Neurophysiological evaluation of visual function in iRBD: potential role in stratifying RBD conversion risk.

STUDY OBJECTIVES: To evaluate neurophysiological alterations of visual function in idiopathic REM sleep Behavior Disorder (iRBD) both as markers and predictors of neurodegenerative disorders. METHODS: In a longitudinal follow-up study of 46 consecutive iRBD patients (follow-up duration 8.4 ± 3.4 years), the baseline parameters in luminance-contrast pattern (VEPp), red-green color (VEPc) and motion-onset (VEPm) Visual Evoked Potentials in iRBD were compared to early (ePD) and advanced (aPD) Parkinson's Disease subjects. Parameters of latency and amplitude of iRBD converters to neurodegenerative disease were compared with those of the non-converters. RESULTS: The VEP P100 mean latency values for both eyes and for both stimulation checks (30' and 15') were significantly longer in all the three groups of patients as compared to controls; moreover latencies were longer in aPD than in the iRBD group who did not differ from the ePD group. The same held true when we analyzed the number of abnormal subjects belonging to each diagnostic group with a higher number of abnormal subjects in the aPD group compared to both the ePD and in iRBD groups. Chromatic and motion potentials were not different from controls and did not differ in the 3 diagnostic groups. The iRBD subjects who converted to a neurodegenerative disorder showed longer P100 latencies and a higher occurrence of VEPp abnormalities than those who did not convert. Again chromatic and motion VEPs were not different depending on conversion. CONCLUSIONS: In iRBD patients the detection of an abnormal VEPp should be considered as a red flag for possible synnucleinopathy, eventually contributing in stratifying the risk of phenoconversion.

Air pollution as a contributor to the inflammatory activity of multiple sclerosis.

OBJECTIVE: Air pollution has been recently identified as a risk factor for multiple sclerosis. Aim of this study was to investigate the immunological mechanism underlying the clinical association between air pollution, namely exposure to particulate matter 10 (PM10), and inflammatory activity of multiple sclerosis (MS) METHODS: Daily recording of PM10 was obtained by monitors depending on the residence of subjects. Expression of molecules involved in activation, adhesion, and migration of T lymphocytes were tested by flow cytometry in 57 MS patients and 19 healthy controls. We next assessed in vitro the effect of PM10 on expression of C-C chemokine receptors 6 (CCR6) by peripheral blood mononuclear cells (PBMCs), on cytokine production by monocyte-derived dendritic cells (mdDC), and on T cell polarization in PBMC/mdDC mixed cultures. RESULTS: We identified a significant correlation between mean PM10 levels and expression of CCR6 CD4+ T circulating cells in MS patients. This was paralleled by the observation in vitro of a higher level of CCR6 expression on PBMC following treatment with increased doses of particulate matter. Moreover, in mdDC cultures, particulate matter induced the secretion by mdDC of Th17 polarizing IL1 beta, IL6, and IL23 and, in mdDC/PBMC mixed cultures, enhanced generation of IL17-producing T cells. CONCLUSIONS: Ex vivo and in vitro studies support the pro-inflammatory role of PM in MS, by upregulating expression of CCR6 on circulating CD4+ T cells and inducing in innate immune cells the production of Th17 polarizing cytokines. Therefore, we speculate that in MS respiratory exposure to PM10 may induce the production in the lung of autoreactive Th17 lymphocytes and boost their migratory properties through the blood-brain barrier.

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

BACKGROUND: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. METHODS: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. RESULTS: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. CONCLUSION: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.

Air pollution is associated to the multiple sclerosis inflammatory activity as measured by brain MRI.

BACKGROUND: Some environmental factors have been already associated to increased risk of multiple sclerosis (MS), but it is plausible that additional factors might play a role. OBJECTIVE: To investigate in MS patients the relationship between inflammatory activity, detected by brain magnetic resonance imaging (MRI) with gadolinium (Gd), and air pollution, namely, particulate matters with diameter less than 10 µm (PM10). METHODS: We analyzed from 52 remitting MS patients 226 brain MRIs, 34% with (Gd+MRI) and 66% without (Gd-MRI) T1-Gd-enhancing lesions. Daily recording of PM10 in the 30 days before MRI examination was obtained by monitors depending on the residence of subjects. RESULTS: PM10 levels in the 5, 10, 15, 20, and 25 days before brain MRIs were higher (plus 16%, 21%, 24%, 25%, and 21%, respectively) with reference to Gd+MRI versus Gd-MRI. There was a significant association between Gd+MRI and PM10 levels ( p = 0.013), independent of immune therapies, smoker status, and season. In patients who had two repeated MRIs with opposite outcomes (Gd-MRI and Gd+MRI), PM10 levels were strongly higher in concurrence with Gd+MRI ( p < 0.0001). CONCLUSION: Our findings suggest that air pollution may be a risk factor for MS favoring inflammatory exacerbations.

Do MRI Structured Reports for Multiple Sclerosis Contain Adequate Information for Clinical Decision Making?

OBJECTIVE: Few data are available on how often MRI reports provide sufficient information for clinical decision making in patients with multiple sclerosis (MS). The aim of this study is to evaluate if structured reporting of MRI in MS contain adequate information for clinical decision making compared with nonstructured reporting. MATERIALS AND METHODS: Brain and spinal cord MRI reports of patients with suspected or known MS before and after implementation of a structured reporting template were included. Brain and spinal cord MRI reports were assessed for presence of 11 and three key features relevant for management of MS, respectively. Three neurologists evaluated reports and images to assess lesion load, presence of sufficient information for clinical decision making, and necessity to review MR images for clinical decision making. Statistical analysis included t tests and chi-square tests. RESULTS: Thirty-two structured and 37 nonstructured reports were reviewed. Brain MRI nonstructured reports contained a mean ± SD of 3.59 ± 0.76 key features, and structured reports contained a mean of 10.25 ± 1.32 key features (p < 0.001). No significant difference was observed in the number of key features in nonstructured and structured spinal cord MRI reports. All neurologists could understand lesion load significantly more often when reading structured versus nonstructured reports (p < 0.001). For two of the three neurologists, structured reports contained adequate information for clinical decision making more often than did nonstructured reports (p < 0.001 and p = 0.006). When reading nonstructured reports, two of the three neurologists needed to evaluate images significantly more often (p < 0.001). CONCLUSION: Structured reports of MRI in patients with MS provided more adequate information for clinical decision making than nonstructured reports.

Immunomodulatory therapies delay disease progression in multiple sclerosis.

BACKGROUND: Few studies have analysed long-term effects of immunomodulatory disease modifying drugs (DMDs). OBJECTIVE: Assessment of the efficacy of DMDs on long-term evolution of multiple sclerosis, using a Bayesian approach to overcome methodological problems related to open-label studies. METHODS: MS patients from three different Italian multiple sclerosis centres were divided into subgroups according to the presence of treatment in their disease history before the endpoint, which was represented by secondary progression. Patients were stratified on the basis of the risk score BREMS (Bayesian risk estimate for multiple sclerosis), which is able to predict the unfavourable long-term evolution of MS at an early stage. RESULTS: We analysed data from 1178 patients with a relapsing form of multiple sclerosis at onset and at least 10 years of disease duration, treated (59%) or untreated with DMDs. The risk of secondary progression was significantly lower in patients treated with DMDs, regardless of the initial prognosis predicted by BREMS. CONCLUSIONS: DMDs significantly reduce the risk of multiple sclerosis progression both in patients with initial high-risk and patients with initial low-risk. These findings reinforce the role of DMDs in modifying the natural course of the disease, suggesting that they have a positive effect not only on the inflammatory but also on the neurodegenerative process. The study also confirms the capability of the BREMS score to predict MS evolution.

Postinfectious neurologic syndromes: a prospective cohort study.

OBJECTIVES: Postinfectious neurologic syndromes (PINSs) of the CNS include heterogeneous disorders, sometimes relapsing. In this study, we aimed to a) describe the spectrum of PINSs; b) define predictors of outcome in PINSs; and c) assess the clinical/paraclinical features that help differentiate PINSs from multiple sclerosis (MS). METHODS: In this prospective cohort study, adult inpatients with PINSs underwent extensive diagnostic assessment and therapeutic protocols at inclusion and during a minimum 2-year follow-up. We compared them with newly diagnosed, treatment-naive patients with MS, also prospectively recruited. RESULTS: The study sample comprised 176 patients with PINSs aged 59.9 ± 17.25 years (range: 18-80 years) divided into 2 groups: group 1 (CNS syndromes, 64%)-encephalitis, encephalomyelitis, or myelitis; and group 2 (CNS + peripheral nervous system [PNS] syndromes, 36%)-encephalomyeloradiculoneuritis or myeloradiculoneuritis. We observed the patients for 24 to 170 months (median 69 months). Relapses, almost invariably involving the spinal cord, occurred in 30.5%. PNS involvement was an independent risk factor for relapses (hazard ratio 2.8). The outcome was poor in 43% of patients; risk factors included older age, greater neurologic disability at onset, higher serum-CSF albumin percentage transfer, myelitis, and PNS involvement. Steroid resistance occurred in 30% of the patients, half of whom responded favorably to IV immunoglobulins. Compared with MS, PINSs were characterized by older age, lower tendency to relapse, and distinct CSF findings. CONCLUSIONS: The category of PINSs should be revised: most of the clinical variants have a poor prognosis and are not readily classifiable on the basis of current knowledge. PNS involvement has a critical role in relapses, which seem to affect the spine only.

Search for cellular stress biomarkers in lymphocytes from patients with multiple sclerosis: a pilot study.

Multiple Sclerosis (MS) is a chronic disease of the central nervous system, the etiology of which, although not completely known, involves inflammation and autoimmunity. In the present study we aimed at identifying molecular markers of apoptosis, cellular stress and DNA damage in isolated peripheral blood mononuclear cells (PBMCs) of MS patients. The analysis was carried on 19 relapsing-remitting untreated MS patients and 13 healthy individuals. We investigated the emergency-driven synthesis of poly(ADP-ribose) (PAR), the expression level of the constitutive enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and the DNA damage-induced phosphorylation of histone H2AX. PAR accumulation, PARP-1 and phosphorylated H2AX (γH2AX) were detected by immunofluorescence experiments on PBMCs isolated from 19 patients and 13 healthy volunteers. Our results show for the first time a net increased amount in PAR and γH2AX in MS patients compared to healthy individuals. Patients were further subdivided in three groups, according to the neuroimaging (MRI)-based classification of disease phase. Remarkably, we found a positive correlation between the level of γH2AX and MS aggressiveness. In addition, apoptosis in PBMCs was monitored by flow cytometry of both phosphatidylserine exposure (revealed by Annexin V-FITC labeling) and membrane permeability to propidium iodide. Our observations provide the evidence that the number of apoptotic cells was significantly higher in patients compared to healthy individuals, thus suggesting that apoptosis could affect MS lymphocyte function.

Chronic cerebrospinal venous insufficiency in multiple sclerosis: clinical correlates from a multicentre study.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) has recently been reported to be associated with multiple sclerosis (MS). However, its actual prevalence, possible association with specific MS phenotypes, and potential pathophysiological role are debated. METHOD: We analysed the clinical data of 710 MS patients attending six centres (five Italian and one Canadian). All were submitted to venous Doppler sonography and diagnosed as having or not having CCSVI according to the criteria of Zamboni et al. RESULTS: Overall, CCSVI was diagnosed in 86% of the patients, but the frequency varied greatly between the centres. Even greater differences were found when considering singly the five diagnostic criteria proposed by Zamboni et al. Despite these differences, significant associations with clinical data were found, the most striking being age at disease onset (about five years greater in CCSVI-positive patients) and clinical severity (mean EDSS score about one point higher in CCSVI-positive patients). Patients with progressive MS were more likely to have CCSVI than those with relapsing-remitting MS. CONCLUSION: The methods for diagnosing CCSVI need to be refined, as the between-centre differences, particularly in single criteria, were excessively high. Despite these discrepancies, the strong associations between CCSVI and MS phenotype suggest that the presence of CCSVI may favour a later development of MS in patients with a lower susceptibility to autoimmune diseases and may increase its severity.

Systemic sclerosis in aquaporin-4 antibody-positive longitudinally extensive transverse myelitis.

We report on the first patient with a relapsing, anti-aquaporin-4 (AQP-4) antibody-positive, longitudinally extensive transverse myelitis (LETM) who developed systemic sclerosis (SSc). A 62-year-old woman, who presented with bilateral, distal lower limb and perineal numbness, developed clinical manifestations and paraclinical features of SSc. Spinal cord imaging revealed lesions that were consistent with LETM. Patient's serum was positive for neuromyelitis optica (NMO)-IgG/AQP-4 antibodies. High-dose intravenous corticosteroids improved the neurological symptoms. The present case expands the list of autoimmune systemic diseases that occur in neuromyelitis optica spectrum disorders associated with NMO-IgG/AQP-4 antibodies.

Epileptic mechanisms in Charles Bonnet syndrome.

Epileptic phenomena are usually not considered a possible cause of prolonged hallucinatory states such as Charles Bonnet syndrome (CBS). A 65-year-old woman with previous right hemorrhagic strokes developed complex visual hallucinations (CVHs), featuring CBS, and delayed palinopsic phenomena, along with new neurological signs and worsening of existing deficits. Video/EEG/polygraphy monitoring revealed the presence of right-sided periodic lateralized epileptiform discharges of the "plus" type (PLEDs plus) and documented a focal seizure in close relation to a delayed palinopsia episode. Adjustment of antiepileptic drug treatment led to remission of the CVHs with simultaneous disappearance of PLEDs plus and epileptic seizures and return to previous neurological status. We discuss the role of continuous (PLEDs plus) and intermittent (focal seizures) epileptic activities in this episodic form of CBS, considering current theories on the genesis of CVHs. EEG assessment is recommended if CBS develops in a patient with unexplained worsening of existing neurological signs.

Clinico-pathological findings in a patient with progressive cerebellar ataxia, autoimmune polyendocrine syndrome, hepatocellular carcinoma and anti-GAD autoantibodies.

OBJECTIVE: To report clinical and pathological findings of a patient with late onset insulin-dependent diabetes mellitus (IDDM), progressive cerebellar ataxia (PCA) and hepatocellular carcinoma (HCC). PATIENT: A 64-year-old woman, with a long lasting IDDM, progressively developed a severe cerebellar syndrome and died 2 years after the onset of the symptoms for a systemic infection. Autoantibodies to antigastric parietal cell and anti-pancreatic islet cell resulted positive. Autopsy showed a selective loss of Purkinje cells in the cerebellum, with an increase of Bergmann glia and variable microglial proliferation; furthermore, it disclosed an HCC. GAD-Abs were detected both in serum and CSF. CONCLUSIONS: Clinical and experimental reports suggest a possible role of neoplastic cells in producing GAD-Abs. We postulate, in our case, that HCC could have been responsible for an overproduction of GAD-Abs, leading to the onset of PCA. Thus, GAD-Abs could be considered as a paraneoplastic marker in a subgroup of patients with PCA.

Inverse relationship between multiple sclerosis and allergic respiratory diseases.

Th1 up-regulation seems to favour autoimmunity, while Th2 up-regulation seems to favour humoral immunity. Accordingly, subjects affected by atopic diseases (such as allergic respiratory diseases, ARDs) should be less prone to autoimmune diseases (such as multiple sclerosis, MS), and vice versa. The recent identification of Th17 cells, which seem to favour the development of both autoimmunity and allergy, led to the revision of the classic Th1/Th2 paradigm. We studied 200 MS patients and 200 controls to analyze the relationships between ARDs and MS. MS patients had less probability to suffer from ARDs (OR = 0.30, p < 0.001) and allergic rhinitis (OR = 0.25, p < 0.001), after adjusting for environmental factors. MS tended to be less severe when associated to ARDs. Our findings add some elements for the comprehension of immune mechanisms involved in MS pathogenesis and suggest to analyze other MS cohorts, in order to evaluate if MS patients affected by allergic diseases show particular clinical findings.

The treatment of fatigue.

Fatigue is a psychophysiological state that acts on the subject's motivation to engage in and/or to continue strenuous physical or cognitive activities. In various pathological conditions fatigue seems to lose this homeostatic function and presents itself as a symptom. The pathophysiology of fatigue is complex and includes neurological (central and peripheral) dysfunction, and altered neurotransmitter, cytokine, and hormonal settings. Treatment interventions are generally based on a sequential approach including treatment of comorbid factors, nonpharmacological treatments, and drugs.

Varicella zoster virus meningo-encephalo-myelitis in an immunocompetent patient.

OBJECTIVE: To describe clinical, MRI and cerebrospinal fluid (CSF) features of a varicella zoster virus (VZV) related meningo-encephalo-myelitis (MEM) without rash in an immunocompetent female. PATIENT: An 85 year old immunocompetent woman with mild hyperthermia and acute, severe MEM. INTERVENTION: Serum antibodies and CSF PCR were searched for several viruses. Brain and spinal cord MRI were performed. Immunological profile. TREATMENTS: i.v. acyclovir 30 mg/kg/day; i.v. 6-MP 125 mg/day. RESULTS: Marked CSF lymphomonocytic pleocytosis, blood-brainbarrier damage, and PCR detection of 3.05 X 10 6 copies of VZV DNA. MRI revealed lesions of the meninges, brain and spinal cord. No evidence of immunosuppression. CONCLUSION: We highlight the importance of considering the possibility of VZV related MEM, even in immunocompetent patients. We also provide a MRI description of VZV related multifocal myelitis, not previously available. As supported by other reports, we underline the necessity of a prompt therapeutic intervention in this life-threatening condition.

Early prediction of the long term evolution of multiple sclerosis: the Bayesian Risk Estimate for Multiple Sclerosis (BREMS) score.

AIM: To propose a simple tool for early prediction of unfavourable long term evolution of multiple sclerosis (MS). METHODS: A Bayesian model allowed us to calculate, within the first year of disease and for each patient, the Bayesian Risk Estimate for MS (BREMS) score that represents the risk of reaching secondary progression (SP). RESULTS: The median BREMS scores were higher in 158 patients who reached SP within 10 years compared with 1087 progression free patients (0.69 vs 0.30; p<0.0001). The BREMS value was related to SP risk in the whole cohort (p<0.0001) and in the subgroup of 535 patients who had never been treated with immune therapies, thus reasonably representing the natural history of the disease (p<0.000001). CONCLUSIONS: The BREMS score may be useful both to identify patients who are candidates for early or for more aggressive therapies and to improve the design and analysis of clinical therapeutic trials and of observational studies.

The N3 potential compared to sound and galvanic vestibular evoked myogenic potential in healthy subjects and in multiple sclerosis patients.

Both sound (s-) and galvanic (g-) vestibular-evoked myogenic potential (VEMP) enable us to study the saccular pathways. However, the VEMP can be abnormal for non-vestibular factors, such as insufficient activation of the sterno-cleido-mastoid (SCM) muscle or a lesion that involves the accessory nucleus and/or nerve or the SCM muscle. These drawbacks do not affect another technique that evaluates the saccular function: the N3 potential. We recorded both the s- and the g-VEMP and the N3 potential in a group of 31 healthy subjects to establish a reference range. The N3 potential and the s-VEMP were recordable bilaterally from all the subjects, whereas the g-VEMP was undetectable uni- or bilaterally in 7 subjects. The latency and amplitude values of the s-VEMP did not differ from those of the g-VEMP. For all three techniques, the latency and amplitude values from the right and from the left recording and/or stimulation side were the same. We suggest using normative latency and amplitude values based on the mean and ratio of the right- and left-side values. The s-VEMP, the N3 potential and the auditory evoked response (ABR) were compared in 15 subjects suffering from multiple sclerosis. The three techniques detected a similar number of abnormalities, but these abnormalities were not correlated. This suggests that these different techniques should be regarded as complementary in evaluating saccular function.

Cytokines and chemokines in cerebrospinal fluid and serum of adult patients with acute disseminated encephalomyelitis.

Cytokines and chemokines contribute to the pathogenesis of acute disseminated encephalomyelitis (ADEM). Using a multiplex immunochemiluminescence ELISA, we measured 8 Th1/Th2 cytokines and 18 chemokines in the cerebrospinal fluid (CSF) and serum of 17 ADEM patients, 14 multiple sclerosis (MS) patients, and 7 healthy controls (HCs). Relative to HCs, ADEM patients had significantly high mean CSF concentrations of chemokines with attractant/activating properties towards neutrophils (CXCL1 and CXCL7), monocytes/T cells (CCL3 and CCL5), Th1 cells (CXCL10), and Th2 cells (CCL1, CCL22, and CCL17). Mean CSF concentrations of CXCL7, CCL1, CCL22, and CCL17 were higher in ADEM than in MS, whereas those of CCL11 were lower in MS than in ADEM and HCs. CSF pleocytosis correlated with CSF concentrations of CXCL1, CXCL10, CCL1, CCL17, and CCL22. Most of the functionally homologous chemokines correlated with each other. CSF Th1/Th2 cytokines were not detectable in most samples. Their mean concentrations did not differ in the three groups, and the same held for serum cytokines and chemokines. Our data suggest that the upregulation of chemokines active on neutrophils and Th2 cells differentiates ADEM from MS inflammation, and that both Th1 and Th2 chemokines might be produced in ADEM. Chemokines upregulated in ADEM could become CSF biomarkers after a posteriori evaluations in unselected case series.

Acute oculomotor impairment with anti-GQ1b IgG due to central nervous system dysfunction.

We report the case of a patient with isolated central oculomotor impairment and anti-GQ1b antibody. The patient was referred to us with acute vertical diplopia. The neurological examination revealed right internuclear ophthalmoplegia (INO), skew deviation and mild gait ataxia. Extensive laboratory analyses, CSF study, multimodal evoked potentials and brain MRI were normal. Eye movement recording showed saccade dysmetria in addition to the INO. The subjective visual vertical was abnormally tilted to the left. The anti-GQ1b IgG antibody was detectable on serum DOT-BLOT. The brainstem and cerebellar features of the oculomotor impairment suggested that in our patient the anti-GQ1b IgG antibody showed a preferential cross-reaction with central nervous system epitopes. This finding is at variance with previous reports on anti-GQ1b syndrome with acute ophthalmoplegia, all of which argue for a localization of GQ1b epitopes within the peripheral nervous system, even though, in the light of the description of the ocular motor disorder, a central involvement might have co-occurred in this case.