Jean-Baptiste Chanson

White matter volume is decreased in the brain of patients with neuromyelitis optica.

Neuromyelitis optica (NMO) is an inflammatory disease involving predominantly the spinal cord and optic nerves. Whether patients with NMO have a loss in white or grey matter (GM) volumes remains to be determined.

Evaluation of health‐related quality of life, fatigue and depression in neuromyelitis optica

Background:  The burden of multiple sclerosis (MS) includes fatigue, depression and worsening of health‐related quality of life (HRQOL). These changes have not been yet measured in neuromyelitis optica (NMO). Our aim was to assess the HRQOL, fatigue and depression in NMO.

Diffusion tensor imaging of normal-appearing white matter in neuromyelitis optica.

OBJECTIVES Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterized by severe attacks of optic neuritis and myelitis. Brain was classically, unlike in multiple sclerosis (MS), spared. Nevertheless recent studies showed that brain lesions can be seen with MRI. We studied the diffusion characteristics of normal-appearing white matter (NAWM) and abnormal white matter in NMO patients compared with NAWM in healthy subjects. PATIENTS AND METHODS Diffusion tensor imaging (DTI) scans of the brain and spinal cord were obtained from 25 patients with NMO and 20 age- and gender-matched healthy subjects. Region of interest (ROI) analysis of the apparent diffusivity coefficient (ADC) and fractional anisotropy (FA) was performed in brain NAWM (optic radiations, corpus callosum [CC] and anterior and posterior limbs of the internal capsule [IC]) and in spinal cord NAWM and in lesions. RESULTS ADC was increased and FA decreased in NMO patients in the posterior limb of the IC in the optic radiations and in spinal cord NAWM. FA was lower in spinal cord lesions. In contrast, there was no difference between the two groups in the anterior limb of the IC nor in the CC. CONCLUSION These results suggest that DTI abnormalities are very severe in NMO spinal cord lesions. In our study, DTI abnormalities in NAWM were restricted to optic radiations and cortico-spinal tracts, suggesting secondary Wallerian degeneration. In contrast, NAWM outside these tracts (CC and anterior IC) remained normal suggesting that, unlike what is observed in MS, there is no infra-lesional abnormality in NMO.

Reduction of the washout time between natalizumab and fingolimod

Drugs such as natalizumab (Tysabri) and fingolimod (Gilenya) are now available to treat multiple sclerosis (MS) and are usually proposed for patients with active MS. Several studies recently reported that the disease was frequently reactivated between 3 and 6 months after the withdrawal of Tysabri treatment.1–2 These results suggest the need for a therapeutic alternative that can be quickly introduced if Tysabri has to be withdrawn. However, there are also recommendations for a delay of 3 months between two immunosuppressive drugs. We extracted clinical data from the all patients in our region (Alsace, France) who had received at least one month of Gilenya treatment (n=164) between the 1 January 2012 and 1 January 2013. Some 59 patients in this cohort (36%) had switched from Tysabri to Gilenya, mainly due to positive JC virus serology (96.6%). All patients had stopped Tysabri at least 6 months before the time of data analysis, thus allowing us to evaluate the high-risk period (3–6 months) for MS reactivation. We then compared the subgroup of patients with and the subgroup of patients without relapses in terms of the mean delay between stopping Tysabri and starting Gilenya. We also compared the frequency of relapses in patients treated with Gilenya less than 3 months after stopping Tysabri and those treated 3 months or more after. The mean time on Gilenya treatment was 7 months (range: 1–12 months). All patients but three (94.9%) were treated with Gilenya for 6 months or more and were still receiving the treatment at the end of the study. Of the three patients who stopped Gilenya, one stopped because of disease reactivation (three relapses in 5 months) and two stopped because of side effects (gastro-intestinal symptoms) after 1 month. We did not find any differences between the two subgroups regarding age, sex ratio, Expanded Disability Status Scale (EDSS) score or disease duration. Eleven patients (18.6%) had at least one relapse. We observed eight patients (50%) with at least one relapse in the subgroup treated with Gilenya after a delay of 3 months or more (n=16) but only three patients (7%) in the group treated after a delay of less than 3 months (n=43) (p=0.02). The mean delay between the two drugs was 1.7 months (±0.55) for the whole cohort. However, in the subgroup without relapses the mean delay was 1.3 months (±0.32) versus 3.3 months (±1.1) in the group with relapses (p<0.05). Our results clearly argue in favour of an early switch between Tysabri and Gilenya instead of applying the classical washout period of 3 months or more. These results are in accordance with the recent studies showing frequent relapses in patients treated with Gilenya after a delay of 3 months or more.3–5 We recommend reducing as much as possible the delay between the withdrawal of natalizumab and the introduction of fingolimod, to reduce the likelihood of a reactivation of the disease during this high-risk period. One month could be a suitable delay, but this proposition will need to be confirmed in larger studies.

Foreign accent syndrome as a first sign of multiple sclerosis

Background Foreign accent syndrome (FAS) consists of a speech rhythm disorder different from dysarthia or aphasia. It is unusually met in multiple sclerosis (MS). Objective We report a case of FAS as an initial symptom of a MS. Methods A right-handed French woman developed an isolated German foreign accent. Brain magnetic resonance imaging (MRI), SPECT and analysis of CSF were performed. Results Brain MRI revealed a large hypersignal on T2-weighted images in the left prerolandic white matter. Single photon emission computed tomography showed a right prerolandic hypoperfusion. Unmatched oligoclonal bands in cerebrospinal fluid and occurrence of new abnormal hypersignals on the following MRI led us to diagnose MS. Conclusion FAS may be the first symptom of MS. It could result from extensive disturbances of brain function involving the right hemisphere.

Longitudinal follow-up of vision in a neuromyelitis optica cohort

Background: Neuromyelitis optica (NMO) is an inflammatory disease associated with optic neuritis and myelitis. Recently, several studies showed that optical coherence tomography (OCT) could be an interesting method for the evaluation of disease severity; however, to date there are no studies with a longitudinal follow-up of visual function in NMO. The aim of this study was to assess the ability of OCT to evaluate the progression of visual dysfunction in NMO. Patients and methods: A group of 30 NMO patients (thus, 60 eyes), comprised of 20 women and 10 men with a mean age of 43.7 +/− 12.3 years, were prospectively evaluated clinically and by a whole neuro-ophthalmological work-up, including: visual acuity (VA), fundoscopy, visual evoked potential (VEP), visual field (VF) and optical coherence tomography (OCT). All patients were tested at baseline (after a mean disease duration of 6.1 years) and after a mean time of follow-up of 18 months (range: 12–36 months). Results: Mean VA was similar at the two evaluation times (0.77 +/− 0.36 versus 0.77 +/− 0.35). The mean VF defect decreased slightly, but the difference was not significant (−5.9 +/− 1.3 dB versus −5.3 +/− 1.3 dB). In contrast, the mean retinal thickness seen on OCT decreased from 87.4 +/− 23.3 µm to 79.7 +/- 22.4 µm (p = 0.006). These modifications were only observed in eyes with a past or a recent history of optic neuritis (−15.1 µm; p < 0.001) and not in eyes without any history of optic neuritis (−2.4 µm; not significant). Also, they occurred independently of the occurrence of relapses (n = 13) and especially optic neuritis episodes; however, the number of optic neuritis episodes was low (n = 5). Conclusion: OCT seems to be a more sensitive test than VA or VF for monitoring ophthalmological function in NMO and it seems to be helpful for the detection of infra-clinical episodes in patients with a past history of optic neuritis. Our results suggest that this easily performed technique should be used in the follow-up of NMO, but complementary studies are warranted to confirm its interest at an individual level.

A novel variation in the Twinkle linker region causing late-onset dementia

Variations in the mitochondrial helicase Twinkle (PEO1) gene are usually associated with autosomal dominant chronic progressive external ophthalmoplegia (PEO). We describe five patients from two unrelated Alsatian families with the new R374W variation in the Twinkle linker region who progressively developed an autosomal dominant multisystem disorder with PEO, hearing loss, myopathy, dysphagia, dysphonia, sensory neuropathy, and late-onset dementia resembling Alzheimer’s disease. These observations demonstrate that Twinkle variations in the linker domain alter cerebral function and further implicate disrupted mitochondrial DNA integrity in the pathogenesis of dementia.

TDP43-Positive Intraneuronal Inclusions in a Patient with Motor Neuron Disease and Parkinson’s Disease

Background: The role of the 43-kDa transactivation-responsive DNA-binding protein (TDP43) in neurodegenerative diseases is not yet clearly established. Objective: To assess for the first time the presence of TDP43 in a patient with motor neuron disease (MND) and Parkinson’s disease (PD). Methods: A 78-year-old woman developed poorly dopa-responsive parkinsonism without cognitive alteration. Three years later, MND appeared and led to death in less than a year. Neuropathologic examination was performed. Results: We observed the presence of PD and MND lesions with TDP43-positive cytoplasmic inclusions in the spinal cord and bulbar nuclei but not in the dentate gyrus and neocortex. The MND was characterized by a severe degeneration of bulbar and cervical lower motor neurons. Numerous senile plaques and topographically limited neurofibrillary tangles were also observed. Conclusion: The mechanisms underlying the rare co-occurrence of PD and MND are still unclear. The assessment of an abnormal reactivity for TDP43 in our case might gain more insight into the pathophysiology of this association of two diseases. Further studies are needed to confirm these findings and to understand the role of TDP43 in neurodegenerative diseases.

Central nervous system abnormalities in patients with PMP22 gene mutations: a prospective study

Background Mutations of the peripheral myelin protein-22 (PMP22) gene are the most common cause of inherited disease of the peripheral nervous system (PNS), with its deletion resulting in hereditary neuropathy with liability to pressure palsies (HNPP), and its duplication inducing Charcot–Marie–Tooth 1A (CMT1A) disease. Although mainly expressed in the PNS, PMP22 mRNA and protein are also present in the central nervous system (CNS). Objective To investigate whether patients with PMP22 mutations present with CNS abnormalities. Methods Fifteen patients with HNPP and 15 patients with CMT1A disease were prospectively included and their brain MRI and neuropsychological assessment were compared with those of healthy subjects. We evaluated, in particular, the volumes of grey and white matter (GM and WM) and looked for metabolic changes using spectroscopy, and abnormal architecture using fractional anisotropy (FA) measurement. A post mortem examination of the CNS of a patient with PMP22 gene duplication was also performed. Results We found a decrease in the volume of WM in 70% of patients, a reduced creatine level in WM in 28% and a cognitive impairment in 70%. FA was significantly altered in several areas of WM, including the columns of the fornix. The results for WM volume, creatine level in WM and cognitive testing showed that 47% of patients (patients with HNPP and those with CMT1A) presented with at least two abnormal results. Pathological examination of the brain of a patient with PMP22 gene duplication showed diffuse hypomyelination sparing the U fibres. Conclusions This study demonstrates that altered PMP22 gene expression induces significant CNS alterations in patients with HNPP and CMT1A, including cerebral WM abnormalities and cognitive impairment.

Evaluation of Clinical Interest of Anti-Aquaporin-4 Autoantibody Followup in Neuromyelitis Optica

Neuromyelitis optica (NMO) is an autoimmune disease in which a specific biomarker named NMO-IgG and directed against aquaporin-4 (AQP4) has been found. A correlation between disease activity and anti-AQP4 antibody (Ab) serum concentration or complement-mediated cytotoxicity has been reported, but the usefulness of longitudinal evaluation of these parameters remains to be evaluated in actual clinical practice. Thirty serum samples from 10 NMO patients positive for NMO-IgG were collected from 2006 to 2011. Anti-AQP4 Ab serum concentration and complement-mediated cytotoxicity were measured by flow cytometry using two quantitative cell-based assays (CBA) and compared with clinical parameters. We found a strong correlation between serum anti-AQP4 Ab concentration and complement-mediated cytotoxicity (P < 0.0001). Nevertheless, neither relapse nor worsening of impairment level was closely associated with a significant increase in serum Ab concentration or cytotoxicity. These results suggest that complement-mediated serum cytotoxicity assessment does not provide extra insight compared to anti-AQP4 Ab serum concentration. Furthermore, none of these parameters appears closely related to disease activity and/or severity. Therefore, in clinical practice, serum anti-AQP4 reactivity seems not helpful as a predictive biomarker in the followup of NMO patients as a means of predicting the onset of a relapse and adapting the treatment accordingly.