk factors such as diabetes, hyperglycaemia and body height. After adjustment for age, sex, HbA1c and hypertension, the odds ratio (95% CI) for any polyneuropathy per 5 micromol L-1 (about 1 SD) serum total homocysteine increment was 1.00 (0.72-1.39). After adjustment for age and sex, it was 0.62 (0.21-1.89) for definite polyneuropathy. CONCLUSION: Although a weak relation (as judged from the confidence intervals) cannot be excluded, we conclude that hyperhomocysteinaemia is probably not related to risk of distal somatic polyneuropathy.

Reproducibility of different methods for diagnosing and monitoring diabetic neuropathy.

Conflicting results have been published concerning the reliability of methods to assess diabetic polyneuropathy. Therefore we compared the reproducibility of nerve conduction studies and quantitative measurements of vibratory sensation in 23 diabetic patients with clinically and/or neurophysiologically established neuropathy. Motor nerve conduction of peroneal and median nerves, sensory nerve conduction of sural and median nerves and vibratory perception thresholds of index fingers and big toes (forced-choice method) were assessed on three occasions with an interval of one to fourteen days, within a period of three weeks. We conclude that both nerve conduction studies and vibratory perception threshold measurements are reproducible methods to assess diabetic neuropathy. Determination of vibration perception thresholds has the advantage of being a simple and unobtrusive method. Nerve conduction studies are less variable and therefore more suited for monitoring diabetic neuropathy.

Impaired blood flow response following pressure load in diabetic patients with cardiac autonomic neuropathy.

OBJECTIVE: An impaired blood flow response is associated with an increased risk of developing decubitus ulcers. This study investigated whether diabetic patients with autonomic neuropathy show an impaired blood flow response following pressure load, compared with healthy controls. DESIGN: Before-after trial. SETTING: University hospital. PATIENTS: Eighteen patients with type I diabetes and autonomic neuropathy, and 15 healthy volunteers. RESULTS: The blood flow response starts with a latency period, followed by a temperature increase (described by the "time constant"). The blood flow response in both groups showed significant (p < .01) differences. In diabetic patients, the latency time was 312 +/- 221 sec, the time constant was 339 +/- 149 sec, and the recovery time was 538 +/- 184 sec. In controls, latency time was 83 +/- 47 sec, time constant was 79 +/- 69 sec, and recovery time was 162 +/- 103 sec. The velocity of the blood flow response decreased with increasing duration of diabetes mellitus (p = .02). CONCLUSIONS: Diabetic patients with autonomic neuropathy show an impaired blood flow response after pressure relief. This finding suggests that these patients have an increased risk of developing decubitus ulcers.

Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2.

There is evidence that treatment with an antibody to tumor necrosis factor alpha (TNF alpha) improves an animal model of multiple sclerosis (MS) and is beneficial in two systemic inflammatory disease in humans, but there are no reports about anti-TNF treatment of MS. Therefore, we treated two rapidly progressive MS patients with intravenous infusions of a humanized mouse monoclonal anti-TNF antibody (cA2) in an open-label phase I safety trial and monitored their clinical status, gadolinium-enhanced brain magnetic resonance imaging (MRI), and peripheral blood and cerebrospinal fluid (CSF) immunologic status. We did not notice any clinically significant neurologic changes in either patient. The number of gadolinium-enhancing lesions increased transiently after each treatment in both patients. CSF leukocyte counts and IgG index increased after each treatment. The transient increase in the number of gadolinium-enhancing lesions that followed each infusion of cA2 together with the increase in cells and immunoglobulin in the CSF of each patient suggest that the treatment caused immune activation and an increase in disease activity. These results suggest that further use of cA2 in MS is not warranted and that studies of other agents that antagonize TNF alpha should be carried out with frequent monitoring of gadolinium-enhanced MRIs.

Peripheral somatic nerve function in relation to glucose tolerance in an elderly Caucasian population: the Hoorn study.

Only sparse and contradictory data are available on peripheral somatic nerve function in relation to the total range of glucose tolerance. A random sample (n = 708) of people, stratified by age, sex, and glucose tolerance, from a Caucasian population aged 50 to 74 years was invited to undergo an examination including measures of large-fibre nerve function (ankle and knee reflexes, vibration sense, vibratory perception threshold (VPT) at the foot) and one measure of small-fibre function (thermal discrimination threshold (TDT) at the foot). A total of 267 subjects with a normal glucose tolerance (NGT), 167 with impaired glucose tolerance (IGT), 90 with newly diagnosed diabetes mellitus (NDM), and 73 with previously known diabetes (KDM) were included. KDM was associated with the highest prevalence of large-fibre nerve dysfunction. Within the range from NGT to NDM, most large-fibre function measures showed a decline with decreasing glucose tolerance. The TDT showed a decrease with an increase in fasting and post-load insulin levels (p < 0.05). We conclude that glucose intolerance is associated with impaired peripheral large-fibre nerve function, an association which seems to apply even in the non-diabetic range. Higher insulin levels were associated with a better small-fibre nerve function.

Reference values for touch sensibility thresholds in healthy Nepalese volunteers.

A hundred and thirty-six apparently healthy volunteers between the ages of 16 and 67 were used to determine normative thresholds of tactile sensibility in the Nepali adult population. Tactile sensibility thresholds on standardized sites on hands and feet were assessed for two sensory tests: Semmes-Weinstein monofilaments (SWM) and moving-point discrimination (M2PD). Results are reported as the proportion of subjects able to feel a given threshold. The effect of age, sex, side, occupation, smoking habit and alcohol consumption on the results was examined with quantile regression. On the hand 200 mg seemed an appropriate threshold for 'normal' touch sensibility measured with monofilaments. About 99% (95% confidence interval 97-100) of individuals could detect this filament at all sites. A similar proportion could discriminate two points 4 mm apart which were moved from proximal to distal on the volar pad of the distal phalanx of the index and little finger. For the sole of the foot the thresholds were 2 g and 8 mm. Variability of results was greatest at the heel. Normal thresholds for tactile sensibility were higher than those published for the North American population. Monofilament thresholds suitable for screening were 200 mg (log number 3 center dot 61) and 2 g (log number 4 center dot 31) for hand and foot, respectively. For moving 2-point discrimination on the hand this threshold was 4 mm.

Treatment of diabetic polyneuropathy with the neurotrophic peptide ORG 2766.

The efficacy of the neurotrophic peptide ORG 2766 in diabetic patients with polyneuropathy was evaluated in a double-blind, placebo-controlled, multicentre trial. One hundred and twenty four patients were randomised in five groups to receive 0.1, 0.4, 2 or 5 mg ORG 2766 or placebo, once daily, administered subcutaneously 52 weeks. Thermal discrimination thresholds (TDT) and vibration perception thresholds (VPT), motor and sensory nerve conduction velocity, Hoffmann reflex, heart rate variation during deep breathing and heart rate response after standing up, neurological examination score and neuropathic symptom score were determined at baseline and after 17, 34 and 52 weeks of treatment. Of the nerve function indices studied, at week 52 the TDTwarmth of the hand in the ORG 2766 0.1, 0.4 and 5 mg groups and the TDTcold of the foot in the ORG 2766 0.1 and 0.4 mg groups significantly improved compared with placebo. Further significant improvement as compared with placebo was observed in the paraesthesia score at week 34 and week 52 in the ORG 2766 2 mg group. Only at week 34 had both the heartbeat variation during deep breathing and the VPT of the foot in the ORG 2766 0.1 mg group improved significantly, compared with placebo. No further statistically significant differences were observed at time for the other measures. No adverse reactions were observed. The only recorded drug-induced side effect was pain at the injection site. Taking all measures of efficacy into account, the statistically significant results observed did not show consistency within each measure. Therefore, it is concluded that ORG 2766, in contrast to earlier reports, is not effective in treating diabetic polyneuropathy.

Multiple cranial nerve palsy after otitis externa: a case report.

We report in this paper a case of a patient who developed extensive cranial nerve paresis on the left and right side after otitis externa. Investigation revealed an osteomyelitis of the skull base. We describe this disease and stress the importance of the gallium scan in the diagnostic process and therapeutic follow up.

4-Aminopyridine is superior to 3,4-diaminopyridine in the treatment of patients with multiple sclerosis.

OBJECTIVE: To compare the efficacy and toxicity of 4-aminopyridine and 3,4-diaminopyridine in patients with multiple sclerosis. DESIGN: Intervention study with a before-after design and a randomized, double-blind, crossover design. SETTING: University referral center. PATIENTS: Twenty-four patients with definite multiple sclerosis who had been treated in a previous clinical trial with 4-aminopyridine. INTERVENTIONS: Nonresponders to treatment with 4-aminopyridine (14 patients) were treated with 3,4-diaminopyridine in a 4-week, open-label trial with doses up to 1.0 mg/kg of body weight (before-after design). Responders to treatment with 4-aminopyridine (10 patients) participated in a comparative study of 6 weeks' duration with 4-aminopyridine and 3,4-diaminopyridine according to a randomized, double-blind, double-crossover design. MAIN OUTCOME MEASURES: Neurophysiologic variables for nonresponders, neurologic functions and symptoms on a visual analogue scale for responders, and side effects for both groups. RESULTS: Toxicity profiles of 4-aminopyridine and 3,4-diaminopyridine were different, and systemic tolerability was reduced for 3,4-diaminopyridine. 4-Aminopyridine was more effective than 3,4-diaminopyridine, especially for ambulation, fatigue, and overall daily functioning. CONCLUSION: Our data suggest that, concerning both efficacy and side effects, 4-aminopyridine is superior to 3,4-diaminopyridine in the treatment of patients with multiple sclerosis.

Complaints of neuropathy related to the clinical and neurophysiological assessment of nerve function in patients with diabetes mellitus.

To determine the value of a detailed evaluation of neuropathic sensory complaints in assessing diabetic polyneuropathy, a questionnaire listing different sensory symptoms was compared with a clinical and neurophysiological examination of the peripheral nerves. Thirty-seven insulin dependent and thirty-one non-insulin dependent diabetic patients who were consecutively referred because of suspected polyneuropathy were investigated. In all patients both clinical and neurophysiological examination confirmed the diagnosis of polyneuropathy. Only the scores of the clinical examination were significantly correlated with the scores of the sensory symptoms (r = 0.31, P < 0.01). Using a factor analysis, a dimension of complaints of sensory alteration could be distinguished from a dimension of complaints of neuropathic pain (alpha coefficients 0.88 and 0.86, respectively). Tingling sensations turned out to be an expression of the dimension of complaints of sensory alteration. The scores of clinical and neurophysiological examinations were only significantly correlated with the dimension of sensory alteration (r = 0.38, P < 0.002; r = 0.37, P < 0.02, respectively). We conclude that only symptoms of numbness and tingling sensations in hand and feet are associated with objectively assessed diabetic polyneuropathy.

The effects of 4-aminopyridine on cognitive function in patients with multiple sclerosis: a pilot study.

4-Aminopyridine (4-AP) has a favorable effect on the disability of certain patients with MS. We investigated the effect of 4-AP on neuropsychological performance in 20 MS patients using a randomized, double-blind, placebo-controlled, crossover design. Although there was a trend for improved performance with 4-AP for two of the tests, we could not demonstrate significant effects of 4-AP on cognitive function.

Sensory thresholds in older adults: reproducibility and reference values.

To evaluate the test-retest reproducibility of vibratory perception (VPT) and thermal discrimination (TDT) thresholds on the foot in older adults, we examined 20 50-76-year-old subjects with, and 19 without non-insulin-dependent diabetes mellitus. Adjusted reference values for both thresholds were obtained by assessing the relations with age, body height, and sex among 216 subjects with normal glucose tolerance, of the same age, sampled randomly from a geographically defined general population. The VPT appeared to be more reproducible than the TDT (reliability coefficient 0.89 vs. 0.54). The reproducibility of the VPT was inversely related to age and better for men than for women. Diabetes and glycemic level did not affect the reproducibility of either threshold. Both thresholds were related to age and height. Women had a higher VPT than men. The relations between sex and sensory thresholds at the lower limb, reported in previous studies, were probably confounded by height.

4-aminopyridine in the treatment of patients with multiple sclerosis. Long-term efficacy and safety.

OBJECTIVE: To study the long-term efficacy and safety of 4-aminopyridine in patients with multiple sclerosis. DESIGN: Case series, follow-up varying from 6 to 32 months. SETTING: University referral center. PATIENTS: Thirty-one patients with definite MS, 23 of them being exposed to long-term administration (6 to 32 months) of 4-aminopyridine, since they showed a favorable initial response to the drug. INTERVENTIONS: Long-term oral treatment with 4-aminopyridine in daily doses of up to 0.5 mg/kg of body weight. MAIN OUTCOME MEASURES: Neurologic functions and symptoms as reported by the patients; side effects. RESULTS: Twenty of 23 patients who showed a favorable initial response benefited from long-term administration. Ambulation and fatigue (each in 13 patients) and visual function (in five patients) were most frequently reported to be improved. Three major side effects did occur during a follow-up of 406 patient months: a generalized epileptic seizure in two patients and hepatitis in one. CONCLUSIONS: Although a substantial proportion of patients with multiple sclerosis seem to benefit from long-term administration of 4-aminopyridine, additional studies are needed to clarify the exact value of the drug.

The validity and reproducibility of the skin vasomotor test--studies in normal subjects, after spinal anaesthesia, and in diabetes mellitus.

Skin sympathetic vasomotor control can be examined in the extremities by the skin vasomotor test. In this test the change in skin blood flow and skin temperature in the hand and foot in response to a cold stimulus is utilized as an index of distal sympathetic nerve fibre integrity. This is of importance in conditions such as diabetes mellitus as peripheral autonomic neuropathy is associated with orthostatic hypotension and diabetic foot complications. The validity and reproducibility of the test as a marker of distal sympathetic nerve function has been studied. The test was performed in nine healthy control subjects and in nine subjects (undergoing minor surgery) after a sympathetic nerve conduction block (L2-L3) was achieved in the lower extremities by spinal analgesia. Changes in skin temperature (p < 0.001) and skin blood flow (p < 0.005) in responses to cooling were significantly larger in the control group than in the group with spinal analgesia. Repeated skin temperature measurements on 42 occasions (test-retest period of 4 weeks) in eight healthy and 34 diabetic subjects indicated a reliability coefficient of 80%. We conclude, therefore, that the skin vasomotor test provides a valid and reproducible quantitative assessment of skin sympathetic nerve function in upper and lower extremities.