Jan Fagius

Long-term variability and reproducibility of resting human muscle nerve sympathetic activity at rest, as reassessed after a decade

Human muscle nerve sympathetic activity measured by microneurography during supine rest is known to vary considerably between healthy subjects, whereas in a given individual the level of muscle nerve sympathetic activity is stable over weeks and months. To further characterize long-term variability or reproducibility microneurographic recordings of muscle nerve sympathetic activity were performed in 15 healthy, normotensive subjects (mean age 51 years) who had undergone the same procedure between 10 and 14 years earlier (mean 12 years). The range of muscle nerve sympathetic activity was 9–59 in the first and 13–61 bursts/min in the second recording. Subjects maintained the level of muscle nerve sympathetic activity displayed previously, although with a slight but significant tendency to a higher outflow with increasing age.It is concluded that muscle nerve sympathetic activity is characterized by large inter-individual differences and strong intra-individual reproducibility over many years, with a tendency to increase with age. The age relationship is only in a minor part responsible for the variability, the cause of which remains unexplained. Because of the marked difference between individuals, strict normality criteria are difficult to define when comparing groups of subjects. There remains the risk of either obtaining spurious differences or obscuring a true abnormality. This is unlikely to apply when results in individual subjects are compared.

Variability of sensory threshold determination in clinical use

The variability of perception threshold determination for vibration, tactile stimuli and thermal stimuli, with instruments intended for clinical use, was studied in 13 healthy subjects and 27 patients with chronic polyneuropathy. Normal thresholds for tactile and thermal stimuli were determined in 51 healthy subjects. Determinations were made for vibration on hand, lower leg and foot, for touch on pulp of forefinger and great toe and for temperature on hand and foot. Normal thresholds for both tactile and thermal stimuli were age-dependent. Short-term variation, with intervals of some minutes between determinations, remained within 8-18% change from first value. Long-term variation, with intervals of days to some weeks, was pronounced for all types of threshold, with extremes of -90% and +256% change from first determination in 3 or 4 subsequent determinations. Variation was most marked for tactile stimuli and smallest for vibration, but magnitude and pattern of variation was similar for all sensory modalities and for both patients and healthy subjects. Confidence intervals, derived from analysis of variance, showed than as an average a change of less than -60% or greater than +150% from the initial value was needed to ascertain with 95% probability that a subsequent value will reflect a true change of sensory threshold. Basing every threshold value on 2 or more measurements per occasion will reduce the confidence interval. The main cause of variability seems to be central processing mechanisms, i.e. the psychological variability. With proper attention to the variability, sensory threshold determinations should still be a valuable aid in clinical practice and clinical research.

Effects of aldose reductase inhibitor treatment in diabetic polyneuropathy - a clinical and neurophysiological study.

The efficacy of treatment with an aldose reductase inhibitor (1,3-dioxo-1 H-benz-de-isoquinoline-2(3H)-acetic acid, AY-22,284, Alrestatin) on peripheral nerve function in diabetic polyneuropathy was assessed. Thirty patients with long-standing diabetes and slight to moderate neuropathy participated in the double-blind placebo trial. Clinical examination, sensory threshold determinations for vibratory, tactile and thermal stimuli, conduction velocity measurements and studies of automatic function were performed to evaluate the treatment. Significant differences favouring Alrestatin over placebo were found for many of the measured variables, whereas no changes occurred on placebo. The apparent improvement of neuropathy occurred despite persisting hyperglycaemia. The results indicate that aldose reductase inhibitor treatment may be of value in diabetic polyneuropathy, and provide support for the sorbitol pathway hypothesis of diabetic polyneuropathy.

Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience

Background Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS. Methods Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months. Results At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%). Conclusions HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

Time to secondary progression in patients with multiple sclerosis who were treated with first generation immunomodulating drugs

Background: It is currently unknown whether early immunomodulatory treatment in relapsing–remitting MS (RRMS) can delay the transition to secondary progression (SP). Objective: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. Methods: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995–2004, n = 730) and a historical population-based incidence cohort (onset 1950–64, n = 186). We retrospectively analyzed the difference in time to SP, termed the “period effect” within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. Results: We found that the “period” affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). Conclusion: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given.

Assessing tissue damage in multiple sclerosis: a biomarker approach.

Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS.

Early relapse of acute inflammatory polyradiculoneuropathy after successful treatment with plasma exchange.

ABSTRACT— Symptoms reappeared within 2–4 weeks in 6 of 23 patients with acute Guillain‐Barré syndrome who had demonstrated significant clinical improvement following plasma exchange therapy; all however improved to full recovery after a second series of plasma exchanges. The procedure appears to be associated with increased risk of early relapse. Our observations suggest that a relationship may exist between rapid removal of large amounts of plasma and the possibility of relapse.

Variation of sympathetic reflex latency in man

Microelectrode recordings of muscle nerve sympathetic activity (MSA) in man have shown a reflex relationship between heart beat and corresponding sympathetic burst, the latency of which is stable at rest and independent of heart rate. In peroneal nerve recordings in 35 healthy subjects this latency was reduced during the Valsalva manoeuvre by 120 ms (mean; range 40-245 ms; P less than 0.001) from a mean value at rest of 1300 ms. Slow deep breathing and simulated diving shortened the latency by 60 (P less than 0.001) and 80 ms (P less than 0.05), respectively. When intrinsic heart rate was induced by i.v. administration of atropine and propranolol, the latency was increased by 70 ms (P less than 0.001). A number of other manoeuvres affecting the outflow of MSA did not change the latency. It is suggested that the findings indicate the existence of more than one central pathway involved in the baroreflex regulation of MSA. Alternatively, altered central processing time may follow influence from other receptors in different manoeuvres.

Increase in muscle nerve sympathetic activity after glucose intake is blunted in the elderly

Muscle nerve sympathetic activity (MSA; involved in blood pressure regulation) was recorded by microneurography in the peroneal nerve for 90 min after ingestion of 100 gd-glucose in three groups of healthy subjects: young subjects (mean age 26 years) and 70-year-old men with normal and reduced insulin sensitivity as assessed by euglycaemic insulin clamp. Muscle nerve sympathetic activity at rest was lowest in the young and highest in the insulin-resistant subjects (burst frequencies 19.8±6.0, 47.7±7.0 and 55.1±11.5 bursts/min for the three groups, respectively). The young subjects responded to glucose intake with a pronounced increase in MSA, a response that was blunted in the elderly and weakest in the insulin-resistant subjects. A similar relationship was observed during a Valsalva manoeuvre, indicating that the blunted response in the elderly is a generalized phenomenon. Blood pressure remained stable in the young subjects but fell slightly and significantly in the elderly subjects. It is concluded that old subjects utilize their total capacity for MSA close to maximum at rest. Thus, the reserve for response to stimuli normally evoking a strong increase in MSA is restricted. This restriction may contribute to postprandial hypotension in the healthy elderly.

Antibody-mediated suppression of Vβ5.2/ 5.3+ T cells in multiple sclerosis: Results from an MRI-monitored phase II clinical trial

The objective of this study was to evaluate the safety and efficacy of the humanized antibody ATM‐027 in a baseline versus treatment magnetic resonance imaging‐monitored study. Expansion of Vβ5.2/5.3+ T cells has been demonstrated in the peripheral blood, cerebrospinal fluid, and brain lesions of MS patients. In a phase I study, ATM‐027 depleted these cells in peripheral blood and, in parallel, T‐cell MBP reactivity and IFN‐γ expression were reduced. We studied 59 patients with relapsing‐remitting MS (47 on ATM‐027 and 12 on placebo) stratified for HLA‐DR2 status. Monthly intravenous injections were given for 6 months. Individual dose titration was employed to obtain depletion of the target T‐cell level and downregulation of antigen receptor density as monitored by flow cytometry. Five monthly magnetic resonance imaging scans were performed before treatment to establish baseline activity, six during treatment, and three during follow‐up. Additional immunological assessments were performed to elucidate the mechanism of action of ATM‐027. The treatment was safe and well tolerated, inducing consistent suppression of the target cell population. During run‐in, active lesions were found in 78.7% (37/47) of patients treated with ATM‐027. During treatment, the median number of lesions was reduced by 33% (p = 0.13) independent of DR2 status. The corresponding volume of enhancement was 221 mm3 at baseline, with a reduction of 10% during treatment. Decreased numbers of cells expressing interferon‐γ messenger RNA, and decreased T‐cell reactivity to several myelin antigens were found in ATM‐027 treated patients. In conclusion, consistent suppression of Vβ 5.2/5.3+ T cells was achieved. However, the effect size on magnetic resonance imaging was considerably less than the targeted 60%.