Papers by Paola Sarchielli
Neuroscience Letters, Apr 1, 2008
In recent years a role has been recognized for fibroblast growth factor (FGF)-2 in the pathogenes... more In recent years a role has been recognized for fibroblast growth factor (FGF)-2 in the pathogenesis of demyelination and the failure of remyelination in experimental models of multiple sclerosis (MS). FGF-2 levels were determined using a sensitive immunoassay in the cerebrospinal fluid (CSF) of 20 patients with clinically isolated syndrome (CIS), 40 patients with relapsing-remitting (R-R) MS, and 30 patients with secondary progressive (SP) MS, correlated with MRI measures. Control CSF samples were obtained from 20 subjects who underwent lumbar puncture for diagnostic purposes and for whom all instrumental and laboratory analyses excluded systemic and nervous system diseases. FGF-2 levels in the CSF of MS and CIS patients were significantly higher than controls (P < 0.001 and P < 0.05, respectively). The highest levels were detected in R-R MS patients during relapse and in SP MS patients with an increase of 1 point in EDSS scores in the last 6 months. A significant correlation was found in SP MS patients with lesional load (R = 0.43, P < 0.01) but not with parenchymal fractions as measures of brain atrophy. A slight increase in serum FGF-2 levels was also found in R-R MS patients during relapse with gadolinium enhancing lesions and in SP patients with disability progression. These findings support the implication of FGF-2 in the pathogenesis of MS and concur with recent reports of the involvement of FGF receptor signalling in the disruption of myelin production in differentiated oligodendrocytes and in the loss of adult oligodendrocytes and myelin in vivo due to FGF-2.
Cephalalgia, Oct 1, 1995
We measured, by RIA methods, ictal and interictal levels of substance P (SP), calcitonin-gene rel... more We measured, by RIA methods, ictal and interictal levels of substance P (SP), calcitonin-gene related peptide (CGRP) and neurokinin A (NKA) in the plasma of 30 young migraine patients with aura (MPA) and 45 migraine patients without aura (MWA), and compared the results with those of 30 age-matched controls. There were no significant differences between the levels of these vasoactive peptides in the control group and the levels in both migraine groups studied in headache-free periods. An elevation of CGRP levels in plasma was found during attacks in MPA and, to a lesser extent, in MWA (p &lt; 0.03 and p &lt; 0.05, respectively). A significant increase in NKA levels was also demonstrated in the MPA and MWA groups (p &lt; 0.02 and p &lt; 0.04, respectively). These data suggest, although indirectly, that CGRP and NKA could be involved in the pathogenesis of migraine attacks in juvenile migraine patients.
Cephalalgia, Dec 1, 2000
Despite evidence emerging from the experimental model of nitroglycerin-induced headache, the endo... more Despite evidence emerging from the experimental model of nitroglycerin-induced headache, the endogenous increase in nitric oxide (NO) production during migraine attacks is only speculative. It has been hypothesized that there is a close relationship between activation of the L-arginine/NO pathway and production of certain vasoactive and algogenic prostaglandins during spontaneous migraine attacks, but this suggestion also needs to be con®rmed. In the present study the levels of nitrites, the stable metabolites of NO, were determined with high performance liquid chromatography (HPLC) in the internal jugular venous blood of ®ve patients affected by migraine without aura examined ictally. These samples were taken within 30 min, 1, 2, and 4 h from the onset of the attack and at the end of the ictal period. At the same time, the plasma levels of calcitonin gene-related peptide (CGRP), neurokinin A (NKA), prostaglandin E 2 (PGE 2) and 6 keto PGF1a, the stable product of PGI 2 , were assessed with radioimmunoassay (RIA) kits in the same samples. The levels of the intracellular messengers, cGMP and cAMP, were also measured with the RIA method. Nitrite, cGMP, CGRP and NKA levels reached their highest values at the ®rst hour, then they tended to decrease progressively and returned, after the end of attacks, to values similar or below those detected at the time of catheter insertion (ANOVA, statistical signi®cance: P<0.001; P%0.002; P<0.002; P<0.003, respectively). PGE 2 and 6 keto PGF1a, as well as cAMP levels also signi®cantly increased at the ®rst hour but reached a peak at the 2nd hour and remained in the same range until the 4th and 6th hours. Then their values tended to decrease after the end of attacks, becoming lower than those measured immediately after catheter positioning for internal jugular venous blood drawing (ANOVA: P<0.002, P<0.004, P<0.001, respectively). Our results support early activation of the L-arginine/ NO pathway which accompanies the release of vasoactive peptides from trigeminal endings and a late rise in the synthesis of prostanoids with algogenic and vasoactive properties which may intervene in maintaining the headache phase. u Nitrites, calcitonin gene-related peptide, neurokinin A, prostaglandins, internal jugular blood, migraine attacks
Cephalalgia, Oct 1, 1995
Interuniversity Center for the Study of Headache and Neurotransmitter Disorders-Universities of P... more Interuniversity Center for the Study of Headache and Neurotransmitter Disorders-Universities of Perugia-Roma-Sassari and Bari. Unit of Perugia, Italy.
Neurological Sciences, Mar 20, 2023
Background The Cluster Headache Impact Questionnaire (CHIQ) is a specific and easy-to-use questio... more Background The Cluster Headache Impact Questionnaire (CHIQ) is a specific and easy-to-use questionnaire to assess the current impact of cluster headache (CH). The aim of this study was to validate the Italian version of the CHIQ. Methods We included patients diagnosed with episodic CH (eCH) or chronic CH (cCH) according to the ICHD-3 criteria and included in the "Italian Headache Registry" (RICe). The questionnaire was administered to patients through an electronic form in two sessions: at first visit for validation, and after 7 days for test-retest reliability. For internal consistency, Cronbach's alpha was calculated. Convergent validity of the CHIQ with CH features and the results of questionnaires assessing anxiety, depression, stress, and quality of life was evaluated using Spearman's correlation coefficient. We included 181 patients subdivided in 96 patients with active eCH, 14 with cCH, and 71 with eCH in remission. The 110 patients with either active eCH or cCH were included in the validation cohort; only 24 patients with CH were characterized by a stable attack frequency after 7 days, and were included in the test-retest cohort. Internal consistency of the CHIQ was good with a Cronbach alpha value of 0.891. The CHIQ score showed a significant positive correlation with anxiety, depression, and stress scores, while showing a significant negative correlation with quality-of-life scale scores. Conclusion Our data show the validity of the Italian version of the CHIQ, which represents a suitable tool for evaluating the social and psychological impact of CH in clinical practice and research. Keywords Cluster headache • Questionnaire • Cluster Headache Impact Questionnaire • Quality of life • Disability Abbreviations CH Cluster headache cCH Chronic cluster headache eCH Episodic cluster headache PRO(s) Patient-reported outcome(s) CHIQ Cluster Headache Impact Questionnaire ICHD-3 International Classification of Headache Disorders, 3rd Edition RICe Italian Headache Registry (Registro Italiano delle Cefalee) REDCap Research Electronic Data Capture DASS-21 Depression, Anxiety, and Stress Scale Short Version SF-36 Short Form Health Survey IQR Interquartile range ICC Intraclass correlation coefficients Background Cluster headache (CH) is a primary headache disorder that affects approximately 0.1% of the population [1]. Approximately 85% of individuals afflicted by CH have episodic CH
European Neurology, Sep 8, 2006
Journal of Neurology, Jan 11, 2018
Introduction The MRI evidence of persistent black holes (pBHs) on T1-weighted images reflects bra... more Introduction The MRI evidence of persistent black holes (pBHs) on T1-weighted images reflects brain tissue loss in multiple sclerosis (MS). The evolution of contrast-enhancing lesions (CELs) into pBHs probably depends on the degree and persistence of focal brain inflammation. The aim of our retrospective study was to evaluate the effect of a single cycle of intravenous methylprednisolone (IVMP), as for MS relapse treatment, on the risk of CELs' evolution into pBHs. Patients and methods We selected 57 patients with CELs on the baseline MRI scan. We evaluated the evolution of CELs into pBHs on a follow-up MRI scan performed after ≥ 6 months in patients exposed and not exposed to IVMP for the treatment of relapse after the baseline MRI. Results In our cohort, 182 CELs were identified in the baseline MRI and 57 of them (31.3%) evolved into pBHs. In the multivariate analysis, the exposure of CELs to IVMP resulted to be a significant independent protective factor against pBHs' formation (OR 0.28, 95% CI 0.11-0.766, p = 0.005), while ring enhancement pattern and the fact of being symptomatic were significant risk factors for CELs' conversion into pBHs (OR 6.42, 95% CI 2.55-17.27, p < 0.001 and OR 13.19, 95% CI 1.56-288.87, p = 0.037). Conclusions The exposure of CELs to a cycle of IVMP as for relapse treatment is associated with a lower risk of CELs' evolution into pBHs. Future studies are required to confirm the potential independent protective effect of IVMP on CELs' evolution into pBHs.
PubMed, Oct 1, 1993
Epidemiological studies performed to identify the possible cause of Multiple Sclerosis (MS) sugge... more Epidemiological studies performed to identify the possible cause of Multiple Sclerosis (MS) suggest that an environmental agent could be involved in its etiopathogenesis. For a long time it has been hypothesized that this agent was a virus, but until now no virus specific to MS has been consistently identified. Animal models indicate that the demyelination of the central nervous system can be induced by certain families of viruses, but the implication of this in the etiopathogenesis of MS has not been clearly demonstrated. Morbilliviruses were the most studied. Research on this subject arose from the observation of the similarity between the brain lesions occurring in MS and encephalitis caused by the measles virus (Subacute Sclerosing Panencephalitis). Antimeasles, antirubella, antiherpes zoster antibodies have been found in the blood and the cerebrospinal fluid of MS patients, but the relationship between this finding and the disease is not clear. It has recently been proposed that the pathogenetic immune response in the brain of MS patients might be directed predominantly towards antigens of a DNA virus, such as JCV. This preferentially infects glial cells and causes a demyelinating syndrome in immunodeficient subjects, called Progressive Multifocal Leucoencephalopathy. The target JC viral antigens in MS could be synthesized during transient viral reactivation. A recent hypothesis is that retroviruses may intervene in the etiopathogenesis of MS. Strong interest has been taken in HTLV-I after its identification in Tropical Spastic Paraparesis, a disease with certain similarities to MS. Serologic and polymerase chain reaction findings from various authors have suggested an association between this human retrovirus and MS. However more recent data are not consistent with this. Current experiments aimed at detecting retroviral particles in long-term cultured peripheral blood monocytes and cerebrospinal fluid mononuclear cells in MS could clarify whether these cells provide a reservoir for such viruses, with a latency of many years without expression at brain level.
PubMed, 1994
An impairment in the autonomic function has been demonstrated in patients with multiple sclerosis... more An impairment in the autonomic function has been demonstrated in patients with multiple sclerosis (MS) using electrophysiological, pupillary and biochemical tests. Particularly evident were alterations in the cardiovascular reflexes, cutaneous sympathetic response and lymphomonocyte adrenergic binding. Electrophysiological and biochemical findings in MS patients have only occasionally been compared. Among the peripheral markers of the autonomic system, Neuropeptide Y (NPY) and dopamine-beta-hydroxylase (DBH) have been singled out as reliable indices of sympathetic function. The former is a peptide with a strong vasoconstrictive action, which is released from adrenergic endings together with noradrenaline following sympathetic activation. The latter is the enzyme which catalyses the conversion of dopamine to norepinephrine. It is located both in sympathetic endings and the chromaffin granules of adrenal medulla. To verify a failure in autonomic function in the course of MS, a battery of cardiovascular tests (assessing sympathetic and parasympathetic functions) was performed on 25 MS patients. The results were compared with a group of 20 age- and sex-matched control individuals. The plasma levels of NPY and the serum DBH activity were also determined in both groups. 52% of patients showed an impairment in sympathetic function in one or more tests (sustained handgrip, postural hypotension, cold face test). 48% of the patients had abnormal values in deep breathing test, indicating a failure of the parasympathetic function. 44% of patients showed also a paroxysmal tachycardia after cold face test, indicating an abnormal function of the vagal-cardiac and sympathetic-vascular smooth muscle pathways of the trigeminal nerve.(ABSTRACT TRUNCATED AT 250 WORDS)
European Journal of Neurology, Apr 11, 2018
Background and purposeEducational intervention has proved to be effective in reducing drug abuse ... more Background and purposeEducational intervention has proved to be effective in reducing drug abuse in uncomplicated medication‐overuse headache (MOH). This ancillary of the SAMOHA multicentre study aimed to assess any differences in phenotypic characteristics, type and amount of drugs overused, and comorbidities between patients with MOH who responded to simple advice and those who did not.MethodsDemographic and clinical headache data of the last 3 months before enrollment of patients were collected and patients were then asked to fill out a daily headache diary for 4 weeks. Patients were then divided into two subgroups, i.e. those with confirmed MOH continued in the study [randomized (R) group], whereas those who did not still show any features of MOH dropped out of the study.ResultsA total of 88 (67.7%) patients still met the inclusion criteria after the baseline 4 weeks (R group). Conversely, 42 (32.3%) patients dropped out of the study. A detailed analysis of those who dropped out revealed that only 34 were not randomized at visit 2 because they no longer satisfied the inclusion criteria for MOH [screening failures (SF) group]. The SF group was significantly younger and had fewer years of migraine history than the R group. Moreover, the SF group had a significantly shorter history of chronicity compared with the R group.ConclusionsOur findings suggest that in MOH trials, after an educational session, an observational period is needed in order to confirm the diagnosis of MOH and to avoid overestimation of the effect of other treatments used to manage MOH. Future research should focus mainly on those patients with MOH who do not respond to simple advice and with unsuccessful withdrawal.
Italian Journal of Neurological Sciences, Jun 1, 1992
Background: Polyunsaturated fatty acids are essential nutrients for humans. They are structural a... more Background: Polyunsaturated fatty acids are essential nutrients for humans. They are structural and functional components of cell membranes and pre-stages of the hormonally and immunologically active eicosanoids. Recent discoveries have shown that the long-chained omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also play an important role in the central nervous system. They are essential for normal brain functioning including attention and other neuropsychological skills. Materials and methods: In our large observational study we monitored 810 children from 5 to 12 years of age referred for medical help and recommended for consuming polyunsaturated fatty acids (PUFA) in combination with zinc and magnesium by a physician over a period of at least 3 months. The food supplement ESPRICO® (further on referred to as the food supplement) is developed on the basis of current nutritional science and containing a combination of omega-3 and omega-6 fatty acids as well as magnesium and zinc. Study objective was to evaluate the nutritional effects of the PUFA-zinc-magnesium combination on symptoms of attention deficit, impulsivity, and hyperactivity as well as on emotional problems and sleep related parameters. Assessment was performed by internationally standardised evaluation scales, i.e. SNAP-IV and SDQ. Tolerance (adverse events) and acceptance (compliance) of the dietary therapy were documented. Results: After 12 weeks of consumption of a combination of omega-3 and omega-6 fatty acids as well as magnesium and zinc most subjects showed a considerable reduction in symptoms of attention deficit and hyperactivity/impulsivity assessed by SNAP-IV. Further, the assessment by SDQ revealed fewer emotional problems at the end of the study period compared to baseline and also sleeping disorders. Mainly problems to fall asleep, decreased during the 12 week nutritional therapy. Regarding safety, no serious adverse events occurred. A total of 16 adverse events with a possible causal relationship to the study medication were reported by 14 children (1.7%) and only 5.2% of the children discontinued the study due to acceptance problems. Continuation of consumption of the food supplement was recommended by the paediatricians for 61.1% of the children. Conclusion: Our results suggest a beneficial effect of a combination of omega-3 and omega-6 fatty acids as well as magnesium and zinc consumption on attentional, behavioural, and emotional problems of children and adolescents. Thus, considering the behavioural benefit in combination with the low risk due to a good safety profile, the dietary supplementation with PUFA in combination with zinc and magnesium can be recommended.
Multiple Sclerosis Journal, Feb 25, 2013
Background: The elucidation of mechanistic aspects of relapsing–remitting multiple sclerosis (RRM... more Background: The elucidation of mechanistic aspects of relapsing–remitting multiple sclerosis (RRMS) pathogenesis may offer valuable insights into diagnostic decisions and medical treatment. Results: Two lysosomal proteases, cathepsins S and D (CatS and CatD), display an exclusive pattern of expression in CD34+ hematopoietic stem cells (HSCs) from peripheral blood of acute MS (A-MS) patients ( n = 20). While both enzymes normally exist as precursor forms in the HSCs of healthy individuals ( n = 30), the same cells from A-MS patients consistently exhibit mature enzymes. Further, mature cathepsins are expressed at lower rates in stable MS subjects (S-MS, n = 15) and revert to precursor proteins after interferon-β1a treatment ( n = 5). Mature CatD and CatS were induced in HSCs of healthy donors that were either co-cultured with PBMCs of A-MS patients or exposed to their plasma, suggesting a functional involvement of soluble agents. Following HSC exposure to several cytokines known to be implicated in MS, and based on relative cytokine levels displayed in A-MS, S-MS and control individuals, we identified IL-16 as a specific cell signaling factor associated with cathepsin processing. Conclusions: These data point to an evident correlation between CatS and CatD expression and MS clinical stage, and define a biochemical trait in HSCs with functional, medical, and diagnostic relevance.
Journal of Neurology, Sep 8, 2018
Objectives To investigate the impact of the 2017 revisions of McDonald criteria on the diagnosis ... more Objectives To investigate the impact of the 2017 revisions of McDonald criteria on the diagnosis of multiple sclerosis (MS) in a cohort of patients with clinically isolated syndrome (CIS) and dissemination in space (DIS) of demyelinating lesions. Methods We retrospectively analyzed 137 patients with CIS + DIS from two Italian MS centers. Results Application of the 2017 revisions of McDonald criteria in our cohort led to a diagnosis of MS in 82.5% of the patients who could have not been diagnosed with MS according to the previous criteria at the time of the first demyelinating event. After a follow-up of 3.8 ± 2.9 years, 85.8% of these patients eventually satisfied also the previous ( ) criteria. Conclusions Application of the 2017 revisions of McDonald criteria results in an earlier diagnosis of MS in a large percentage of CIS patients destined to convert to MS.
Scientific Reports, Feb 18, 2016
Cognitive impairment is common in multiple sclerosis (MS). Unfortunately, the synaptic and molecu... more Cognitive impairment is common in multiple sclerosis (MS). Unfortunately, the synaptic and molecular mechanisms underlying MS-associated cognitive dysfunction are largely unknown. We explored the presence and the underlying mechanism of cognitive and synaptic hippocampal dysfunction during the remission phase of experimental MS. Experiments were performed in a chronic-relapsing experimental autoimmune encephalomyelitis (EAE) model of MS, after the resolution of motor deficits. Immunohistochemistry and patch-clamp recordings were performed in the CA1 hippocampal area. The hole-board was utilized as cognitive/behavioural test. In the remission phase of experimental MS, hippocampal microglial cells showed signs of activation, CA1 hippocampal synapses presented an impaired long-term potentiation (LTP) and an alteration of spatial tests became evident. The activation of hippocampal microglia mediated synaptic and cognitive/behavioural alterations during EAE. Specifically, LTP blockade was found to be caused by the reactive oxygen species (ROS)-producing enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We suggest that in the remission phase of experimental MS microglia remains activated, causing synaptic dysfunctions mediated by NADPH oxidase. Inhibition of microglial activation and NADPH oxidase may represent a promising strategy to prevent neuroplasticity impairment associated with active neuro-inflammation, with the aim to improve cognition and counteract MS disease progression.
Acta Neurologica Scandinavica, Jan 29, 2009
We determined the plasma levels of ETI, both interictally and ictally, in 50 migraine patients, 2... more We determined the plasma levels of ETI, both interictally and ictally, in 50 migraine patients, 20 with aura (MPA) and 30 without aura (MPWA), comparing them with the levels of 40 age-matched tension-type headache patients (20 episodic and 20 chronic) (ETTHP and CTTHP) and the levels of a group of 20 healthy control subjects (CS). No statistically significant difference was evident between the mean ET1 plasma levels of MPA and those of MPWA, assessed in headache-free periods. The mean ETl plasma levels of MPA and MPWA. assessed interictally, were significantly higher than those of CS. However, the values of plasma ET1 in ETTP and in CTTHP did not differ statistically from those of CS. MPA and MPWA ET1 plasma levels increased significantly within 2 h from the onset of attacks (p<O.OOOI) and remained significantly higher between 4 and 6 h from the onset. The ET1 plasma levels of ETTHP and CTTHP assessed during altacks did not differ statistically from thosc of the same patients assessed in the headache-free periods. The increase in ET1 levels in MPA and MPWA patients when assessed ictally. suggests that this peptide is involved in the haeniodynamic changes and vascular tone modifications observed during migraine attacks, particularly in the first phase of the ictal period. In the last few years the endothelium of cerebral blood vessels has been shown not only to be a physical barrier between the brain and the cerebral blood, but also to be an organ characterized by several functions. The most important of these is the production of vasoactive substances in response to a variety of biochemical and physical stimuli. Due to the production of these vasoactive factors, the endothelium actively contributes to the regulation of the vessels' smooth muscular tone (1, 2). Recently, Y anagisawa et al. discovered a potent vasoconstrictor peptide, named endothelin, produced by the vascular endothelial cells; they determined its aminoacid sequences and clones its peptide precursor (3-5). Endothelin is an extremely potent, biologically stable peptide, with high-affinity binding sites on the vascular muscle cells, and it produces an intense substained vasoconstriction (6-9). The long-lasting cffect of endothelin is due not only to the release of pre-formed endothelin but also to the induction of de IIOW endothelin synthesis by endothelial cells (10).
Cephalalgia, Jul 1, 2008
The study set out to investigate the role of corticotrophin-releasing factor (CRF) and orexin-A i... more The study set out to investigate the role of corticotrophin-releasing factor (CRF) and orexin-A in chronic migraine (CM) and medication-overuse headache (MOH). Twenty-seven patients affected by CM and 30 with MOH were enrolled. Control CSF specimens were obtained from 20 age-matched subjects who underwent lumbar puncture for diagnostic purposes, and in all of them CSF and blood tests excluded central nervous system or systemic diseases. Orexin-A and CRF were determined by radioimmunoassay methods. Significantly higher levels of orexin-A and CRF were found in the CSF of MOH and to a lesser extent in patients with CM compared with control subjects (orexin-A: P < 0.001 and P < 0.02; CRF: P < 0.002 and P < 0.0003). A significant positive correlation was also found between CSF orexin-A values and those of CRF (R = 0.71; P < 0.0008), monthly drug intake group (R = 0.39; P < 0.03) and scores of a self-completion 10-item instrument to measure dependence upon a variety of substances, the Leeds Dependence Questionnaire (LDQ) in the MOH group (R = 0.68; P < 0.0003). The significantly higher orexin-A levels found in CM and MOH can be interpreted as a compensatory response to chronic head pain or, alternatively, as an expression of hypothalamic response to stress due to chronic pain. A potential role for orexin-A in driving drug seeking in MOH patients through activation of stress pathways in the brain can also be hypothesized. ᮀ Cerebrospinal fluid, chronic migraine, corticotrophin-releasing factor, medication-overuse headache, orexin-A
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Papers by Paola Sarchielli