Iñigo Gabilondo

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).

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

Late-onset anti-NMDA receptor encephalitis.

Objective: To describe the clinical features and outcome of anti–NMDA receptor (NMDAR) encephalitis in patients ≥45 years old. Method: Observational cohort study. Results: In a cohort of 661 patients with anti-NMDAR encephalitis, we identified 31 patients ≥45 years old. Compared with younger adults (18–44 years), older patients were more often male (45% vs 12%, p < 0.0001), had lower frequency of tumors (23% vs 51%, p = 0.002; rarely teratomas), had longer median time to diagnosis (8 vs 4 weeks, p = 0.009) and treatment (7 vs 4 weeks, p = 0.039), and had less favorable outcome (modified Rankin Scale score 0–2 at 2 years, 60% vs 80%, p < 0.026). In multivariable analysis, younger age (odds ratio [OR] 0.15, confidence interval [CI] 0.05–0.39, p = 0.0001), early treatment (OR 0.60, CI 0.47–0.78, p < 0.0001), no need for intensive care (OR 0.09, CI 0.04–0.22, p < 0.0001), and longer follow-up (p < 0.0001) were associated with good outcome. Rituximab and cyclophosphamide were effective when first-line immunotherapies failed (OR 2.93, CI 1.10–7.76, p = 0.031). Overall, 60% of patients older than 45 years had full or substantial recovery at 24 months follow-up. Conclusions: Anti-NMDAR encephalitis is less severe in patients ≥45 years old than in young adults, but the outcome is poorer in older patients. In this age group, delays in diagnosis and treatment are more frequent than in younger patients. The frequency of underlying tumors is low, but if present they are usually carcinomas instead of teratomas in younger patients. Early and aggressive immunotherapy will likely improve the clinical outcome.

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.

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.

Analysis of prognostic factors associated with longitudinally extensive transverse myelitis

Objective: The aim of this study is to report the clinical profile and outcome of longitudinally extensive transverse myelitis (LETM). Methods: We prospectively studied adult patients who presented with LETM from January 2008 to December 2011. Information on demographic, clinical course, magnetic resonance imaging (MRI) and outcome was collected. HLA-DRB1 genotype was compared with those of 225 normal controls and patients with MS (228) and neuromyelitis optica (NMO) (22). Results: In total, 23 patients (16 female) with a median age of 44.5 years (range: 20–77 years) were included. Most (74%) had moderate–severe disability at nadir (48% non-ambulatory), normal/non-multiple sclerosis (MS) brain MRI (96%) and a median MRI cord lesion of 5 vertebral segments (range: 3–19). Laboratory analysis showed cerebrospinal fluid pleocytosis (45%), NMO-IgG (9%), antinuclear antibodies (70%), and genotype HLA-DRB1*13 (57%). The frequency of DRB1*13 genotype was higher compared with controls (p=0.002), MS (p=0.001) and NMO (p= 0.003) patients. After a median follow-up of 32 months, one patient converted to MS, two had relapsing LETM with NMO-IgG, and 20 remained as idiopathic with recurrences in four (20%). Twelve (52%) patients recovered with minimal disability (Expanded Disability Status Scale (EDSS) <2.5) and three (13%) remained wheelchair dependent. Disability at nadir was associated with the final outcome and extension of the spinal cord lesion with risk of recurrence. Recurrence was not associated with worse outcome. Conclusions: Inflammatory LETM is mostly idiopathic with a good outcome. It includes a relatively homogenous group of patients with an overrepresentation of the HLA-DRB1*13 genotype. EDSS at nadir is a predictor of the final outcome and extension of the myelitis of the recurrence risk.

Colour vision impairment is associated with disease severity in multiple sclerosis

Background: Colour vision assessment correlates with damage of the visual pathway and might be informative of overall brain damage in multiple sclerosis (MS). Objective: The objective of this paper is to investigate the association between impaired colour vision and disease severity. Methods: We performed neurological and ophthalmic examinations, as well as magnetic resonance imaging (MRI) and optical coherence tomography (OCT) analyses, on 108 MS patients, both at baseline and after a follow-up of one year. Colour vision was evaluated by Hardy, Rand and Rittler plates. Dyschromatopsia was defined if colour vision was impaired in either eye, except for participants with optic neuritis (ON), for whom only the unaffected eye was considered. We used general linear models adjusted for sex, age, disease duration and MS treatment for comparing presence of dyschromatopsia and disease severity. Results: Impaired colour vision in non-ON eyes was detected in 21 out of 108 patients at baseline. At baseline, patients with dyschromatopsia had lower Multiple Sclerosis Functional Composite (MSFC) scores and Brief Repeatable Battery-Neuropsychology executive function scores than those participants with normal colour vision. In addition, these patients had thinner retinal nerve fiber layer (RNFL), and smaller macular volume, normalized brain volume and normalized gray matter volume (NGMV) at baseline. Moreover, participants with incident dyschromatopsia after one-year follow-up had a greater disability measured by the Expanded Disability Status Scale and MSFC-20 and a greater decrease in NGMV than participants with normal colour vision. Conclusions: Colour vision impairment is associated with greater MS severity.

Response to immunotherapy in CLIPPERS syndrome

Dear Sirs,Chronic lymphocytic inflammation with pontine perivas-cular enhancement responsive to steroids (CLIPPERS) is arecently described treatable, brainstem-predominant, clin-ical and radiological entity [1]. Patients with this conditionpresent with an episodic brainstem syndrome and showcharacteristic scattered and punctate gadolinium (Gd)enhancement in the pons and adjacent CNS structures.They prototypically respond to high dose glucocorticos-teroids and may require chronic steroid or immunosup-pressive treatment, although the effect of intravenousimmunoglobulins (IVIG) in this disease is unknown. Herewe report a patient with CLIPPERS that experienced aclinical rebound of the disease after a short pulse of IVIG.A 28-year-old woman with subacute gait ataxia anddiplopia was admitted to the hospital. Neurologicalexamination revealed internuclear ophthalmoplegia, hori-zontal bidirectional nystagmus and gait and four-limbataxia. Brain and spinal MRI showed multiple punctate Gdenhancing lesions in the mesencephalon, cerebellum andcervical spinal cord. The patient was tested for the presenceof systemic auto-antibodies, anti-neuronal antibodies,infectious pathogens (HIV, T. Pallidum, Brucella spp., B.burgdorferi) and tumoral serum biomarkers. CSF analysisincluded standard biochemistry, cytology and bacteriolog-ical cultures, oligoclonal bands and tests for Tropherymawhippelii and Herpesviridae, with no significant findingsexcept for mildly raised CSF protein. Body-CT and bodyand brain PET-CT were also normal. The patient wastreated with intravenous methylprednisolone for 3 days(1 g/day) followed by oral prednisone tapering startingfrom a dose of 60 mg/day. One week after starting meth-ylprednisolone, she had completely recovered and wascontinued on a slow reduction of oral steroid dose. How-ever, any attempt to taper the oral steroid dose below12.5 mg/day led to neurological relapse of the symptomsand, therefore this dose was maintained for the next6 months. After this period (1 year after disease onset), shewas asymptomatic and physical examination was normal,and therefore treatment discontinuation was reassessed.After she stopped steroids for a few days she suffered arebound of her symptoms: she had new onset mild gaitataxia and brisk symmetric ankle- and knee-jerks. Newbrain and spinal cord MRI disclosed multiple scatteredpunctuate and non-confluent enhancing lesions of a maxi-mum diameter of 0.7 cm visible mainly in the white matterof both cerebellar hemispheres, cerebellar peduncles and inthe cervical spinal cord. (Fig. 1a). At that moment, pontineGd enhancement was relatively scarce compared with thecerebellar hemispheres. Additionally, mild but appreciableamount of diffuse Gd peppering was visible in the whitematter of the whole brain adjacent to the cortico-subcor-tical border. Prednisone dose was increased to 30 mg/dayand the patient recovered to normal in 3 days. Thereafter, a12.5 mg/day dose was maintained for the following9 months and the patient remained asymptomatic. A newMRI 3 months after restoration of steroid therapy showedclear improvement of Gd lesions (Fig. 1b). Notwithstand-ing, steroid side-effects became evident with amenorrhea,hirsutism, mild weight gain and acne. Any attempt to tapersteroid dose below 10 mg/day resulted in a blooming ofneurological symptoms. After assuring 2 weeks of clinicalstability, a short attack pulse of intravenous immunoglob-ulins (IVIG) was administered (0.4 g/kg/day for 5 days)

Retinal periphlebitis is associated with multiple sclerosis severity

Objectives: To assess the association of primary retinal inflammation, namely retinal periphlebitis (RP) and microcystic macular edema, with clinical, brain, and retinal imaging biomarkers of multiple sclerosis (MS) severity. Methods: One hundred patients with MS underwent a neurologic and ophthalmic examination, MRI, and optical coherence tomography. Disability was assessed using the Expanded Disability Status Scale at baseline and after a 1-year follow-up. The normalized brain volume, the normal-appearing gray matter volume, and T1 lesion volume were assessed at baseline as radiologic biomarkers of disease severity. Retinal nerve fiber layer thickness and macular volume at baseline were used as surrogate markers of axonal damage. We used general linear models adjusted for sex, age, disease duration, and MS treatment to compared adjusted means of these parameters among patients with RP and patients without primary retinal inflammation. Results: Five patients showed RP, 2 showed microcystic macular edema, and the retina was normal in the remaining 93. Patients with RP had a tendency toward a higher adjusted-mean Expanded Disability Status Scale score at baseline and disability progression after a 1-year follow-up compared with patients without primary retinal inflammation. These patients also had a higher adjusted-mean T1 lesion volume (adjusted differences: 10.4, 95% confidence interval [CI]: 0.6 to 20.2; p = 0.038) and lower T1 brain volume (adjusted differences: −68, 95% CI: −139 to 2; p = 0.059). Patients with RP had a lower adjusted-mean retinal nerve fiber layer thickness (adjusted differences: −13.4, 95% CI: −24.4 to −2.3; p = 0.018) and a trend toward lower macular volume. Conclusions: These results support the role of RP as a biomarker of MS severity.