Marco Puthenparampil

Natalizumab strongly suppresses cortical pathology in relapsing–remitting multiple sclerosis

Background: Since cortical pathology has been indicated to play a relevant role in the physical and cognitive disability of multiple sclerosis (MS) patients, this study aims to analyze the efficacy of natalizumab in slowing down its progression. Methods: A total of 120 relapsing–remitting MS patients completed a 2-year prospective study: 35 received natalizumab, 50 received interferon beta-1a or glatiramer acetate (immunomodulatory agents - IMA) and 35 remained untreated. Forty healthy subjects constituted the reference population. Clinical and magnetic resonance imaging (MRI) evaluations (including cortical lesions and atrophy) were performed at baseline and after 2 years. Results: Natalizumab significantly reduced accumulation of new cortical lesions (0.2±0.6,range 0–3) compared to immunomodulatory agents (1.3±1.1 togli spazio, range 1–6, p=0.001) and no treatment (2.9±1.5, range 1–8, p<0.001). The percentage of patients with new cortical lesions was also lower in natalizumab-treated patients (20%) compared to IMA-treated and untreated patients (68.0% and 74.2%; p<0.001 for both comparisons). Furthermore, the progression of cortical atrophy was significantly reduced by natalizumab (% change=1.7%) compared to IMA (3.7%, p=0.003) and no therapy (4.6%, p<0.001). Finally, a greater percentage (51.4%) of natalizumab-treated patients remained disease-free (no clinical or MRI evidence of disease activity or progression) compared to IMA-treated (18%, p=0.001) and untreated patients (5.7%, p<0.001). Conclusions: Natalizumab treatment significantly decreases cortical lesion accumulation and cortical atrophy progression in severe relapsing–remitting MS. While supporting the inflammatory origin of cortical lesions, our results highlight the significant impact of natalizumab on cortical pathology.

Cortical lesions and cognitive impairment in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system. In the last decade, pathological and magnetic resonance imaging (MRI) studies have shown that a significant portion of inflammatory lesions are located in the grey matter, especially in the cerebral cortex, of MS patients. Cortical inflammatory lesions (CL) can be demonstrated in vivo in MS patients by double inversion recovery (DIR) MRI sequence. Neuropsychological deficits constitute a major clinical aspect of MS, being demonstrated in a percentage ranging from 40 to 65% of patients, and have been shown to be associated with cortical demyelination and atrophy. Recent DIR studies in MS patients having different clinical forms of the disease have disclosed that CL burden not only correlates with the severity of physical disability, but is also one of the major structural changes associated with disease-related cognitive impairment.

Cerebrospinal fluid IL-1β correlates with cortical pathology load in multiple sclerosis at clinical onset

The cerebrospinal fluid levels of interleukin-1 beta and structural magnetic resonance parameters of cortical damage, i.e., cortical lesion number and volume, and global cortical thickness, were analysed in multiple sclerosis patients at clinical onset. Cerebrospinal fluid interleukin-1 beta levels strongly correlated with cortical lesion load and cortical thickness, while correlation with white matter lesion load was modest. Interleukin-1 beta, intrathecally produced by infiltrating lymphocytes and activated microglia, may constitute a possible link between inflammation and neurodegeneration in multiple sclerosis.

Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis: Neurofilament Light Chain Levels in Definite Subtypes of Disease

Importance A clearer definition of the role of neurofilament light chain (NFL) as a biomarker in amyotrophic lateral sclerosis (ALS) is needed. Objectives To assess the ability of NFL to serve as a diagnostic biomarker in ALS and the prognostic value of cerebrospinal fluid NFL in patients with ALS. Design, Setting, and Participants In this single-center, retrospective, longitudinal study, disease progression was assessed by the ALS Functional Rating Score–Revised and the ALS Milano-Torino Staging system at baseline and 6, 12, 24, and 36 months. Cerebrospinal fluid samples were obtained from 176 patients admitted to the Department of Neurosciences of the University of Padua, Padova, Italy, from January 1, 2010, through February 29, 2016. Patients with ALS underwent ambulatory follow-up at the same department. Main Outcomes and Measures Levels of NFL. Results The study included 94 patients with ALS (64 men [36.4%] and 30 women [17.0%]; median age, 62.5 years), 20 patients with frontotemporal dementia (FTD) (8 men [4.5%] and 12 women [6.8%]; median age, 65 years), 18 patients with motor neuropathies (14 men [8.0%] and 4 women [2.3%]; median age, 63 years), and 44 controls (24 men [13.6%] and 20 women [11.4%]; median age, 54 years). Log-transformed NFL (log[NFL]) concentrations were higher in the ALS and FTD groups compared with the motor neuropathies and control groups (hazard ratio [HR], 2.45; 95% CI, 1.66-3.61; P < .001). Patients with typical ALS (HR, 1.0 [reference]), progressive bulbar palsy (HR, 1.48; 95% CI, 0.58-3.75; P = .41), and upper motor neuron dominant ALS (HR, 0.12; 95% CI, 0.02-0.61; P = .01) had higher levels of NFL than did those with flail arm or leg syndrome (HR, 0.28; 95% CI, 0.08-0.10; P = .049) and progressive muscular atrophy (HR, 0.17; 95% CI, 0.22-1.36; P = .10). There was an inverse correlation between log[NFL] concentration and overall survival (HR, 2.45; 95% CI, 1.66-3.61; P < .001). There was no evidence of different log[NFL] concentrations and survival in genetic ALS. Conclusions and Relevance This study confirms the role of NFL as a biomarker in ALS. Elevation in NFL levels in patients with upper motor neuron involvement and FTD might reflect the corticospinal tract degeneration. Low NFL levels in patients with lower motor neuron signs might be a prognostic indicator of milder phenotypes of disease.

Increased incidence of multiple sclerosis in the Veneto region, Italy

Background: To what extent the progressive increase in the incidence of multiple sclerosis (MS) observed in the province of Padova over the period 1970–1999 was an expression of a real increased risk of developing MS remained unclear. Objective: The objective of this paper is to update the epidemiological figures of MS and probe whether the risk of having MS has increased in the province of Padova during the decade 2000–2009. Methods: All patients born in Italy and having a diagnosis of MS or possible MS identified through analysis of all available sources of information were included in the study. The incidence and prevalence rates between 2000 and 2009 were obtained and compared with our previously published data. Results: On 31 December 2009, the overall prevalence was 139.5/100,000, 192.0±9.5 for females and 83.9±6.3 for males. During the decade 2000–2009, the overall incidence rate of MS was 5.5±0.5, 7.4±0.8 for females and 3.5±0.6 for males. The onset-diagnosis delay, the female/male ratio and the mean age at onset did not significantly change compared to the prior period of observation. Conclusion: Our findings support the hypothesis of a real increased risk of developing MS in the province of Padova. Moreover, the actual prevalence of 1.4/1000 makes our region a high-risk geographical area for MS. The role played by exogenous factors in determining susceptibility to MS needs to be thoroughly investigated.

Cortical relapses in multiple sclerosis

Background: Multiple sclerosis (MS) is a white and grey matter disease of the central nervous system (CNS). It is recognized that cortical damage (i.e. focal lesions and atrophy) plays a role in determining the accumulation of physical and cognitive disability that is observed in patients with progressive MS. To date, an association of cortical lesions with clinical relapses has not been described. Results: We report clinical and magnetic resonance imaging (MRI) findings of five relapsing–remitting MS (RRMS) patients who had clinical relapses characterized by the acute appearance of cortical symptoms, due to the development of large, snake-like, cortical inflammatory lesions. Symptoms were: acute Wernicke’s aphasia mimicking stroke; agraphia with acalculia, not associated to a motor deficit nor linguistic disturbance; hyposthenia of the left arm, followed by muscle twitching of the hand, spreading to arm and face; acute onset of left lower limb paroxysmal hypertonia; and temporal lobe status epilepticus, with psychotic symptoms. Conclusions: Cortical relapses may occur in MS. MRI examination in MS should include sequences, such as double inversion recovery (DIR) or phase sensitive inversion recovery (PSIR), that are aimed at visualizing cortical lesions, especially in the presence of symptoms of cortical dysfunction. Our observation further stresses and extends the clinical relevance of cortical pathology in MS.

Trans-synaptic degeneration in the optic pathway. A study in clinically isolated syndrome and early relapsing-remitting multiple sclerosis with or without optic neuritis

Objective Increasing evidence suggest that neuronal damage is an early and diffuse feature of Multiple Sclerosis (MS) pathology. Analysis of the optic pathway may help to clarify the mechanisms involved in grey matter damage in MS. Purpose of our study was to investigate the relationship between inflammation and neurodegeneration and to achieve evidence of trans-synaptic degeneration in the optic pathway in MS at clinical onset. Methods 50 clinically isolated syndromes/early relapse-onset MS (CIS/eRRMS) with mean disease duration of 4.0±3.5 months, 28 MRI healthy controls (HC) and 31 OCT-HC were studied. Ten patients had optic neuritis at presentation (MSON+), 40 presented with other symptoms (MSON-). MRI examination included 3D-T1, 3D-FLAIR and 3D-DIR sequences. Global cortical thickness (gCTh), pericalcarin CTh (pCTh) and white matter volume (WMV) were analysed by means of Freesurfer on 3D-T1 scans. Optic radiation morphology (OR) and volume (ORV) were reconstructed on the base of the Jülich’s Atlas. White matter lesion volume (WMLV), OR-WMLV and percent WM damage (WMLV/WMV = WMLV% and OR-WMLV/ORV = ORWMLV%) were obtained by 3D-FLAIR image segmentation. 3D-DIR sequences were applied to identify inflammatory lesions of the optic nerve. Optic coherence tomography (OCT) protocol included the analysis of global peripapillary retinal nerve fiber layer (g-RNFL) and the 6 fundus oculi’s sectors (temporal, T-RNFL; temporal superior, TS-RNFL; nasal superior, NS-RNFL; nasal, N-RNFL; nasal inferior, NI-RNFL, temporal inferior, TI-RNFL). The retina of both eyes was analyzed. The eyes of ON+ were further divided into affected (aON+) or not (naON+). Results No difference in CTh was found between CIS/eRRMS and HC, and between MSON+ and MSON-. Moreover, MSON+ and MSON- did not differ for any WM lesion load parameter. The most significant correlations between RNFL thickness and optic radiation WM pathology were found in MSON+. In these patients, the temporal RNFL inversely correlated to ipsilateral optic radiation WM lesion load (T-RNFL: r -0.7, p<0.05; TS-RNFL: r -0.7, p<0.05), while nasal RNFL inversely correlated to contralateral optic radiation WM lesion load (NI: r -0.8, p<0.01; NS-RNFL: r -0.8, p<0.01). Conclusions Our findings suggest that in MSON+ the optic pathway is site of a diffuse pathological process that involves both directly and via trans-synaptic degeneration the RNFL.

BAFF is decreased in the cerebrospinal fluid of multiple sclerosis at clinical onset

B-cells are thought to play a relevant role in multiple sclerosis (MS) pathology. BAFF (B cell activating factor of the TNF family) is a B-cell survival factor constitutively produced inside the CNS by astrocytes. We studied the intrathecal synthesis of BAFF in MS at clinical onset. Paired serum and cerebrospinal fluid (CSF) specimens from 40 clinically isolated syndromes (CIS) suggestive of MS or early relapse-onset MS (eRRMS) and from 18 healthy controls (HC) were analysed. Patients were classified based on the detection of oligoclonal IgG bands in the CSF (IgGOB+ and IgGOB-). BAFF was detected by highly sensitive ELISA and its ratio (CSF-BAFF/serum-BAFF, QBAFF) and Index (QBAFF/QAlb, BAFF-Index) were calculated. IgGOB+ presented lower CSF concentrations of BAFF compared to both HC and IgGOB- (p<0.05). BAFF Index was significantly lower in IgGOB+ compared to both HC and IgGOB- (p<0.01). A significant inverse correlation between QIgG and QBAFF (r: -0.4, p<0.05) and between BAFF index and IgGIF (r: -0.4, p<0.05) or IgG Index (r: -0.4, p=0.05) was found in IgGOB+. The decreased CSF levels of BAFF in IgGOB+ at clinical onset suggest the absorption of this factor by intrathecally recruited B cells since the early disease phases.

Evidence of B-cell dysregulation in severe CNS inflammation after alemtuzumab therapy

Cases of severely exacerbated CNS inflammation have been described in patients with MS under treatment with alemtuzumab, a pan-lymphocyte–depleting anti-CD52 monoclonal antibody.1,2 On the basis of the peripheral lymphocyte subset network (higher B-cell and suppressed T-cell counts)2 and marked clinical improvement following plasmapheresis and rituximab treatment (anti-CD20 antibody),1 a B-cell–driven intrathecal autoimmune reaction was hypothesized.

Acute simultaneous development of brain tumour–like lesion and demyelinating polyneuropathy in a patient with chronic relapsing myelitis:

Combined central and peripheral demyelination (CCPD) is a rare chronic inflammatory disorder of the nervous system. We describe the case of a patient with a history of recurrent myelitis that acutely and simultaneously developed a brain tumour–like lesion and a sensitive-motor demyelinating polyneuropathy. The diagnosis of CCPD was supported by a detailed diagnostic workup. Up to date, no similar cases have been reported in the literature.