Application of serum natalizumab levels during plasma exchange in MS patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab treatment. Restoring immune function by plasmapheresis/immunoadsorption (PLEX/IA) is important for the outcome of PML. We report on four multiple sclerosis (MS) patients whom developed PML during natalizumab treatment, in whom we measured serum natalizumab concentrations before and during PLEX. Depending on the serum natalizumab concentration at the time of PML diagnosis, the number of PLEX treatments necessary to reach subtherapeutic serum natalizumab concentrations is variable. Measuring serum natalizumab concentrations before and during PLEX is helpful to determine the optimum number of PLEX treatments in individual MS patients with PML.

Influence of personalized extended interval dosing on the natalizumab wearing-off effect - a sub-study of the NEXT-MS trial.

BACKGROUND AND OBJECTIVES: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID. METHODS: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated. RESULTS: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms. DISCUSSION: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.

Diffuse alveolar hemorrhage as an early complication of alemtuzumab treatment: A case report of a multiple sclerosis patient and an overview of 14 cases.

Alemtuzumab is effective in relapsing remitting multiple sclerosis (RRMS). Serious adverse events have led to a renewed safety reassessment by the European Medicines Agency (EMA), leading to an approval under strict conditions. We report a RRMS patient experiencing diffuse alveolar hemorrhage (DAH) on day 4 of her first alemtuzumab cycle. In addition, we present an overview of the cases of alemtuzumab-induced DAH that were included in EMA's review procedure, additional well documented cases reported to the EMA and those cases reported in the literature. Combining these cases revealed striking similarities. Importantly, DAH was an early complication. All RRMS patients with known outcome showed complete recovery.

A tumefactive demyelinating lesion in a person with MS after five years of fingolimod.

A 38-year-old man with relapsing remitting multiple sclerosis (RRMS) developed a tumefactive demyelinating lesion (TDL) after being clinically and radiologically stable on fingolimod for the last five years. TDLs in MS tend to occur early on in the disease and are uncommon in longstanding MS. Compared to other immune modifying drugs used in MS, there is a relatively high and still increasing number of reports describing the development of TDL under treatment with fingolimod, suggesting a causal relation.

High work absence around time of diagnosis of multiple sclerosis is associated with fatigue and relapse rate.

BACKGROUND: Multiple sclerosis (MS) is associated with high rates of disability pension and work absence. Little is known about work absence in early MS. The objectives of this study were (1) to assess the prevalence of work absence shortly after MS diagnosis, (2) to explore health-related quality of life (HRQoL) and disease impact in relation to work absence and (3) to investigate demographic and clinical factors that may be associated with high work absence. METHODS: Patients with relapsing remitting (RRMS) or primary progressive MS (PPMS) were included shortly after MS diagnosis. We collected data on work absence due to MS in the year prior to inclusion, disability (Expanded Disability Status Scale), relapse rate, fatigue (Neurological Fatigue Index), health-related quality of life (HRQoL, 36-Item Short Form Survey) and disease impact (Multiple Sclerosis Impact Scale). For analysis, patients were divided in 2 groups: low work absence (<1 month) and high work absence (≥1 month). Data was analyzed using backward logistic regression techniques. RESULTS: In total, 90 MS patients participated (80 RRMS, 10 PPMS, mean age = 39.3 years, median disease duration since diagnosis = 0.5 year). Work absence in the year prior to inclusion was reported by 66 patients (73.3%). High work absence of ≥ 1 month was reported by 41 patients (45.6%). Disability, gender, age, disease duration and education did not differ between groups. Patients with high work absence reported a lower HRQoL and higher disease impact compared to patients with low work absence. Backward regression analysis showed that high work absence is associated with being single/not married, fatigue and relapses. The strongest association was found for fatigue (highest fatigue vs. lowest fatigue level: OR total group = 7.8, RRMS = 15.8). In RRMS patients the second-strongest association was relapse rate (≥2 relapses in the past year vs. no relapses: OR 11.1). CONCLUSION: Prevalence of work absence is high in early MS. Patients with high work absence report a lower HRQoL and a higher disease impact. High work absence is associated with being single/not married, fatigue and relapses. Interventions aimed at fatigue and prevention of relapses may help maintain employment in early MS.

Axonal neuropathy with prolonged sulphasalazine use.

Sulphasalazine, one of the 5-amino-salicylates, is widely used for the treatment of inflammatory bowel diseases and arthritis. Among the reported adverse effects are blood dyscrasias and hepatic failure. Peripheral neuropathy has been reported as a rare adverse drug reaction to sulphasalazine. Most reported patients developed symptoms several weeks after onset of treatment. We describe a patient with an axonal polyneuropathy that occurred after two years of treatment with sulphasalazine.

Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naive T cells but does not affect IFN-gamma secreting TH1 cells in humans.

CD4(pos) TH1 T cells are considered to play a central role in a number of human autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis. Experimental treatment protocols aimed at selectively eliminating CD4(pos) T cells thus far have yielded disappointing clinical results. Here we analyzed phenotype and function of circulating T cells in multiple sclerosis patients treated with the chimeric CD4 mAb cM-T412 in a randomized, double-blind, placebo-controlled, magnetic resonance imaging-monitored phase II trial. Treatment resulted in a long-lasting depletion of CD4(pos) T cells but did not affect CD8(pos) T cell numbers. Analysis of CD4(pos) subpopulations showed that unprimed, CD45RA(pos)/R0(neg) lymphocytes were approximately three times more sensitive to the mAb than primed, CD45RA(neg)/R0(pos) T cells. Notably, within the CD45RA(pos) subset, T cells with phenotypic evidence of prior activation, i.e., expressing Fas, were relatively insensitive to cM-T412, compared with Fas(neg) cells. Remarkably, while a decrease in the number of IL-4-producing T helper 2 (TH2)-type cells in the anti-CD4 treated group was observed, numbers of IFN-gamma-producing T helper 1 (TH1)-type cells remained stable, resulting in a significant increase in the TH1/TH2 ratio. Our data show that treatment with depleting CD4 mAb does not eliminate the cells most strongly involved in the disease process, i.e., primed, IFN-gamma-producing TH1-type cells, and may therefore give an explanation for the lack of beneficial clinical effects of depleting CD4 mAb in human chronic autoimmune disease.

Increased production of tumor necrosis factor alpha, and not of interferon gamma, preceding disease activity in patients with multiple sclerosis.

OBJECTIVE: To study whether tumor necrosis factor (TNF) alpha or interferon (IFN) gamma production by stimulated white blood cells precedes or accompanies clinical and magnetic resonance imaging signs of disease activity in patients with multiple sclerosis. DESIGN: Prospective study with a follow-up of 9 months. SETTING: Patients visiting an outpatient university clinic. PATIENTS: The 30 Amsterdam-based patients (28 completing all evaluations) participating in a multicenter, randomized, placebo-controlled, double-blind trial of a chimeric anti-CD4 antibody in the treatment of active relapsing-remitting and secondary progressive multiple sclerosis. Patients in both treatment arms were included, because for these patients anti-CD4 treatment in this study did not affect TNF-alpha and IFN-gamma production and did not reduce signs of disease activity on magnetic resonance imaging. MAIN OUTCOME MEASURE: Distribution of classes of TNF-alpha and IFN-gamma production (expressed as z scores) in patients with or without clinical or magnetic resonance imaging signs of disease activity. RESULTS: One month preceding exacerbations of multiple sclerosis, there was a shift toward higher z scores of TNF-alpha production (P<.05), but not of IFN-gamma production. There was no statistically significant relationship between IFN-gamma and TNF-alpha production and magnetic resonance imaging markers of multiple sclerosis activity. CONCLUSION: The production of TNF-alpha, and not of IFN-gamma, is significantly higher in patients with multiple sclerosis before exacerbations than in patients with stable disease. Although present, this relationship is too weak to use TNF-alpha production as a surrogate marker of disease activity in multiple sclerosis.

Development of hypointense lesions on T1-weighted spin-echo magnetic resonance images in multiple sclerosis: relation to inflammatory activity.

OBJECTIVE: To evaluate whether degree of inflammatory activity in multiple sclerosis, expressed by frequency of gadolinium enhancement, has prognostic value for development of hypointense lesions on T1-weighted spin-echo magnetic resonance images, a putative marker of tissue destruction. DESIGN: Cohort design with long-term follow-up. Thirty-eight patients with multiple sclerosis who in the past had been monitored with monthly gadolinium-enhanced magnetic resonance imaging for a median period of 10 months (range, 6-12 months) were reexamined after a median period of 40.5 months (range, 33-80 months). SETTING: Magnetic Resonance Center for Multiple Sclerosis Research, Amsterdam, the Netherlands, referral center. MAIN OUTCOME MEASURES: The new enhancing lesion rate (median number of gadolinium-enhancing lesions per monthly scan) during initial monthly follow-up; hypointense T1 and hyperintense T2 lesion load at first and last visit. RESULTS: The number of enhancing lesions on entry scan correlated with the new enhancing lesions rate (r = 0.64; P<.001, Spearman rank correlation coefficient). The new enhancing lesion rate correlated with yearly increase in T1 (r = 0.42; P<.01, Spearman rank correlation coefficient) and T2 (r = 0.47; P<.01, Spearman rank correlation coefficient) lesion load. Initial T1 lesion load correlated more strongly with yearly increase in T1 lesion load (r = 0.68; P<.01, Spearman rank correlation coefficient). CONCLUSIONS: Degree of inflammatory activity only partially predicted increase in T1 (and T2) lesion load at long-term follow-up. Initial T1 lesion load strongly contributed to subsequent increase in hypointense T1 lesion load, suggesting that there is a subpopulation of patients with multiple sclerosis who are prone to develop destructive lesions.

Accumulation of hypointense lesions ("black holes") on T1 spin-echo MRI correlates with disease progression in multiple sclerosis.

MRI findings are increasingly used as outcome measures in therapeutic trials in MS. The discrepancy between the extent of the lesions on conventional T2 images and the clinical condition of the patient is one of the problems encountered in such studies. This clinical-radiological paradox prevents the use of MRI data as surrogate markers of disability in MS. A recent pilot study suggested a relationship between hypointense lesions on T1 MRI and disability. To assess in more detail the correlation of changes in hypointense lesion load on T1-weighted spin-echo MR images ("black holes") with changes in disability in MS, we studied 46 patients with clinically definite MS at baseline and after a median follow-up of 40 months. There was a significant correlation between baseline disability and hypointense lesion load (Spearman rank correlation coefficient [SRCC] = 0.46, p = 0.001). In secondary progressive patients, the rate of accumulation of these "black holes" was significantly related to progression rate (SRCC = 0.81, p < 0.0001). We speculate that the appearance of hypointense lesions is the MRI equivalent of a failure of remission. Overall, T1 lesion load measurements correlated better with clinical assessments than T2 lesion load measurements. Quantification of hypointense lesion load on T1-weighted spin-echo MRI helps to resolve the clinical-radiological paradox between disability and MRI and has the potential to be a surrogate marker of disability in MS.

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.

Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial.

We report the results of a randomized, double-blind, placebo-controlled exploratory trial of the chimeric monoclonal anti-CD4 antibody cM-T412 in 71 patients suffering from active relapsing-remitting and secondary progressive multiple sclerosis. Infusion of the antibody produced frequent but usually minor side effects and resulted in a long-lasting reduction of circulating CD4-positive T cells. There was no significant effect on the primary measure of efficacy, the number of active lesions on monthly gadolinium-enhanced MRI over 9 months. Further statistical evaluation provided evidence that the degree of depletion of CD4-positive cells was important with regard to treatment efficacy; using CD4 counts as a covariate there was a statistically significant effect on the number of active lesions over 18 months (p = 0.04). There was a statistically significant reduction of 41% in the number of clinical relapses (a secondary efficacy parameter) after 9 months (p = 0.02), which was still present after 18 months, but this finding may be partly due to physician unblinding. Other secondary efficacy parameters (Expanded Disability Status Scale progression, number of courses of methylprednisolone) were not influenced by anti-CD4 treatment. We conclude that intravenous treatment with the monoclonal antibody cM-T412 in the dosage we used results in a substantial and sustained reduction of the number of circulating CD4-positive cells, but is not able to reduce MS activity as measured by monthly gadolinium-enhanced MRI, and is therefore unlikely to have a beneficial effect on the clinical disease course. We found preliminary evidence suggesting that more aggressive depletion of CD4-positive cells might lead to a more substantial reduction in MRI activity.

A pilot study investigating the effects of orally administered pentoxifylline on selected immune variables in patients with multiple sclerosis.

Multiple sclerosis is probably mainly mediated by T-helper 1 (TH1)-lymphocytes. TH1-function can be down-regulated in vitro and in animal experiments by pentoxifylline. Therefore, we included 20 multiple sclerosis patients in an open label pilot trial of pentoxifylline. Outcome parameter was the effect of treatment on levels of various cytokines and adhesion molecules in cerebrospinal fluid and serum, on production of TH1- and TH2-cytokines using cell stimulation assays, as well as on measures of T-cell activation and proliferation. Kurtzke's EDSS was a secondary efficacy parameter. A convincing and consistent effect of pentoxifylline could not be demonstrated.

TNF-alpha promoter polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients.

TNF-alpha production in whole blood cultures upon stimulation with LPS was determined in 179 individuals from 61 families in order to characterise the magnitude of inherited differences in TNF-alpha production. The three families characterised by highest TNF production showed 7.1 +/- 0.3 ng TNF/ml upon culture with 10 ng LPS and 10.2 +/- 0.2 ng TNF/ml upon culture with 1000 ng LPS. in contrast to the three families characterised by the lowest TNF production that showed a production of 1.6 +/- 0.1 ng TNF upon culture with 10 ng and 2.5 +/- 0.2 ng/ml upon culture with 1000 ng LPS/ml. This difference could not be attributed to the promoter polymorphisms -308 G to A. -238 G to A or -376 G to A, although the -238 GA donors produced 2.1 +/- 0.9 ng TNF upon culture with 10 ng endotoxin compared to 3.2 +/- 2.2 ng TNF for the -238 GG donors. In line with these results the frequency of the -238 GG genotype was increased in hospitalized MS patients in a nursing home (100% 238GG, n = 57) compared to MS patients in an outpatient's clinic (94% 238GG, n = 98) or Dutch controls (90% 238GG, n = 180). These results suggest that the -238 GG genotype is differently distributed in hospitalized MS patients in a nursing home.

Choosing drug therapy for multiple sclerosis. An update.

Multiple sclerosis (MS) is an immunologically mediated disorder in which inflammation and demyelination of the central nervous system white matter are prominent features, resulting in various neurological signs and symptoms. In most patients, the course of the disease is initially characterised by relapses and remissions. In patients with chronic disease there is a tendency towards a gradually progressive disease course. MS relapses can best be treated with a course of high dose intravenous methylprednisolone. In ambulatory patients with relapsing remitting MS, partial prevention of relapses can be achieved by the use of interferon-beta-1a or -1b, whereas there is (as yet less convincing) evidence that glatiramer acetate (copolymer-1) might also be effective. At this time, there is no proof that these drugs are effective in patients with progressive MS, although trial results are expected to be available soon. In patients with rapidly progressive disease, it might be worth considering the effect of methotrexate. Future treatment options include new strategies to interfere with disease-relevant, specific or nonspecific immune mechanisms as well as drugs that might promote remyelination. In spite of the advances that have been made over the past few years, symptomatic treatment, including a multidisciplinary rehabilitation approach, remains the mainstay of treatment of the majority of MS patients.

Multiple sclerosis therapy. A practical guide.

A growing amount of evidence suggests that a disturbance of immunological function is of importance in the pathogenesis of multiple sclerosis. This is reflected in the drugs used to slow progression and to treat relapses. Immunosuppressive drugs such as azathioprine, cyclophosphamide and cyclosporin might have some potential to slow down progression of multiple sclerosis, but their use is limited by potentially serious adverse effects. Recently, it was shown that interferon-beta-1b can diminish the exacerbation rate in multiple sclerosis without leading to unacceptable adverse effects. Nevertheless, symptomatic treatment remains of crucial importance in the management of multiple sclerosis patients. Spasticity, depression, fatigue and urinary, paroxysmal and sensory symptoms can all be alleviated to some extent with pharmacological interventions, although rehabilitation procedures and psychosocial consultations are no less important. Further therapeutic approaches to multiple sclerosis will be directed at either the specificity of the immune response or the grade of activation of the immune response. Magnetic resonance imaging techniques will play an important role in the evaluation of efficacy of new therapeutic agents.

[New diagnostic criteria for multiple sclerosis in clinical practice]. / Nieuwe diagnostische criteria voor multiple sclerose in de praktijk.

In two women, aged 29 and 49 years respectively, and a man aged 44 years, neurological signs pointed to multiple sclerosis (MS). In 2001, an international panel of experts revised the diagnostic criteria for multiple sclerosis (MS), which had been in use since 1983. As before, the fundamental diagnostic criterion remains dissemination in time and place of neurological abnormalities suggestive of demyelination. In contrast to the old criteria, the new criteria give diagnostic rules for the diagnosis of primary progressive MS. An even more important step is the further integration of MRI results in the new diagnostic criteria. This allows neurologists to diagnose MS earlier in the disease course, as was the case in the first woman: three months after the first symptoms a new MRI scan revealed dissemination in time. Recent research has shown, that MRI scans are reliable and can be used in clinical practice. If used correctly, the reliability of the diagnosis will also improve. The male patient had word-finding problems that do not fit with MS, and there were more than 9 MRI abnormalities, including juxtacortical, but no periventricular and infratentorial abnormalities. He had a vasculopathy. The second woman had dissemination in time and place, but there was a better explanation for the symptoms: neuromyelitis optica.

[Problems in weaning from artificial ventilation: 'motor neuron disease']. / Problemen bij het ontwennen van kunstmatige ventilatie: 'motor-neuron disease'.

Three patients, two men aged 71 and one aged 73 years, were given artificial respiration because of acute respiratory failure. Subsequently they could not be weaned from artificial respiration, due to causes that were not immediately clear. It was ultimately found that the patients suffered from 'motor neuron disease', in two of them due to progressive spinal muscular atrophy, while the third, apart from loss of anterior horn motor cells, also had thoracic hydromelia. The patients died after termination of the artificial respiration.

[Eyelid drooping: diagnosis on the basis of an algorithm]. / Een hangend ooglid; diagnostiek op basis van een algoritme.

Five patients presented with eyelid drooping (blepharoptosis). A 26-year-old man with oculomotor disorders without anisocoria and a slow progressive course without fluctuations had a myogenic condition. His diplopia was alleviated by prism glasses. Surgical correction of the ptosis was planned. An 81-year-old man in whom the symptoms showed a course that varied over time had a disordered neuromuscular transmission that responded well to pyridostigmine. A 57-year-old man with oculomotor disorders and a dilated pupil on the affected side had an injury to the oculomotor nerve (and other cranial nerves), which remained stable after endovascular treatment of the causative aneurysm. A 22-year-old man had a constricted pupil (Horner's syndrome) and pain in the head and neck due to dissection of the internal carotid; his symptoms disappeared spontaneously. A 34-year-old woman had an isolated ptosis due to detachment of the aponeurosis of the M. levator palpebrae superioris following the chronic use of hard contact lenses; she was advised as to how to remove the lenses cautiously, to prevent further detachment. Eyelid drooping can have many causes. A systematic arrangement of the information gathered by a careful medical history and neurological examination often provides a reasonably accurate indication of the possible causes of the complaints.