Sara Llufriu

Trans-Synaptic Axonal Degeneration in the Visual Pathway in Multiple Sclerosis

To evaluate the association between the damage to the anterior and posterior visual pathway as evidence of the presence of retrograde and anterograde trans‐synaptic degeneration in multiple sclerosis (MS).

Plasma exchange for acute attacks of CNS demyelination Predictors of improvement at 6 months

Background: Plasma exchange (PE) is used to treat severe episodes of CNS demyelination unresponsive to corticosteroids. Predictors of long-term response are not well known. Methods: We retrospectively reviewed the medical records of 41 patients consecutively treated by PE between January 1995 and July 2007. The primary outcome was improvement at 6 months after PE defined as decrease of ≥1 point in the Expanded Disability Status Scale (EDSS) score for patients with EDSS ≤7.5 or 1.5 points with EDSS ≥8.0 or improvement of more than 2 lines in the visual acuity chart for patients with optic neuritis (ON). Results: Twenty-five patients (61%) were women, and the median age was 33 years (range 14–57 years). Twenty-three (56%) had multiple sclerosis, 2 (5%) had clinically isolated syndrome, 2 (5%) had Marburg disease, 7 (17%) had acute disseminated encephalomyelitis, 4 (10%) had neuromyelitis optica, 2 (5%) had idiopathic ON, and 1 (2%) had idiopathic transverse myelitis. The median EDSS score before the attack was 1.0 (range 0–6.5). At PE onset, the median EDSS score was 7.0 (range 3.0–9.5). Sixteen patients (39%) improved at discharge, and 26 (63%) improved at 6 months. In the multivariate analysis, early initiation of PE (odds ratio [OR] 6.29, 95% confidence interval [CI] 1.18–52.96) and improvement at discharge (OR 7.32, 95% CI 1.21–44.38) were significantly associated with response at 6 months. Conclusions: Plasma exchange (PE) was associated with clinical improvement in 63% of patients at 6 months. Early initiation of PE and improvement at discharge were predictors of this response. Twelve patients (48%) who did not improve early did so during follow-up.

Autoimmune post–herpes simplex encephalitis of adults and teenagers

Objective: To report 14 patients with immune-mediated relapsing symptoms post–herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with those of young children. Methods: Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously. Results: Among the teenage and adult group (8 patients, median age 40 years, range 13–69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6–20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17–296, vs 4 days, range 0–33, p = 0.037). Conclusion: In teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective.

Cytotoxic effect of neuromyelitis optica antibody (NMO-IgG) to astrocytes: An in vitro study

NMO-IgG is a disease-specific autoantibody for neuromyelitis optica (NMO) that binds selectively to aquaporin-4 (AQ4), an astrocytic water channel. The normal distribution of AQP4 coincides with the sites of immunoglobulin and complement deposits in lesions found in autopsy studies. The underlying mechanisms of cytotoxicity by NMO-IgG on astrocytes are not well known. In this study we show that serum samples from seropositive NMO patients (21) induce a higher rate of cell death compared with sera from seronegative NMO (16), relapsing-remitting MS (20) patients, and healthy controls (24) on primary cultures of astrocytes. Similar results were obtained by two different techniques: lactate dehydrogenase release and tetrazolium-based viability assay. Cell death was only observed in the presence of active complement. The complement-dependent cytotoxicity was not accompanied by caspase-3/7 activation or increase in the percentage of apoptotic cells. Our data show that NMO-IgG induces a complement-dependent cytotoxicity of astrocytes in vitro, and suggest that a mechanism of cellular death by necrosis might be implicated in the pathophysiology of NMO.

Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis.

Objective Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study. Methods Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0–6.5 were randomized to receive IV 1–2×106 bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects. Results At baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1–8.8 vs 12.3, 95% CI = 4.4–34.5, p = 0.064), and at the end of study to reduced mean GEL (−2.8±5.9 vs 3±5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients. Conclusion Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties. ClinicalTrials.gov NCT01228266

Dynamics of retinal injury after acute optic neuritis

We set out to assess the dynamics of retinal injury after acute optic neuritis (ON) and their association with clinical visual outcomes.

Influence of Corpus Callosum Damage on Cognition and Physical Disability in Multiple Sclerosis: A Multimodal Study

Background Corpus callosum (CC) is a common target for multiple sclerosis (MS) pathology. We investigated the influence of CC damage on physical disability and cognitive dysfunction using a multimodal approach. Methods Twenty-one relapsing-remitting MS patients and 13 healthy controls underwent structural MRI and diffusion tensor of the CC (fractional anisotropy; mean diffusivity, MD; radial diffusivity, RD; axial diffusivity). Interhemisferic transfer of motor inhibition was assessed by recording the ipsilateral silent period (iSP) to transcranial magnetic stimulation. We evaluated cognitive function using the Brief Repeatable Battery and physical disability using the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC) z-score. Results The iSP latency correlated with physical disability scores (r ranged from 0.596 to 0.657, P values from 0.004 to 0.001), and with results of visual memory (r = −0.645, P = 0.002), processing speed (r = −0.51, P = 0.018) and executive cognitive domain tests (r = −0.452, P = 0.039). The area of the rostrum correlated with the EDSS (r = −0.442, P = 0.045). MD and RD correlated with cognitive performance, mainly with results of visual and verbal memory tests (r ranged from −0.446 to −0.546, P values from 0.048 to 0.011). The iSP latency correlated with CC area (r = −0.345, P = 0.049), volume (r = −0.401, P = 0.002), MD (r = 0.404, P = 0.002) and RD (r = 0.415, P = 0.016). Conclusions We found evidence for structural and microstructural CC abnormalities associated with impairment of motor callosal inhibitory conduction in MS. CC damage may contribute to cognitive dysfunction and in less extent to physical disability likely through a disconnection mechanism.

Rapidly progressive diffuse Lewy body disease

Lewy body syndromes (mainly Parkinsons disease and dementia with Lewy bodies) share many clinical features and usually have a slowly progressive course. Some patients may show rapid symptoms progression.

Lipid‐specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab

Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS). PML risk increases in individuals seropositive for anti–John Cunningham virus (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid‐specific immunoglobulin M oligoclonal bands in cerebrospinal fluid (CSF; IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML.

Cognitive functions in multiple sclerosis: impact of gray matter integrity.

Objectives: Our aim was to investigate the impact of gray matter (GM) integrity on cognitive performance in multiple sclerosis (MS), and its relationship with white matter (WM) integrity and presence of lesions. Methods: Sixty-seven patients with MS and 26 healthy controls underwent voxel-based analysis of diffusion tensor images (DTI) in GM and tract-based spatial statistics (TBSS) from WM to identify the regional correlations between cognitive functions and integrity. Lesion probability mapping (LPM) was generated for correlation analysis with cognition. Multiple linear regression analyses were used to identify the imaging measures associated with cognitive scores. Results: Compared with controls, patients showed abnormal DTI indices in several GM regions and in most WM tracts. Impairment in DTI indices in specific GM regions was associated with worse performance of distinct cognitive functions. Those regions showed anatomical correspondence with cognitively relevant tracts in TBSS and LPM. The combination of regional GM and WM DTI and lesion volume accounted for 36–51% of the variance of memory and attention scores. Regional GM DTI explained less than 5% of that variance. Conclusion: GM and WM integrity of specific networks influences cognitive performance in MS. However, GM damage assessed by DTI only adds a small increment to the explained variance by WM in predicting cognitive functioning.