Alberto Romagnolo

Involvement of the choroid plexus in multiple sclerosis autoimmune inflammation: A neuropathological study

An immunological function has been proposed for the choroid plexus (CP). In multiple sclerosis (MS) brains, CPs show (immunohistochemistry to HLA-DR, CD3, CD20, CD68, VCAM-1, CD138) T lymphocytes in vessels and stroma, VCAM-1 expression on endothelia, intense HLA-DR immunostaining on cells in CP stroma, among CP epithelium and on epiplexus cells. CPs in control or amyotrophic lateral sclerosis brains do not show such inflammatory changes. Intense CP inflammation is observed in viral encephalitis. Changes in MS CPs suggest persisting immune activation, with intensity similar to acute encephalitis, even in MS phases in which neurodegeneration prevails. In MS, CPs could represent a site for lymphocyte entry in the CSF and for CSF antigens presentation.

Multiple sclerosis relapses: a multivariable analysis of residual disability determinants.

Background –  Recovery from multiple sclerosis (MS) relapses is variable. The factors influencing persistence of residual disability (RD) after a relapse are still to be thoroughly elucidated.

Progranulin expression in brain tissue and cerebrospinal fluid levels in multiple sclerosis

Background: Progranulin (PGRN) is a fundamental neurotrophic factor, and is also involved in inflammation and wound repair. PGRN may have pro- or anti-inflammatory properties, depending upon proteolysis of the anti-inflammatory parent PGRN protein and the generation of pro-inflammatory granulin peptides. Objectives: Our objectives were as follows: (1) to evaluate the presence and distribution of PGRN in multiple sclerosis (MS) brain tissue, correlating it with demyelination and inflammation; (2) to evaluate cerebrospinal fluid (CSF) PGRN concentrations in patients with MS and controls, in relationship to the clinical features of the disease. Methods: Our study involved the following: (1) neuropathological study of PGRN on post-mortem tissue of 19 MS and six control brains; (2) evaluation of PGRN CSF concentration in 40 MS patients, 15 non-inflammatory controls and five inflammatory controls (viral encephalitis). Results: In active demyelinating lesions, PGRN was expressed on macrophages/microglia. In the normal-appearing white matter (NAWM), expression of PGRN was observed on activated microglia. PGRN was expressed by neurons and microglia in cortical lesions and in normal-appearing cortex. No expression of PGRN was observed in controls, except on neurons. PGRN CSF concentrations were significantly higher in patients with relapsing–remitting MS during relapses and in progressive MS patients, compared with relapsing–remitting MS patients during remissions and with non-inflammatory controls. Conclusions: PGRN is strongly expressed in MS brains, by macrophages/microglia in active lesions, and by activated microglia in the NAWM; PGRN CSF concentrations in MS are correspondingly increased in conditions of enhanced macrophage/microglia activation, such as during relapses and in progressive MS.

Peripheral neuropathy associated with levodopa–carbidopa intestinal infusion: a long‐term prospective assessment

Subacute and chronic peripheral neuropathies (PNP) have been reported in Parkinsons disease (PD) patients treated with levodopa/carbidopa intestinal gel infusion (LCIG), although several aspects of their incidence and pathogenesis still remain to be clarified. This study main objective is to prospectively report the 2‐year incidence of PNP in patients treated with LCIG.

Subcutaneous immunoglobulin in CIDP and MMN: a different long-term clinical response?

Subcutaneous immunoglobulin (SCIg) has been recently proposed as an effective alternative to intravenous immunoglobulin (IVIg) for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) treatment. The non-inferiority of SCIg over IVIg has been recently confirmed by a 4-month multicentre Italian observational study,1 where a similar efficacy was observed between the two therapies, with the SCIg showing possible advantages of stable plasmatic concentration2 and independence from hospital care. Here we report the 2-year experience of six Italian Neurological Centres, describing the long-term clinical outcomes of 66 patients (45 CIDP and 21 MMN) who were shifted from IVIg to SCIg. All the CIDP and MMN patients treated with SCIg between 2009 and 2014 were considered, including patients with a previous documented response to IVIg (at least 6 months), and a wear-off effect between each IVIg infusion documented by a worsening of at least 1 point at the Overall Neuropathy Limitation Scale (ONLS). Adherence to therapy was the primary outcome measure, while quality of life and clinical predictors of long-term disability were analysed as secondary outcomes. The clinical assessments were regularly performed by means of the ONLS, the Medical Research Council (MRC) scale in eight-muscle group bilaterally, and Life Quality Index (LQI). Clinical worsening was defined as increase of ≥1 ONLS point, requiring augmentation of SCIg dose, SCIg/IVIg combination therapy, or a return to IVIg for stabilising the clinical conditions. SCIg was administered at the patients home, as previously described,1 converting the IVIg dose to an equivalent SCIg dose (20% solution of immunoglobulin ready-to-use) delivered via a programmable infusion pump. All patients signed a written informed consent, and ethical committee approval was obtained (CEI—629 Prot. n 0010675, 25 January 2013). Statistical analyses were carried out utilising the Wilcoxon, Mann-Whitney and Friedman non-parametric tests, Cox proportional hazard regression …

Atypical hereditary spastic paraplegia mimicking multiple sclerosis associated with a novel SPG11 mutation

Multiple sclerosis (MS) is an autoimmune neurological disease characterized by high clinical heterogeneity [1], sometimes presenting with insidious onset and progressive course. Besides medical history, clinical evaluation and laboratory analysis, magnetic resonance imaging (MRI) represents an incomparable tool for a complete MS diagnostic work-up [2]; neuroimaging MS criteria have recently been improved to allow earlier diagnosis [3]. However, extensive use of MRI increases the likelihood of detecting incidental white matter (WM) abnormalities, requiring comprehensive investigations for correct diagnosis. A 22-year-old female was referred to our MS Center because of subacute onset of gait disturbance and large periventricular WM abnormalities detected on brain imaging (Fig. 1). In the following few months she manifested several falls, ‘cramps’, urge incontinence and slight memory disturbances. Her early psychomotor development had been normal with unremarkable family and personal past medical histories. Neurological examination revealed asymmetrical pyramidal signs (mild spasticity, weakness and brisk reflexes in right leg, with extensor plantar reflex), mild right paresis during gait, mild dysarthria and right facial weakness, and diminished vibration sense at right ankle. Mini Mental State Evaluation (MMSE) was normal. A second MRI confirmed WM T2/ FLAIR hyperintense confluent lesions, without gadolinium enhancement, in the frontal, parietal and peritrigonal regions bilaterally, with a tendency to confluence. Furthermore, we noticed a previously undiagnosed atrophy and thinning of the corpus callosum (TCC) (Fig. 2). Spinal MRI was normal. Considering that the medical history, clinical evaluation and MRI findings were not typical for MS, a leucoencephalopathy was suspected. Complete immune-rheumatological and metabolic work-up in blood and cerebrospinal fluid was normal; neurophysiological tests did not reveal any signs of peripheral neuropathy, whereas motor and somatosensory evoked potentials showed mild bilateral central conduction delay. Neuropsychological evaluation revealed mild memory impairment, deficit in selective and focused attention and reduced verbal fluency. Despite the absence of paraplegia and neuropathy, the combination of severe TCC, mild spastic hemiparesis and mental impairment raised the suspicion of a hereditary disorder and suggested testing for alterations in SPG11, a common cause of hereditary spastic paraplegia with TCC (ARHSP-TCC) [4]. In blood DNA from the proposita we found a novel c.4604_4605insC on the paternal allele in compound heterozygosity with a reported c.5989_5992delCTGT variant on the maternal allele, supporting the clinical diagnosis of ARHSP-TCC. During a 2-year follow-up there was a slow disease progression with impairment also on the left leg and worsening of learning skills and verbal fluency. Brain MRI remained unchanged. Mutations in SPG11, encoding spatacsin, a ubiquitously expressed protein believed to be involved in axonal transport [5], are the major cause of ARHSPTCC, with over 100 mutations being

Autonomic dysfunction in Parkinson's disease: A prospective cohort study: Prospective PD Autonomic Function Assessment

Background: Dysautonomia is a frequent and disabling complication of PD, with an estimated prevalence of 30‐40% and a significant impact on the quality of life.

Does intraoperative microrecording really increase the risk of hemorrhagic complications in deep brain stimulation

Stereotactic surgery represents a highly effective therapy for the treatment of Parkinson’s disease and other movement disorders refractory to medical treatment. Despite its demonstrated safety, some rare adverse events could result in potentially disabling outcomes.Amongthem,hemorrhagic complications (HC)areunarguably themost dangerous and dreaded. In a recent systematic survey of the literature, themost important patient-related factors associatedwith an increased risk of HC were age and hypertension, whereas risk factors related to surgical technique included the use of intraoperative microelectrode recording (MER), the number of MER penetrations, and the sulcal or ventricular involvement by the trajectory [1]. The incidence of HC in studies adopting MER was significantly higher than that reported with exclusively image-guided approaches [1e3]. Furthermore, the coexistence of hypertension and MER has been associated to an additional rise of bleeding incidence [4]. Herewe describe a large consecutive series of 221 patients undergoing surgery for Deep Brain Stimulation (DBS) lead placement at our institution mainly for advanced Parkinson’s disease without the occurrence of HC despite the routinely use of intraoperativeMER. Medical records and postoperative imaging studies of all patients who underwent bilateral DBS lead placement at Torino University Hospital between October 1998 and December 2013 were collected. Awritten informedconsentwasobtained for all participants. Theprocedures consisted of a single-session bilateral stereotactic lead implantation [5], performed under local anesthesia by a single primary surgeon (ML), using the CosmaneRobertseWells stereotactic frame (CRW, IntegraRadionics, Burlington,MA). Cranialmagnetic resonance imaging (MRI)/computed tomography (CT) image fusion (Image Fusion, Integra Radionics and I-Plan Stereotaxy, Brainlab AG, Feldkirchen, Germany) was used for anatomical targeting, adopting the Schaltenbrand-Wahren atlas as a reference [6]. Patients were positioned supine with their head slightly elevated (approximately 15 ). A 14-mmburr holewas located along the planned trajectory and specific lead-anchoring systemsfixed to the skull (burr-hole ring and cap early in the series; Stimloc, Medtronic, Minneapolis, MN, more recently). The dural and pial entry points were coagulatedwith bipolar electrocautery and opened sharply. To minimize the risk of HC, a trajectory avoiding sulci, arteries and ventricles was plotted. Intraoperative electrophysiological recording with a single-track MER was performed starting from 10 mm above the anatomical target (Microtargeting Electrodes BP, FHC Inc., Bowdoin,ME, early in the series, and

Prevalence and burden of dysautonomia in advanced Parkinson's disease

We sought to examine the prevalence and burden of dysautonomia in patients with advanced Parkinson’s disease (PD) treated with subthalamic deep brain stimulation (STNDBS) and levodopa-carbidopa intestinal gel infusion (LCIG). Using a standardized battery of autonomic tests, blood pressure measurement protocol, and the Scale for Outcomes in Parkinson’s Disease-Autonomic (SCOPA-AUT), 60 consecutive PD patients treated with STN-DBS (n 5 30) and LCIG (n 5 30) were classified according to the presence or absence of dysautonomia. We evaluated the impairment in activities of daily living/instrumental activities of daily living (ADL/iADL), adjusting for cognitive impairment, as measured by the Montreal Cognitive Assessment (MoCA), age, and motor severity using the motor subscale of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS-III). Additional measures included SCOPA-AUT, Orthostatic Hypotension Symptom Assessment, and the PD Quality-of-Life Questionnaire (PDQ-8). Binary logistic regression was used to estimate the impact (odds ratio [OR]) of dysautonomia on ADL/iADL, adjusting for cognitive impairment, age, and motor severity. A multiple linear regression model was used to estimate the correlation between SCOPA-AUT and PDQ-8. In addition, analysis of covariance was used to estimate the extent to which the dependent variables, ADL/iADL, adjusted for MoCA, age, and MDS-UPDRS-III, were influenced by (1) symptomatic state (symptomatic vs asymptomatic orthostatic hypotension); and (2) therapy (STN-DBS vs LCIG). Mann-Whitney and Fisher’s tests were used for comparisons between groups. The overall prevalence of dysautonomia in this unselected population was 48.3% (29 of 60 patients), similar to that in the STN-DBS (50%) and LCIG (46.7%) cohorts (P 5 0.796). Adjusted analysis showed that dysautonomia was independently associated with a threefold impairment in ADL/iADL (OR, 2.850; 95% CI, 1.044-10.326; P 5 0.042). There was a robust correlation between autonomic symptoms (SCOPA-AUT) and quality-of-life impairment (P< 0.001). The strongest correlation was for gastrointestinal (P< 0.001), urinary/sexual (P 5 0.01), and cardiovascular (P 5 0.017) domains. Adjusted ADL/iADL scores differed between patients with and without orthostatic hypotension (P 0.047). In post hoc analyses, symptomatic (15.0%) and asymptomatic (11.7%) orthostatic hypotension worsened ADL/iADL to a similar extent (P 0.045) compared with patients without orthostatic hypotension (Fig. 1). The adjusted ADL/iADL scores was similar in the STN-DBS and LCIG cohorts (P 0.473). Subanalysis of autonomic domains (Fig. 1) revealed worse cardiovascular impairment in the LCIG cohort (P 5 0.039), potentially because of higher dopaminergic dosage (Supplementary Table) and worse pupillomotor impairment in the STN-DBS cohort (P 5 0.026), plausibly associated with electrical spread to the optic tract.

Subcutaneous vs. intravenous immunoglobulin in CIDP: pharmacokinetic and clinical response

Dear Editor, Subcutaneous immunoglobulin (SCIg) represents an innovative and effective alternative to intravenous immunoglobulin (IVIg) for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (Cocito et al., 2014; 2015). Different tolerability profiles have been reported between SCIg and IVIg, with the SCIg possible advantages of fewer side effects and greater independence from hospital care (Markvardsen et al., 2013; Rajabally, 2014). However, the two routes of administration are associated with a distinctive pharmacological profile (Eftimov et al., 2009), which may result in a differential clinical efficacy. We compare the pharmacokinetic data of eight CIDP patients shifted from IVIg monthly infusions to SCIg weekly administrations, evaluating the possible correlations between clinical response and IgG plasma levels. All patients were receiving IVIg for at least 6 months, reporting a “wear-off effect” between each infusion (increase of≥ 1 point at the inflammatory neuropathy cause and treatment [INCAT] score and/or decrease of≥1 point at the medical research council [MRC] scale). IVIg monthly dose (average dose: 1.25± 0.38 g/ kg/month; ranging from 1 to 2 g/kg/month, according to the individual clinical response) was converted to an equivalent dose of SCIg (20% solution of immunoglobulin ready-to-use) delivered via a programmable pump at the patient’s domicile. The shift from IVIg to SCIg was due to fluctuations in clinical response (wear-off) and patient’s desire of greater independence from hospital care (IVIg administration at the patient’s domicile is not allowed in Italy). Blood samples (5 ml), clinical scales (INCAT and MRC) and Martin vigorimeter measurements were collected immediately before the first day (T-1) and after the second day (T0) of the last IVIg cycle, and at the following time-points: (1) before the first SCIg administration (2 weeks after the last IVIg