Dorothea Heersema

Tremor in multiple sclerosis

Tremor is estimated to occur in about 25 to 60 percent of patients with multiple sclerosis (MS). This symptom, which can be severely disabling and embarrassing for patients, is difficult to manage. Isoniazid in high doses, carbamazepine, propranolol and gluthetimide have been reported to provide some relief, but published evidence of effectiveness is very limited. Most trials were of small size and of short duration. Cannabinoids appear ineffective. Tremor reduction can be obtained with stereotactic thalamotomy or thalamic stimulation. However, the studies were small and information on long-term functional outcome is scarce. Physiotherapy, tremor reducing orthoses, and limb cooling can achieve some functional improvement. Tremor in MS remains a significant challenge and unmet need, requiring further basic and clinical research.

Therapeutic Potential of Fluoxetine in Neurological Disorders

The selective serotonin reuptake inhibitor (SSRI) fluoxetine, which is registered for a variety of psychiatric disorders, has been found to stimulate the cAMP‐responsive element binding protein (CREB), increase the production of brain‐derived neurotrophic factor (BNDF) and the neurotrophic peptide S100β, enhance glycogenolysis in astrocytes, block voltage‐gated calcium and sodium channels, and decrease the conductance of mitochondrial voltage‐dependent anion channels (VDACs). These mechanisms of actions suggest that fluoxetine may also have potential for the treatment of a number of neurological disorders. We performed a Pubmed search to review what is known about possible therapeutic effects of fluoxetine in animal models and patients with neurological disorders. Beneficial effects of fluoxetine have been noted in animal models of stroke, multiple sclerosis, and epilepsy. Fluoxetine was reported to improve neurological manifestations in patients with Alzheimers disease, stroke, Huntingtons disease, multiple sclerosis, traumatic brain injury, and epilepsy. Clinical studies so far were small and often poorly designed. Results were inconclusive and contradictory. However, the available preclinical data justify further clinical trials to determine the therapeutic potential of fluoxetine in neurological disorders.

Effects of fluoxetine on disease activity in relapsing multiple sclerosis: a double-blind, placebo-controlled, exploratory study

Background: Suppressing the antigen-presenting capacity of glial cells could represent a novel way of reducing inflammatory activity in multiple sclerosis (MS). Aims: To evaluate the effects of fluoxetine on new lesion formation in patients with relapsing MS. Methods: In a double-blind, placebo-controlled exploratory study, 40 non-depressed patients with relapsing remitting or relapsing secondary progressive MS were randomised to oral fluoxetine 20 mg or placebo daily for 24 weeks. New lesion formation was studied by assessing the cumulative number of gadolinium-enhancing lesions on brain MRI performed on weeks 4, 8, 16 and 24. Results: Nineteen patients in both groups completed the study. The mean (SD) cumulative number of new enhancing lesions during the 24 weeks of treatment was 1.84 (2.9) in the fluoxetine group and 5.16 (8.6) in the placebo group (p = 0.15). The number of scans showing new enhancing lesions was 25% in the fluoxetine group versus 41% in the placebo group (p = 0.04). Restricting the analysis to the past 16 weeks of treatment showed that the cumulative number of new enhancing lesions was 1.21 (2.6) in the fluoxetine group and 3.16 (5.3) in the placebo group (p = 0.05). The number of patients without enhancing lesions was 63% in the fluoxetine group versus 26% in the placebo group (p = 0.02). Conclusions: This proof-of-concept study shows that fluoxetine tends to reduce the formation of new enhancing lesions in patients with MS. Further studies with this compound are warranted. Trial registration: Number: ISRCTN65586975

Progression in multiple sclerosis: Further evidence of an age dependent process

The relapsing-remitting phase and the progressive phase of multiple sclerosis (MS) seem to be the result of distinct pathophysiological processes. Previous research on the natural history of MS was largely focussed on relapses and disability scores. In this study we evaluated 438 patients with secondary or primary progressive MS. The influence of gender, initial disease course, onset manifestation and age at disease onset on age at progression and time to progression were evaluated with Kaplan-Meier survival analysis and Cox multivariate regression models. The analysis of these data showed that the initial disease course (SPMS or PPMS) had no influence on the age at progression. Gender had no influence on age at progression in PPMS and SPMS patients nor on time to progression in SPMS patients. PPMS patients with visual or brainstem/cerebellar onset had a significantly younger age at progression. SPMS patients with motor onset had a significantly higher age at progression and longer time to progression. Time to progression was significantly shorter in SPMS patients with higher age at disease onset. Our data give further support to the notion that progression in MS is an age dependent process independent of relapses.

Oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of multiple sclerosis

BackgroundThe role of oxidative stress in patients with multiple sclerosis (MS) is poorly understood.ObjectiveTo investigate oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of MS.MethodsDiene conjugate (DC) levels (a measure of lipid peroxidation), total antioxidative activity (AOA) and total antiradical activity (ARA) were measured in serum and peripheral blood leukocytes from 30 patients with benign relapsing remitting MS (BMS), 27 with secondary progressive MS (SPMS), 29 with primary progressive MS (PPMS), and 30 healthy controls. All MS patients were in a clinically stable phase.ResultsSerum DC levels were elevated in patients with BMS (p <0.05), SPMS (p <0.01) and PPMS (p <0.001). Serum total AOA and ARA were not different between MS patients and controls. Compared to controls, leukocyte DC levels were not different in each MS subgroup, but total ARA was elevated. There was a strong correlation, both in controls and MS patients, between leukocyte DC levels and leukocyte total ARA (p <0.0001) and leukocyte total AOA (p <0.0001).ConclusionOxidative stress occurs in progressive as well as benign MS. The finding that cells withstand oxidative stress, due to upregulated cellular antioxidant defence mechanisms, suggests that reactive oxygen species (ROS) formation in MS is not necessarily deleterious.

Plasma lipid peroxidation and progression of disability in multiple sclerosis

Oxidative stress has been implicated in the pathophysiology of multiple sclerosis (MS), but its relation to disease progression is uncertain. To evaluate the relationship of plasma lipid peroxidation with progression of disability in MS, we measured blood plasma fluorescent lipid peroxidation products (PFLPP) levels in 23 patients with RRMS with a benign course, 32 with secondary progressive MS, 24 with primary progressive MS and 30 healthy controls. None of the patients had a relapse within the previous 3 months. Progression of disability was evaluated during a follow‐up period of 5 years by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS). We found plasma PFLPP levels elevated in patients with MS compared with controls (P < 0.0001), but there was no difference between patients with a benign and progressive disease course. There was no correlation between PFLPP levels and worsening of disability on the EDSS and speed of progression on the MSSS. Our data suggest that there is no relation between the degree of oxidative stress in plasma and progression of disability in MS.

A randomized crossover study of bee sting therapy for multiple sclerosis

Background: Bee sting therapy is increasingly used to treat patients with multiple sclerosis (MS) in the belief that it can stabilize or ameliorate the disease. However, there are no clinical studies to justify its use. Methods: In a randomized, crossover study, we assigned 26 patients with relapsing-remitting or relapsing secondary progressive MS to 24 weeks of medically supervised bee sting therapy or 24 weeks of no treatment. Live bees (up to a maximum of 20) were used to administer bee venom three times per week. The primary outcome was the cumulative number of new gadolinium-enhancing lesions on T1-weighted MRI of the brain. Secondary outcomes were lesion load on T2*-weighted MRI, relapse rate, disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Guy’s Neurologic Disability Scale), fatigue (Abbreviated Fatigue Questionnaire, Fatigue Impact Scale), and health-related quality of life (Medical Outcomes Study 36-Item Short Form General Health Survey). Results: During bee sting therapy, there was no significant reduction in the cumulative number of new gadolinium-enhancing lesions. The T2*-weighted lesion load further progressed, and there was no significant reduction in relapse rate. There was no improvement of disability, fatigue, and quality of life. Bee sting therapy was well tolerated, and there were no serious adverse events. Conclusions: In this trial, treatment with bee venom in patients with relapsing multiple sclerosis did not reduce disease activity, disability, or fatigue and did not improve quality of life.

Visual field and grating acuity development in low-risk preterm infants during the first 2 1/2 years after term

The effect of early visual experience on visual field size and grating acuity development was studied longitudinally in 36 appropriate for gestational age (AGA) and 26 small for gestational age (SGA) low-risk preterm infants. These were selected out of 194 very low birth weight (VLBW) infants (birthweight less than 1500 g) born in 1985 and 1986. Criteria for inclusion as low-risk were the absence of neurological, respiratory, circulatory and alimentary problems in the neonatal period; no retinopathy of prematurity and no evidence of abnormality on the neonatal cranial ultrasound scans. Binocular field sizes were assessed using kinetic arc perimetry. Binocular grating acuity was tested by means of the prototype version of the acuity card procedure. Results were compared with norms obtained in control fullterms in earlier studies. Infants were tested at 6 weeks, 6, 6, 9 and 12 months of age from the expected term date. Twenty-two of these infants were retested at 2 1/2 years of corrected age. Visual field size and visual acuity estimates of (both AGA and SGA) low-risk, VLBW preterms and control fullterms overlapped at all test ages, except for a slight but significantly faster development of the upper and the lower visual field at 6 weeks corrected age in the preterm group. These results indicate that for clinical purposes visual experience before the expected term date has not only no measurable effect on the normal development of behavioural acuity, but also no accelerating effect on the development of peripheral vision.

Parity and secondary progression in multiple sclerosis

Background: Pregnancy has a well-documented effect on relapses in multiple sclerosis (MS), whereas little is known about the impact of pregnancy and childbirth on the risk of secondary progression. Objective: To investigate the association of parity and secondary progression in women with MS. Methods: The association of the number of births and secondary progression was studied in a hospital-based cohort of 277 women with MS. Data were analysed in a multivariable logistic regression model, with adjustment for possible confounders. Results: Parity was not independently associated with secondary progression, while the factors disease duration (OR per year increase: 1.05, 95% CI 1.03 to 1.09) and use of immunomodulatory treatments (OR 0.23, 95% CI 0.08 to 0.65) were independently associated with secondary progression. Conclusion: We found no evidence that parity influences the risk of secondary progression in MS. Further population-based studies on the association of pregnancy and childbirth on the long-term prognosis of MS are needed.

Cerebrospinal fluid oligoclonal bands and progression of disability in multiple sclerosis

Antibody‐mediated inflammation is believed to contribute to tissue injury in multiple sclerosis (MS). The majority of patients with MS have oligoclonal bands (OCB), corresponding to antibodies against a variety of antigens, in their cerebrospinal fluid (CSF). The relation of CSF OCB and disease progression in MS is uncertain. To investigate whether there is a relation between CSF OCB and a more aggressive disease course of MS, 143 patients with definite MS according to the Poser diagnostic criteria and CSF analysis at time of diagnosis were followed over a period of 5 years. There were no differences in presence or number of CSF OCB between patients with significant worsening of disability and stable patients. There were no differences in presence or number of CSF OCB between patients with stable relapsing‐remitting MS and patients developing secondary progression during follow‐up. The presence or number of CSF OCB does not seem to influence early disease progression in MS.