Assessment of potential cardiotoxic side effects of mitoxantrone in patients with multiple sclerosis

Previous studies showed that mitoxantrone can reduce disability progression in patients with multiple sclerosis (MS). There is, however, concern that it may cause irreversible cardiomyopathy with reduced left ventricular (LV) ejection fraction (EF) and congestive heart failure. The aim of this prospective study was to investigate cardiac side effects of mitoxantrone by repetitive cardiac monitoring in MS patients. The treatment protocol called for ten courses of a combined mitoxantrone (10 mg/m(2) body surface) and methylprednisolone therapy. Before each course, a transthoracic echocardiogram was performed to determine the LV end-diastolic diameter, the end-systolic diameter and the fractional shortening; the LV-EF was calculated. Seventy-three patients participated (32 males; age 48 +/- 12 years, range 20-75 years; 25 with primary progressive, 47 with secondary progressive and 1 with relapsing-remitting MS) who received at least four courses of mitoxantrone. Three of the 73 patients were excluded during the study (2 patients discontinued therapy; 1 patient with a previous history of ischemic heart disease developed atrial fibrillation after the second course of mitoxantrone). The mean cumulative dose of mitoxantrone was 114.0 +/- 33.8 mg. The mean follow-up time was 23.4 months (range 10-57 months). So far, there has been no significant change in any of the determined parameters (end-diastolic diameter, end-systolic diameter, fractional shortening, EF) over time during all follow-up investigations. Mitoxantrone did not cause signs of congestive heart failure in any of the patients. Further cardiac monitoring is, however, needed to determine the safety of mitoxantrone after longer follow-up times and at higher cumulative doses. Copyright (C) 2005 S. Karger AG, Basel

Marburg variant of multiple sclerosis; a diagnostic and therapeutic challenge

Marburg variant of multiple sclerosis (MS) is a highly aggressive, fulminant demyelinating disease with very high morbidity and mortality. Early diagnosis and aggressive management is vital to limit severe disability and improve the outcome. We present a case of 35 years old male who presented with rapidly progressive demyelinating illness, leading to bed bound status over the course of a month. He was treated aggressively with intravenous (IV) steroids, plasma exchange (PLEX) and Mitoxantrone (MTX), leading to a remarkable recovery

Differential expression of ADAMTS -1, -4, -5 and TIMP -3 in rat spinal cord at different stages of acute experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an animal model of inflammatory demyelination, a pathological event common to multiple sclerosis (MS). During CNS inflammation there are alterations in the extracellular matrix (ECM). A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) -1, -4 and -5 are proteases present in the CNS, which are able to cleave the aggregating chondroitin sulphate proteoglycans, aggrecan, phosphacan, neurocan and brevican. It is therefore important to investigate changes in their expression in different stages of EAE induction. We have investigated expression of ADAMTS-1, -4, -5 and Tissue inhibitor of metalloproteinase (TIMP) -3, by real-time RT-PCR. We have also examined protein expression of ADAMTS-1, -4 and -5 by western blotting and immunocytochemistry in spinal cord from animals at different stages of disease progression. Our study demonstrated a decrease in ADAMTS-4 mRNA and protein expression. TIMP-3 was decreased at the mRNA level although protein levels were increased in diseased animals compared to controls. Our study identifies changes in ADAMTS expression during the course of CNS inflammation which may contribute to ECM degradation and disease progression.</p

White Matter Atrophy and Cognitive Dysfunctions in Neuromyelitis Optica

Neuromyelitis optica (NMO) is an inflammatory disease of central nervous system characterized by optic neuritis and longitudinally extensive acute transverse myelitis. NMO patients have cognitive dysfunctions but other clinical symptoms of brain origin are rare. In the present study, we aimed to investigate cognitive functions and brain volume in NMO. The study population consisted of 28 patients with NMO and 28 healthy control subjects matched for age, sex and educational level. We applied a French translation of the Brief Repeatable Battery (BRB-N) to the NMO patients. Using SIENAx for global brain volume (Grey Matter, GM; White Matter, WM; and whole brain) and VBM for focal brain volume (GM and WM), NMO patients and controls were compared. Voxel-level correlations between diminished brain concentration and cognitive performance for each tests were performed. Focal and global brain volume of NMO patients with and without cognitive impairment were also compared. Fifteen NMO patients (54%) had cognitive impairment with memory, executive function, attention and speed of information processing deficits. Global and focal brain atrophy of WM but not Grey Matter (GM) was found in the NMO patients group. The focal WM atrophy included the optic chiasm, pons, cerebellum, the corpus callosum and parts of the frontal, temporal and parietal lobes, including superior longitudinal fascicle. Visual memory, verbal memory, speed of information processing, short-term memory and executive functions were correlated to focal WM volumes. The comparison of patients with, to patients without cognitive impairment showed a clear decrease of global and focal WM, including brainstem, corticospinal tracts, corpus callosum but also superior and inferior longitudinal fascicles. Cognitive impairment in NMO patients is correlated to the decreased of global and focal WM volume of the brain. Further studies are needed to better understand the precise origin of cognitive impairment in NMO patients, particularly in the WM

Age-dependent favorable visual recovery despite significant retinal atrophy in pediatric MOGAD: how much retina do you really need to see well?

BACKGROUND To investigate age-related severity, patterns of retinal structural damage, and functional visual recovery in pediatric and adult cohorts of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) optic neuritis (ON). METHODS All MOGAD patients from the 5 participating centers were included. Patients with initial manifestation 0.5) visual impairment. Independent of retinal atrophy, age at ON onset significantly correlated with visual outcome. CONCLUSION Pediatric MOGAD ON showed better visual recovery than adult MOGAD ON despite profound and almost identical neuroaxonal retinal atrophy. Age-related cortical neuroplasticity may account for the substantial discrepancy between structural changes and functional outcomes

Very late-onset neuromyelitis optica spectrum disorder beyond the age of 75

Aquaporin-4 antibody (AQP4-Ab)-positive neuromyelitis optica spectrum disorder (NMOSD) is a rare but often severe autoimmune disease with median onset around 40 years of age. We report characteristics of three very-late-onset NMOSD (including complete NMO) patients >75 years of age, in whom this diagnosis initially seemed unlikely because of their age and age-associated concomitant diseases, and briefly review the literature. All three patients, aged 79, 82 and 88 years, presented with a spinal cord syndrome as the first clinical manifestation of AQP4-Ab-positive NMOSD. They all had severe relapses unless immunosuppressive therapy was initiated, and one untreated patient died of a fatal NMOSD course. Two patients developed side effects of immunosuppression. We conclude that a first manifestation of NMOSD should be considered even in patients beyond the age of 75 years with a compatible syndrome, especially longitudinally extensive myelitis. Early diagnosis and treatment are feasible and highly relevant. Special attention is warranted in the elderly to recognize adverse effects of immunosuppressive therapies as early as possible

Age-dependent favorable visual recovery despite significant retinal atrophy in pediatric MOGAD: how much retina do you really need to see well?

Neuritis òptica; Tomografia de coherència òpticaNeuritis óptica; Tomografía de coherencia ópticaOptic neuritis; Optical coherence tomographyBackground To investigate age-related severity, patterns of retinal structural damage, and functional visual recovery in pediatric and adult cohorts of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) optic neuritis (ON). Methods All MOGAD patients from the 5 participating centers were included. Patients with initial manifestation <18 years were included in the pediatric (MOGADped) cohort and patients with ≥18 years in the adult (MOGADadult) cohort. For patients with MOGAD ON, examinations at least ≥6 months after ON onset were included in the analyses. Using spectral domain optical coherence tomography (SD-OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIPL). High- and 2.5% low-contrast visual acuity (HCVA, LCVA) and visual-evoked potentials (VEP) were obtained. Results Twenty MOGADped (10.3±3.7 years, 30 MOGAD ON eyes) and 39 MOGADadult (34.9±11.6 years, 42 MOGAD ON eyes) patients were included. The average number of ON episodes per ON eye was similar in both groups (1.8±1.3 and 2.0±1.7). In both pediatric and adult MOGAD, ON led to pronounced neuroaxonal retinal atrophy (pRNFL: 63.1±18.7 and 64.3±22.9 μm; GCIPL: 0.42±0.09 and 0.44±0.13 mm3, respectively) and moderate delay of the VEP latencies (117.9±10.7 and 118.0±14.5 ms). In contrast, visual acuity was substantially better in children (HCVA: 51.4±9.3 vs. 35.0±20.6 raw letters, p=0.001; LCVA: 22.8±14.6 vs. 13.5±16.4, p=0.028). Complete visual recovery (HCVA-logMAR 0.0) occurred in 73.3% of MOGADped and 31% MOGADadults ON eyes, while 3.3% and 31% demonstrated moderate to severe (logMAR > 0.5) visual impairment. Independent of retinal atrophy, age at ON onset significantly correlated with visual outcome. Conclusion Pediatric MOGAD ON showed better visual recovery than adult MOGAD ON despite profound and almost identical neuroaxonal retinal atrophy. Age-related cortical neuroplasticity may account for the substantial discrepancy between structural changes and functional outcomes.JH is (partially) funded by the German Federal Ministry of Education and Research (Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H] (DIFUTURE)). Open Access funding enabled and organized by Projekt DEAL

La sclerose en plaques en milieu hospitalier a Libreville. A propos de deux cas et revue de la litterature

Introduction: La sclérose en plaques est une pathologie rarement diagnostiquée en Afrique noire. Description: Nous rapportons le cas de deux patientes, respectivement âgées de 23 ans et de 18 ans au début des troubles. La première patiente a été vue initialement pour des troubles visuels et présenta par la suite des signes encéphaliques cérébelleux et pyramidaux. Deux ans plus tard, survenait une seconde poussée marquée par l‘installation d‘un syndrome lésionnel. L‘imagerie par résonance magnétique cérébrale objectivait de nombreuses plaques de démyélinisation sus et sous-tentorielles. Ultérieurement, l‘imagerie médullaire réalisée mettait en évidence une plaque au niveau cervical. La deuxième patiente, rapportait également au début une baisse de l‘acuité visuelle puis plus tard un trouble sensitivo-moteur. L‘étude du LCR a objectivé une discrète augmentation de l‘index IgG.&nbsp; L‘imagerie cérébrale concluait à des multiples hypersignaux flair et T2 disséminés de la substance blanche péri-ventriculaire, du tronc cérébral et de la moelle épinière cervicale. Au niveau médullaire, on notait la présence de plaques de démyélinisation médullaire cervicale en regard de C3. Le diagnostic de sclérose en plaques dans sa forme rémittente a été retenu dans les deux cas sur la dissémination spatio-temporelle apportée par les critères clinico-radiologiques. Le traitement prescrit était uniquement celui de la poussée inflammatoire vu l‘absence d‘immunomodulateurs. Conclusion: La sclérose en plaques au Gabon parait avoir les mêmes caractéristiques cliniques que dans les zones tempérées.&nbsp;&nbsp; L‘avènement de l‘imagerie par résonance magnétique ces dernières années pourrait expliquer la fréquence des cas rapportés. &nbsp; English title: Multiple sclerosis in Libreville, Gabon. about two cases and literature review &nbsp; Introduction: Multiple sclerosis is a disease rarely diagnosed in Africa. We report the case of two patients, 23-years-old and 18- years-old, at the beginning of the disorders. Description: The first patient was seen initially for visual disturbances and presented cerebellar and pyramidal encephalic features. Two years later, there was a second surge marked by the installation of an injury&nbsp; syndrome. Cerebral MRI revealed many additional demyelinated sustentorial and infratentorial plaques. Subsequently, the spinal cord imaging showed a cervical plaque. The second patient, also reported at first a decrease in visual acuity and later a sensory-motor disorder. The CSF study showed a slight increase in the IgG index. Brain imaging showed multiple FLAIR and T2 hyperintensities disseminated on the periventricular white matter, brainstem and cervical spinal cord. On the spinal cord, there were cervical demyelinating plaques opposite to the C3 vertebra. The diagnosis of multiple sclerosis in its relapsing form was retained in both cases on the spatio-temporal dissemination provided by clinico-radiological criteria. The treatment was only corticotherapy given the absence of immunomodulators. Multiple sclerosis in Gabon seems to have the same clinical features as in temperate zones. The advent of magnetic resonance imaging in recent years may explain the reported case frequency