Natalizumab induced freedom from disease activity after failure to previous therapy in relapsing remitting multiple sclerosis.
Belachew, Shibeshih ; ; DELVAUX, Valérie et al
Conference (2009, June)
Objectives: To analyze the efficacy of natalizumab after switching relapsing-remitting multiple sclerosis (RRMS) patients from other disease modifying treaments (DMTs). Background: Natalizumab (Tysabri ... [more ▼]
Objectives: To analyze the efficacy of natalizumab after switching relapsing-remitting multiple sclerosis (RRMS) patients from other disease modifying treaments (DMTs). Background: Natalizumab (Tysabri) is a monoclonal antibody directed against VLA4 that was recently approved for the treatment of RRMS. Due to safety concerns, the use should be restricted to highly active patients and/or patients with insufficient response to other DMTs. The pivotal trials were not designed to examine the effect of natalizumab as an escalation monotherapy. Methods: Prospective, open label, observational study. All patients initiating natalizumab had experienced at least 1 relapse in the previous year under DMTs and had at least 1 Gd-enhancing lesion on their brain MRI. Previous treatment with interferon-beta (IFN-beta) or glatiramer acetate (GA) were stopped at least one week and azathioprine or mitoxantrone at least 3 months before switching. The minimum therapy duration with natalizumab was 6 months for all patients. 21 RRMS patients were included in this analysis. The mean age of the patients was 25,5 yo with mean disease duration of 6,8 years. All patients were under IFN-beta (17) or GA (4) during at least the previous year before starting natalizumab therapy. Four patients had also received azathioprine and 1 patient mitoxantrone. Results: The mean relapse rate in the previous year was 2.15 (1-4), the mean EDSS at baseline was 3.3 (1,0-6.0), the mean number of Gd+ lesions at baseline 2,58 (1-6). Under tysabri treatment the annualized relapse rate dropped to 0,20. Eleven patients improved their EDSS (0,5 to 1,5 steps down), others remained stable at 6 months. The mean number of Gd+ T1 lesions dropped to 0,23 and the mean number of new T2 lesions was 0.25 on the control MRI at 6 months. 55% of patients were free from disease activity, i.e. had no relapses, no EDSS progression, no new T2 lesion and no Gd+ T1 lesions after 6 months of Tysabri. 5 patients experienced minor adverse events (1 zona, 2 flu-like symptoms, 1 gastroenteritis, 1 allergic reaction). Conclusion: Natalizumab was well tolerated and safe as escalation therapy when previous DMTs had failed to control disease progression in this group of highly active RRMS patients. These results suggest comparable efficacy to the phase III AFFIRM trial of natalizumab when the drug is used in a context of breakthrough disease. Although data from preliminary analyses are promising, long term investigations are warranted. [less ▲]Detailed reference viewed: 45 (0 ULg)
The timed 100-meter walk test: an easy-t-use, sensitive tool to detect and evaluate restricted walking capacities in multiple sclerosis.
Belachew, Shibeshih ; CALAY, Philippe ; DELVAUX, Valérie et al
Conference (2009, June)
Objectives: The primary aim of this study was to develop a quantitative ambulation test that correlates with the maximal walking distance in multiple sclerosis (MS) patients. Background: The timed 25-foot ... [more ▼]
Objectives: The primary aim of this study was to develop a quantitative ambulation test that correlates with the maximal walking distance in multiple sclerosis (MS) patients. Background: The timed 25-foot walk (T25FW) weakly correlates with overall walking capacities of MS patients. We developed the timed 100-meter walk test (T100T), which besides reflecting speed may be more sensitive to other walking parameters such as gait and spasticity-related fatigue. Methods: In the T100T, the patient is instructed to walk as fast as possible on a distance of 100 meters. Eighty-eight MS patients with an EDSS score from 0 to 5.5 and 60 normal controls performed the T100T and the T25FW. In addition, 30 normal controls and 30 patients performed the tests twice. Results: T25FW (R2= 0.79) and T100T (R2 = 0.89) correlated with the nonlinear distribution of EDSS scores. The correlation between T100T and T25FW values was high (r2 = 0.81) for the low (0 to 3.0) and high (3.5-5.5) scores of EDSS. The intra-class correlations were excellent and similar for both tests. The range of T100T values in MS patients (40.4 to 114.7 seconds) was 10-fold wider than that of the T25FW (3.0 to 9.1 seconds). The univariate distribution analyses demonstrated that abnormal T100T values appear to be more sensitive than T25FW to predict walking limitations. Finally, the correlation with the reported and/or actual maximal walking distance without aid and rest was significantly better for T100T. Conclusions : The T100T proves to be superior to the T25FW in terms of discriminatory power for the detection and evaluation of restricted walking capacities in MS. The T100T should be of interest for clinical trials studying disability worsening and improvement across the spectrum of EDSS. It may provide more sensitive measure for ambulation change in quantifying progressive MS pathology. [less ▲]Detailed reference viewed: 109 (2 ULg)
Elongator controls the migration and differentiation of cortical neurons through acetylation of a tubulin
Creppe, Catherine ; Malinouskaya, Lina ; Volvert, Marie-Laure et al
in Cell (2009), 136
The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here we report that the multi-subunit histone acetyltransferase Elongator complex, which ... [more ▼]
The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here we report that the multi-subunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha tubulin. A direct reduction of alpha tubulin acetylation leads to comparable defects in cortical neurons and suggests that alpha tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons. [less ▲]Detailed reference viewed: 299 (105 ULg)
Les anticorps monoclonaux en neurologie.
JEDIDI, Zayd ; Jedidi, Haroun ; Moonen, Gustave et al
in Revue Médicale de Liège (2009), 64(5-6), 305-9
Since their inception in the 1970's, monoclonal antibody therapies became increasingly efficient and common in numerous medical conditions and their use in neurology has been boosted during the last ... [more ▼]
Since their inception in the 1970's, monoclonal antibody therapies became increasingly efficient and common in numerous medical conditions and their use in neurology has been boosted during the last couple of years with the rise of natalizumab (Tysabri). Furthermore, if most monoclonal antibodies currently assessed in neurologic conditions remain considered as experimental, they may soon become first-line approved treatments in a broad range of neuromuscular and demyelinating diseases. Since the introduction of new therapies is likely to unravel specific adverse events and sui generis iatrogenic disorders, it is important to be able to recognize the side-effects of monoclonal antibodies delivered for neurological or non-neurological diseases. [less ▲]Detailed reference viewed: 196 (22 ULg)
Adult neurogenesis and the diseased brain.
Vandenbosch, Renaud ; Borgs, Laurence ; Beukelaers, Pierre et al
in Current Medicinal Chemistry (2009), 16(6), 652-66
For a long time it was believed that the adult mammalian brain was completely unable to regenerate after insults. However, recent advances in the field of stem cell biology, including the identification ... [more ▼]
For a long time it was believed that the adult mammalian brain was completely unable to regenerate after insults. However, recent advances in the field of stem cell biology, including the identification of adult neural stem cells (NSCs) and evidence regarding a continuous production of neurons throughout life in the dentate gyrus (DG) and the subventricular zone of the lateral ventricles (SVZ), have provided new hopes for the development of novel therapeutic strategies to induce regeneration in the damaged brain. Moreover, proofs have accumulated this last decade that endogenous stem/progenitor cells of the adult brain have an intrinsic capacity to respond to brain disorders. Here, we first briefly summarize our current knowledge related to adult neurogenesis before focusing on the behaviour of adult neural stem/progenitors cells following stroke and seizure, and describe some of the molecular cues involved in the response of these cells to injury. In the second part, we outline the consequences of three main neurodegenerative disorders on adult neurogenesis and we discuss the potential therapeutic implication of adult neural stem/progenitors cells during the course of these diseases. [less ▲]Detailed reference viewed: 61 (18 ULg)
Period 2 regulates neural stem/progenitor cell proliferation in the adult hippocampus.
Borgs, Laurence ; Beukelaers, Pierre ; Vandenbosch, Renaud et al
in BMC Neuroscience (2009), 10
BACKGROUND: Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Since light ... [more ▼]
BACKGROUND: Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Since light/dark variations of the mitotic index and DNA synthesis occur in many tissues, we wanted to unravel the role of the clock-controlled Period2 gene (mPer2) in timing cell cycle kinetics and neurogenesis in the adult DG. RESULTS: In contrast to the suprachiasmatic nucleus, we observed a non-rhythmic constitutive expression of mPER2 in the dentate gyrus. We provide evidence that mPER2 is expressed in proliferating neural stem/progenitor cells (NPCs) and persists in early post-mitotic and mature newborn neurons from the adult DG. In vitro and in vivo analysis of a mouse line mutant in the mPer2 gene (Per2Brdm1), revealed a higher density of dividing NPCs together with an increased number of immature newborn neurons populating the DG. However, we showed that the lack of mPer2 does not change the total amount of mature adult-generated hippocampal neurons, because of a compensatory increase in neuronal cell death. CONCLUSION: Taken together, these data demonstrated a functional link between the constitutive expression of mPER2 and the intrinsic control of neural stem/progenitor cells proliferation, cell death and neurogenesis in the dentate gyrus of adult mice. [less ▲]Detailed reference viewed: 48 (11 ULg)
Transcranial magnetic stimulation in disorders of consciousness
; Gosseries, Olivia ; DELVAUX, Valérie et al
in Reviews in the Neurosciences (2009), 20(3-4), 235-250Detailed reference viewed: 27 (8 ULg)
Pain and non-pain processing during hypnosis: a thulium-YAG event-related fMRI study.
Vanhaudenhuyse, Audrey ; Boly, Mélanie ; Balteau, Evelyne et al
in NeuroImage (2009), 47(3), 1047-54
The neural mechanisms underlying the antinociceptive effects of hypnosis still remain unclear. Using a parametric single-trial thulium-YAG laser fMRI paradigm, we assessed changes in brain activation and ... [more ▼]
The neural mechanisms underlying the antinociceptive effects of hypnosis still remain unclear. Using a parametric single-trial thulium-YAG laser fMRI paradigm, we assessed changes in brain activation and connectivity related to the hypnotic state as compared to normal wakefulness in 13 healthy volunteers. Behaviorally, a difference in subjective ratings was found between normal wakefulness and hypnotic state for both non-painful and painful intensity-matched stimuli applied to the left hand. In normal wakefulness, non-painful range stimuli activated brainstem, contralateral primary somatosensory (S1) and bilateral insular cortices. Painful stimuli activated additional areas encompassing thalamus, bilateral striatum, anterior cingulate (ACC), premotor and dorsolateral prefrontal cortices. In hypnosis, intensity-matched stimuli in both the non-painful and painful range failed to elicit any cerebral activation. The interaction analysis identified that contralateral thalamus, bilateral striatum and ACC activated more in normal wakefulness compared to hypnosis during painful versus non-painful stimulation. Finally, we demonstrated hypnosis-related increases in functional connectivity between S1 and distant anterior insular and prefrontal cortices, possibly reflecting top-down modulation. [less ▲]Detailed reference viewed: 143 (29 ULg)
Detecting consciousness in a total Locked-in syndrome: an active event related paradigm
Schnakers, Caroline ; ; et al
in Neurocase : Case Studies in Neuropsychology, Neuropsychiatry & Behavioural Neurology (2009), 25
Total locked-in syndrome is characterized by tetraplegia, anarthria and paralysis of eye motility. In this study, consciousness was detected in a 21-year-old woman who presented a total locked-in syndrome ... [more ▼]
Total locked-in syndrome is characterized by tetraplegia, anarthria and paralysis of eye motility. In this study, consciousness was detected in a 21-year-old woman who presented a total locked-in syndrome after a basilar artery thrombosis (49 days post-injury) using an active event-related paradigm. The patient was presented sequences of names containing the patient's own name and other names. The patient was instructed to count her own name or to count another target name. Similar to 4 age- and gender-matched healthy controls, the P3 response recorded for the voluntarily counted own name was larger than while passively listening. This P3 response was observed 14 days before the first behavioral signs of consciousness. This study shows that our active event-related paradigm allowed to identify voluntary brain activity in a patient who would behaviorally be diagnosed as comatose. [less ▲]Detailed reference viewed: 72 (9 ULg)
La vignette thérapeutique de l'étudiant. La maladie de Parkinson debutante
DELVAUX, Valérie ; MOONEN, Gustave ; Garraux, Gaëtan
in Revue Médicale de Liège (2009), 64(4), 228-32
We present a discussion on the treatment options in the case of a patient seen at the outpatient abnormal movement clinic for a resting tremor of both hands. Signs and symptoms of the parkinsonian ... [more ▼]
We present a discussion on the treatment options in the case of a patient seen at the outpatient abnormal movement clinic for a resting tremor of both hands. Signs and symptoms of the parkinsonian syndrome are summarized as well as the current treatment options of early Parkinson's disease. [less ▲]Detailed reference viewed: 137 (17 ULg)
A clinico-pathological report of SCA17 associated with a heterozygote small trinucleotide expansion
Garraux, Gaëtan ; Moonen, Gustave ; Deprez, Manuel
in Movement Disorders : Official Journal of the Movement Disorder Society (2009), 24(Suppl. 1), 12-12Detailed reference viewed: 19 (6 ULg)
De novo interstitial duplication 4q associated with sporadic young-onset dopa-responsive parkinsonism
Garraux, Gaëtan ; VANBELLINGHEN, Jean-François ; JAMAR, Mauricette et al
in Movement Disorders : Official Journal of the Movement Disorder Society (2009), 24(Suppl. 1), 138-139Detailed reference viewed: 9 (2 ULg)
Neural substrates of phonological and lexicosemantic representations in Alzheimer's disease.
; Majerus, Steve ; Collette, Fabienne et al
in Human Brain Mapping (2009), 30(1), 185-99
The language profile of patients suffering from Alzheimer's disease (AD) is characterized not only by lexicosemantic impairments but also by phonological deficits, as shown by an increasing number of ... [more ▼]
The language profile of patients suffering from Alzheimer's disease (AD) is characterized not only by lexicosemantic impairments but also by phonological deficits, as shown by an increasing number of neuropsychological studies. This study explored the functional neural correlates underlying phonological and lexicosemantic processing in AD. Using H(215)O PET functional brain imaging, a group of mild to moderate AD patients and a group of age-matched controls were asked to repeat four types of verbal stimuli: words, wordlike nonwords (WL+), non-wordlike nonwords (WL-) and simple vowels. The comparison between the different conditions allowed us to determine brain activation preferentially associated with lexicosemantic or phonological levels of language representations. When repeating words, AD patients showed decreased activity in the left temporo-parietal and inferior frontal regions relative to controls, consistent with distorted lexicosemantic representations. Brain activity was abnormally increased in the right superior temporal area during word repetition, a region more commonly associated with perceptual-phonological processing. During repetition of WL+ and WL- nonwords, AD patients showed decreased activity in the middle part of the superior temporal gyrus, presumably associated with sublexical phonological information; at the same time, AD patients showed larger activation than controls in the inferior temporal gyrus, typically associated with lexicosemantic levels of representation. Overall, the results suggest that AD patients use altered pathways to process phonological and lexicosemantic information, possibly related to a progressive loss of specialization of phonological and lexicosemantic neural networks. [less ▲]Detailed reference viewed: 138 (19 ULg)
Functional connectivity in the default network during resting state is preserved in a vegetative but not in a brain dead patient.
Boly, Mélanie ; Tshibanda, Luaba ; Vanhaudenhuyse, Audrey et al
in Human Brain Mapping (2009), 30(8), 2393-400
Recent studies on spontaneous fluctuations in the functional MRI blood oxygen level-dependent (BOLD) signal in awake healthy subjects showed the presence of coherent fluctuations among functionally ... [more ▼]
Recent studies on spontaneous fluctuations in the functional MRI blood oxygen level-dependent (BOLD) signal in awake healthy subjects showed the presence of coherent fluctuations among functionally defined neuroanatomical networks. However, the functional significance of these spontaneous BOLD fluctuations remains poorly understood. By means of 3 T functional MRI, we demonstrate absent cortico-thalamic BOLD functional connectivity (i.e. between posterior cingulate/precuneal cortex and medial thalamus), but preserved cortico-cortical connectivity within the default network in a case of vegetative state (VS) studied 2.5 years following cardio-respiratory arrest, as documented by extensive behavioral and paraclinical assessments. In the VS patient, as in age-matched controls, anticorrelations could also be observed between posterior cingulate/precuneus and a previously identified task-positive cortical network. Both correlations and anticorrelations were significantly reduced in VS as compared to controls. A similar approach in a brain dead patient did not show any such long-distance functional connectivity. We conclude that some slow coherent BOLD fluctuations previously identified in healthy awake human brain can be found in alive but unaware patients, and are thus unlikely to be uniquely due to ongoing modifications of conscious thoughts. Future studies are needed to give a full characterization of default network connectivity in the VS patients population. [less ▲]Detailed reference viewed: 85 (20 ULg)
Different beliefs about pain perception in the vegetative and minimally conscious states: a European survey of medical and paramedical professionals.
Demertzi, Athina ; Schnakers, Caroline ; Ledoux, Didier et al
in Progress in Brain Research (2009), 177
Pain management in severely brain-damaged patients constitutes a clinical and ethical stake. At the bedside, assessing the presence of pain and suffering is challenging due to both patients' physical ... [more ▼]
Pain management in severely brain-damaged patients constitutes a clinical and ethical stake. At the bedside, assessing the presence of pain and suffering is challenging due to both patients' physical condition and inherent limitations of clinical assessment. Neuroimaging studies support the existence of distinct cerebral responses to noxious stimulation in brain death, vegetative state, and minimally conscious state. We here provide results from a European survey on 2059 medical and paramedical professionals' beliefs on possible pain perception in patients with disorders of consciousness. To the question "Do you think that patients in a vegetative state can feel pain?," 68% of the interviewed paramedical caregivers (n=538) and 56% of medical doctors (n=1166) answered "yes" (no data on exact profession in 17% of total sample). Logistic regression analysis showed that paramedical professionals, religious caregivers, and older caregivers reported more often that vegetative patients may experience pain. Following professional background, religion was the highest predictor of caregivers' opinion: 64% of religious (n=1009; 850 Christians) versus 52% of nonreligious respondents (n=830) answered positively (missing data on religion in 11% of total sample). To the question "Do you think that patients in a minimally conscious state can feel pain?" nearly all interviewed caregivers answered "yes" (96% of the medical doctors and 97% of the paramedical caregivers). Women and religious caregivers reported more often that minimally conscious patients may experience pain. These results are discussed in terms of existing definitions of pain and suffering, the remaining uncertainty on the clinical assessment of pain as a subjective first-person experience and recent functional neuroimaging findings on nociceptive processing in disorders of consciousness. In our view, more research is needed to increase our understanding of residual sensation in vegetative and minimally conscious patients and to propose evidence-based medical guidelines for the management of possible pain perception and suffering in these vulnerable patient populations. [less ▲]Detailed reference viewed: 43 (11 ULg)
Diagnostic accuracy of the vegetative and minimally conscious state: clinical consensus versus standardized neurobehavioral assessment.
Schnakers, Caroline ; Vanhaudenhuyse, Audrey ; et al
in BMC Neurology (2009), 9
BACKGROUND: Previously published studies have reported that up to 43% of patients with disorders of consciousness are erroneously assigned a diagnosis of vegetative state (VS). However, no recent studies ... [more ▼]
BACKGROUND: Previously published studies have reported that up to 43% of patients with disorders of consciousness are erroneously assigned a diagnosis of vegetative state (VS). However, no recent studies have investigated the accuracy of this grave clinical diagnosis. In this study, we compared consensus-based diagnoses of VS and MCS to those based on a well-established standardized neurobehavioral rating scale, the JFK Coma Recovery Scale-Revised (CRS-R). METHODS: We prospectively followed 103 patients (55 +/- 19 years) with mixed etiologies and compared the clinical consensus diagnosis provided by the physician on the basis of the medical staff's daily observations to diagnoses derived from CRS-R assessments performed by research staff. All patients were assigned a diagnosis of 'VS', 'MCS' or 'uncertain diagnosis.' RESULTS: Of the 44 patients diagnosed with VS based on the clinical consensus of the medical team, 18 (41%) were found to be in MCS following standardized assessment with the CRS-R. In the 41 patients with a consensus diagnosis of MCS, 4 (10%) had emerged from MCS, according to the CRS-R. We also found that the majority of patients assigned an uncertain diagnosis by clinical consensus (89%) were in MCS based on CRS-R findings. CONCLUSION: Despite the importance of diagnostic accuracy, the rate of misdiagnosis of VS has not substantially changed in the past 15 years. Standardized neurobehavioral assessment is a more sensitive means of establishing differential diagnosis in patients with disorders of consciousness when compared to diagnoses determined by clinical consensus. [less ▲]Detailed reference viewed: 57 (4 ULg)
La vignette de l'etudiant. Conseils pratiques pour le redaction d'un cas clinique.
Scheen, André ; Moonen, Gustave
in Revue Médicale de Liège (2009), 64(7-8), 418-22
Case reports are the most accessible publications to the medical student or the practitioner. The appropriate selection of the clinical case that deserves publication is an important first step in the ... [more ▼]
Case reports are the most accessible publications to the medical student or the practitioner. The appropriate selection of the clinical case that deserves publication is an important first step in the process. Afterwards, the report of the case requests much attention, as far as both content and presentation are concerned. The key-message emerging from the clinical case should be emphasized and supported by a clear-cut argumentation. Such an exercise, which might appear difficult at first glance, represents a valuable training for further more complex scientific publications. Here we give some practical advices to help the student or the practitioner who would like to present or publish a case report. [less ▲]Detailed reference viewed: 114 (12 ULg)
Severe liver dysfunction in a patient with multiple sclerosis: the guilty party is not always the disease-modifying therapy
; Belachew, Shibeshih ; Moonen, Gustave et al
in Multiple Sclerosis : Clinical & Laboratory Research (2009), 15(11), 1378-1379Detailed reference viewed: 56 (12 ULg)
Guillain-Barré syndrome following hepatitis E
Loly, Jean-Philippe ; Rikir, Estelle ; Seivert, Maxime et al
in World Journal of Gastroenterology (2009), 15(13), 1645-1647
Guillain-Barré syndrome (GBS) is often triggered by a preceding bacterial or viral infection. Occasionally, it has been observed in association with acute hepatitis A, B and C, and three cases have been ... [more ▼]
Guillain-Barré syndrome (GBS) is often triggered by a preceding bacterial or viral infection. Occasionally, it has been observed in association with acute hepatitis A, B and C, and three cases have been previously described in India in which GBS was associated with acute hepatitis E. A molecular mimicry mechanism is supposed to be involved in the pathogenesis of GBS triggered by infectious agents, although the nature of the shared epitopes has not been characterized in most instances, including that in the case of hepatotropic viruses. We report a case of GBS following acute hepatitis E in a European individual. The presence of antiganglioside GM2 antibodies in this patient suggested molecular mimicry involving ganglioside GM2 in the pathogenesis of GBS associated with hepatitis E. [less ▲]Detailed reference viewed: 74 (9 ULg)