Publications by authors named "Simonetta Gerevini"

56 Publications

Cerebrospinal fluid HIV RNA escape symptomatology.

AIDS 2021 Jun 15. Epub 2021 Jun 15.

Mildmay Hospital, London, UK Unit of Infectious Diseases, San Raffaele Hospital, Milan, Italy Section of Retrovirology, Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK Department of HIV Medicine, St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK Unit of Neuroradiology, ASST Papa Giovanni XXIII, Bergamo, Italy Lazzaro Spallanzani National Institute of Infectious Diseases, Rome, Italy San Paolo Hospital, University of Milan, Milan, Italy University of Bari, Bari, Italy Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Turin, Italy Department of Neurology, St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK Neurosciences, Blizard Institute, Queen Mary University of London, London, UK Grahame Hayton Unit, I&I and Neurology Department, Barts Health NHS Trust, London, UK.

Objective: To characterise the clinical, laboratory and radiological characteristics of persons with HIV (PWH) presenting with cerebrospinal fluid (CSF) HIV RNA escape.

Design: Retrospective case review of PWH presenting with symptomatic CSF HIV RNA escape at seven tertiary HIV clinical sites in UK and Italy.

Method: PWH with symptomatic CSF HIV RNA escape episodes were identified and data obtained from medical records. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in unquantifiable plasma HIV RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV RNA was quantifiable. The onset of clinical symptoms was classified as acute (<2 weeks-6 months), or chronic (>6 months) and differences in presentation in those with CSF HIV RNA below and above 1000 copies/mL determined.

Results: We identified 106 PWH with CSF HIV RNA escape (65 male); 68 (64%) PWH had acute presentations and 38 (36%) had chronic presentations. Cognitive decline (n = 54, 50.9%), confusion (n = 20, 18.9%) and headache (n = 28, 26.4%) were the most common presentations, with cognitive decline being more common in PWH who presented chronically compared with PWH who presented acutely (73.7% vs 35.3%, p = 0.0002). Sixty PWH had CSF HIV RNA ≥1000 copies/mL and presented more frequently with confusion (n = 15/60, 25.0%) compared to PWH with CSF HIV RNA <1000 copies/mL at presentation (n = 5/46, 10.9%; p = 0.03).

Conclusion: Cognitive decline, confusion and headache are the most frequent presenting symptoms of CSF HIV RNA escape and their relative frequency varied according to symptom onset and CSF HIV RNA concentration.
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http://dx.doi.org/10.1097/QAD.0000000000002992DOI Listing
June 2021

SARS-CoV-2 infection and acute ischemic stroke in Lombardy, Italy.

J Neurol 2021 May 24. Epub 2021 May 24.

Department of Neurology and Stroke Unit, Carlo Poma Hospital, ASST Mantova, Mantova, Italy.

Objective: To characterize patients with acute ischemic stroke related to SARS-CoV-2 infection and assess the classification performance of clinical and laboratory parameters in predicting in-hospital outcome of these patients.

Methods: In the setting of the STROKOVID study including patients with acute ischemic stroke consecutively admitted to the ten hub hospitals in Lombardy, Italy, between March 8 and April 30, 2020, we compared clinical features of patients with confirmed infection and non-infected patients by logistic regression models and survival analysis. Then, we trained and tested a random forest (RF) binary classifier for the prediction of in-hospital death among patients with COVID-19.

Results: Among 1013 patients, 160 (15.8%) had SARS-CoV-2 infection. Male sex (OR 1.53; 95% CI 1.06-2.27) and atrial fibrillation (OR 1.60; 95% CI 1.05-2.43) were independently associated with COVID-19 status. Patients with COVID-19 had increased stroke severity at admission [median NIHSS score, 9 (25th to75th percentile, 13) vs 6 (25th to75th percentile, 9)] and increased risk of in-hospital death (38.1% deaths vs 7.2%; HR 3.30; 95% CI 2.17-5.02). The RF model based on six clinical and laboratory parameters exhibited high cross-validated classification accuracy (0.86) and precision (0.87), good recall (0.72) and F1-score (0.79) in predicting in-hospital death.

Conclusions: Ischemic strokes in COVID-19 patients have distinctive risk factor profile and etiology, increased clinical severity and higher in-hospital mortality rate compared to non-COVID-19 patients. A simple model based on clinical and routine laboratory parameters may be useful in identifying ischemic stroke patients with SARS-CoV-2 infection who are unlikely to survive the acute phase.
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http://dx.doi.org/10.1007/s00415-021-10620-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142879PMC
May 2021

Impact of SARS-CoV-2 on reperfusion therapies for acute ischemic stroke in Lombardy, Italy: the STROKOVID network.

J Neurol 2021 Mar 8. Epub 2021 Mar 8.

Department of Neurology and Stroke Unit, Carlo Poma Hospital, ASST Mantova, Mantua, Italy.

Whether and how SARS-CoV-2 outbreak affected in-hospital acute stroke care system is still matter of debate. In the setting of the STROKOVID network, a collaborative project between the ten centers designed as hubs for the treatment of acute stroke during SARS-CoV-2 outbreak in Lombardy, Italy, we retrospectively compared clinical features and process measures of patients with confirmed infection (COVID-19) and non-infected patients (non-COVID-19) who underwent reperfusion therapies for acute ischemic stroke. Between March 8 and April 30, 2020, 296 consecutive patients [median age, 74 years (interquartile range (IQR), 62-80.75); males, 154 (52.0%); 34 (11.5%) COVID-19] qualified for the analysis. Time from symptoms onset to treatment was longer in the COVID-19 group [230 (IQR 200.5-270) minutes vs. 190 (IQR 150-245) minutes; p = 0.007], especially in the first half of the study period. Patients with COVID-19 who underwent endovascular thrombectomy had more frequently absent collaterals or collaterals filling ≤ 50% of the occluded territory (50.0% vs. 16.6%; OR 5.05; 95% CI 1.82-13.80) and a lower rate of good/complete recanalization of the primary arterial occlusive lesion (55.6% vs. 81.0%; OR 0.29; 95% CI 0.10-0.80). Post-procedural intracranial hemorrhages were more frequent (35.3% vs. 19.5%; OR 2.24; 95% CI 1.04-4.83) and outcome was worse among COVID-19 patients (in-hospital death, 38.2% vs. 8.8%; OR 6.43; 95% CI 2.85-14.50). Our findings showed longer delays in the intra-hospital management of acute ischemic stroke in COVID-19 patients, especially in the early phase of the outbreak, that likely impacted patients outcome and should be the target of future interventions.
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http://dx.doi.org/10.1007/s00415-021-10497-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937781PMC
March 2021

Adoptive Transfer of JC Virus-Specific T Lymphocytes for the Treatment of Progressive Multifocal Leukoencephalopathy.

Ann Neurol 2021 04 10;89(4):769-779. Epub 2021 Feb 10.

Cell Factory, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.

Objective: Progressive multifocal leukoencephalopathy (PML) is still burdened by high mortality in a subset of patients, such as those affected by hematological malignancies. The aim of this study was to analyze the safety and carry out preliminary evaluation of the efficacy of polyomavirus JC (JCPyV)-specific T cell therapy in a cohort of hematological patients with PML.

Methods: Between 2014 and 2019, 9 patients with a diagnosis of "definite PML" according to the 2013 consensus who were showing progressive clinical deterioration received JCPyV-specific T cells. Cell lines were expanded from autologous or allogenic peripheral blood mononuclear cells by stimulation with JCPyV antigen-derived peptides.

Results: None of the patients experienced treatment-related adverse events. In the evaluable patients, an increase in the frequency of circulating JCPyV-specific lymphocytes was observed, with a decrease or clearance of JCPyV viral load in cerebrospinal fluid. In responsive patients, transient appearance of punctate areas of contrast enhancement within, or close to, PML lesions was observed, which was interpreted as a sign of immune control and which regressed spontaneously without the need for steroid treatment. Six of 9 patients achieved PML control, with 5 alive and in good clinical condition at their last follow-up.

Interpretation: Among other novel treatments, T cell therapy is emerging as a viable treatment option in patients with PML, particularly for those not amenable to restoration of specific immunity. Neurologists should be encouraged to refer PML patients to specialized centers to allow access to this treatment strategy. ANN NEUROL 2021;89:769-779.
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http://dx.doi.org/10.1002/ana.26020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248385PMC
April 2021

Brain microvascular occlusive disorder in COVID-19: a case report.

Neurol Sci 2020 Dec 9;41(12):3401-3404. Epub 2020 Oct 9.

Anesthesia and Intensive Care Unit, Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, Genoa, Italy.

We describe the case of a COVID-19 patient with severely impaired consciousness after sedation hold, showing magnetic resonance imaging (MRI) findings of (i) acute bilateral supratentorial ischemic lesions involving the fronto-parietal white matter and the corpus callosum and (ii) multiple diffuse susceptibility weighted imaging (SWI) hypointense foci, infra and supratentorial, predominantly bithalamic, suggestive of microhemorrhage or alternatively microthrombi. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA was detected in the cerebrospinal fluid. Our findings suggest the occurrence of vascular damage, predominantly involving microvessels. The underlying mechanisms, which include direct and indirect penetration of the virus to the central nervous system and systemic cardiorespiratory complications, are yet to be elucidated, and a direct correlation with SARS-CoV-2 infection remains uncertain.
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http://dx.doi.org/10.1007/s10072-020-04795-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546130PMC
December 2020

Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy.

J Neurol 2021 Jul 7;268(7):2331-2338. Epub 2020 Oct 7.

Department of Neurology, Papa Giovanni XXIII Hospital, Piazza OMS 1, 24127, Bergamo, Italy.

Objectives: Evidences from either small series or spontaneous reporting are accumulating that SARS-CoV-2 involves the Nervous Systems. The aim of this study is to provide an extensive overview on the major neurological complications in a large cohort of COVID-19 patients.

Methods: Retrospective, observational analysis on all COVID-19 patients admitted from February 23rd to April 30th, 2020 to ASST Papa Giovanni XXIII, Bergamo, Italy for whom a neurological consultation/neurophysiological assessment/neuroradiologic investigation was requested. Each identified neurologic complication was then classified into main neurologic categories.

Results: Of 1760 COVID-19 patients, 137 presented neurologic manifestations that manifested after COVID-19 symptoms in 98 pts and was the presenting symptom in 39. Neurological manifestations were classified as: (a) cerebrovascular disease [53 pts (38.7%)] including 37 ischemic and 11 haemorrhagic strokes, 4 transient ischemic attacks, 1 cerebral venous thrombosis; (b) peripheral nervous system diseases [31 (22.6%)] including 17 Guillain-Barrè syndromes; (c) altered mental status [49 (35.8%)] including one necrotizing encephalitis and 2 cases with RT-PCR detection of SARS-Cov-2 RNA in CSF; (d) miscellaneous disorders, among whom 2 patients with myelopathy associated with Ab anti-SARS-CoV-2 in CSF. Patients with peripheral nervous system involvement had more frequently severe ARDS compared to patients with cerebrovascular disease (87.1% vs 42%; difference = 45.1% 95% CI 42.0-48.2; χ= 14.306; p < 0.0002) and with altered mental status (87.1% vs 55.6%; difference = 31.5% 95% CI 27.5-37.5%; χ= 7.055; p < 0.01).

Conclusion: This study confirms that involvement of nervous system is common in SARS-CoV-2 infection and offers clinicians useful information for prevention and prompt identification in order to set the adequate therapeutic strategies.
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http://dx.doi.org/10.1007/s00415-020-10251-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539268PMC
July 2021

Vaccinations in patients with multiple sclerosis: A Delphi consensus statement.

Mult Scler 2021 03 17;27(3):347-359. Epub 2020 Sep 17.

Multiple Sclerosis Center, IRCCS San Raffaele Hospital, Milan, Italy/Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy.

Background: Patients with multiple sclerosis (MS) are at increased risk of infection. Vaccination can mitigate these risks but only if safe and effective in MS patients, including those taking disease-modifying drugs.

Methods: A modified Delphi consensus process (October 2017-June 2018) was used to develop clinically relevant recommendations for making decisions about vaccinations in patients with MS. A series of statements and recommendations regarding the efficacy, safety and timing of vaccine administration in patients with MS were generated in April 2018 by a panel of experts based on a review of the published literature performed in October 2017.

Results: Recommendations include the need for an 'infectious diseases card' of each patient's infectious and immunisation history at diagnosis in order to exclude and eventually treat latent infections. We suggest the implementation of the locally recommended vaccinations, if possible at MS diagnosis, otherwise with vaccination timing tailored to the planned/current MS treatment, and yearly administration of the seasonal influenza vaccine regardless of the treatment received.

Conclusion: Patients with MS should be vaccinated with careful consideration of risks and benefits. However, there is an urgent need for more research into vaccinations in patients with MS to guide evidence-based decision making.
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http://dx.doi.org/10.1177/1352458520952310DOI Listing
March 2021

The risk of infection in patients with multiple sclerosis treated with disease-modifying therapies: A Delphi consensus statement.

Mult Scler 2021 03 17;27(3):331-346. Epub 2020 Sep 17.

III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, University of Milan, Milan, Italy.

The risk of infection associated with immunomodulatory or immunosuppressive disease-modifying drugs (DMDs) in patients with multiple sclerosis (MS) has been increasingly addressed in recent scientific literature. A modified Delphi consensus process was conducted to develop clinically relevant, evidence-based recommendations to assist physicians with decision-making in relation to the risks of a wide range of infections associated with different DMDs in patients with MS. The current consensus statements, developed by a panel of experts (neurologists, infectious disease specialists, a gynaecologist and a neuroradiologist), address the risk of iatrogenic infections (opportunistic infections, including herpes and cryptococcal infections, candidiasis and listeria; progressive multifocal leukoencephalopathy; human papillomavirus and urinary tract infections; respiratory tract infections and tuberculosis; hepatitis and gastrointestinal infections) in patients with MS treated with different DMDs, as well as prevention strategies and surveillance strategies for the early identification of infections. In the discussion, more recent data emerged in the literature were taken into consideration. Recommended risk reduction and management strategies for infections include screening at diagnosis and before starting a new DMD, prophylaxis where appropriate, monitoring and early diagnosis.
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http://dx.doi.org/10.1177/1352458520952311DOI Listing
March 2021

Relapse of Symptomatic Cerebrospinal Fluid HIV Escape.

Curr HIV/AIDS Rep 2020 10;17(5):522-528

Department of Infectious Diseases, San Raffaele Scientific Institute and San Raffaele Vita-Salute University, Via Stamira d'Ancona 20, 20127, Milan, Italy.

Purpose Of Review: Symptomatic cerebrospinal fluid (CSF) HIV escape defines the presence of neurological disease in combination antiretroviral therapy (cART)-treated persons due to HIV replication in CSF despite systemic suppression or to higher viral replication in CSF than in plasma. The aim was to search for cases of recurrent symptomatic CSF escape and to define their characteristics.

Recent Findings: By review of the literature, we identified symptomatic CSF escape relapses in three patients who had shown clinical remission of a first escape episode following cART optimization. By examination of our cohort of 21 patients with symptomatic CSF escape, we identified five additional patients. In the latter, viral escape relapsed over a median follow-up of 108 months because of low adherence or upon treatment simplification of a previously optimized regimen. cART reoptimization based on resistance profile and potential drug neuropenetration and efficacy led to relapse resolution with no further episodes after a median follow-up of 50 months from relapse. The observation that CSF escape may relapse highlights the importance of long-term neuro-suppressive regimens after a first episode and supports the role of the brain as a reservoir for HIV.
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http://dx.doi.org/10.1007/s11904-020-00526-xDOI Listing
October 2020

GABA receptor autoimmunity after alemtuzumab treatment for multiple sclerosis.

Neurology 2020 09 10;95(9):399-401. Epub 2020 Jul 10.

From the Department of Neurology and Stroke Unit "A. Cardarelli Hospital" (G.T.M., G.S., V.M., M.N., P.C., C.F.); Multiple Sclerosis Centre "A. Cardarelli Hospital" (G.T.M., C.F.), Naples; Neurology Unit (S.M., S.F., S.B.), Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Italy; Institute of Neurology (R.H.), Medical University of Vienna, Austria; Multiple Sclerosis Center (R.C.), ASST - Spedali Civili of Brescia, Montichiari; Department of Neuroradiology (S.G.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; and Ragon Institute of Massachusetts General Hospital (M.S.), Massachusetts Institute of Technology and Harvard Medical School, Cambridge.

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http://dx.doi.org/10.1212/WNL.0000000000010310DOI Listing
September 2020

The IN-DEEP project "INtegrating and Deriving Evidence, Experiences, Preferences": a web information model on magnetic resonance imaging for people with multiple sclerosis.

J Neurol 2020 Aug 2;267(8):2421-2431. Epub 2020 May 2.

Scientific Direction, Carlo Besta Foundation and Neurological Institute, via Celoria 11, 20133, Milan, Italy.

Introduction: The IN-DEEP project aims to provide people with multiple sclerosis (PwMS) with evidence-based information on magnetic resonance imaging (MRI) in diagnosis and monitoring the disease through a website, and to collect their opinions on the clarity of the website's contents and its usefulness.

Methods And Analysis: A multidisciplinary advisory board committee was set up. We investigated the experience, attitude and information needs on MRI through three meetings with 24 PwMS, facilitated by an expert researcher and an observer. We developed the website on the basis of input from PwMS and systematic reviews and guidelines, assessed with AMSTAR and AGREE II. We sought feedback from nine PwMS who pilot-tested the beta-version of the website, during a meeting and through phone interviews and judged whether the contents were clear, understandable and useful, and the website was easily navigable. The website is in Italian.

Results: The website ( https://www.istituto-besta.it/in-deep-risonanza-magnetica2 ) provides two levels of information, different layouts and visualization of data covering MRI diagnostic accuracy, sensitivity and specificity, contents on how MRI can monitor PwMS over time to determine changes in the condition and evaluate treatment effects, practical information on how to prepare for the exam, educational tools and a glossary. The website was judged clear and useful by a sample of PwMS.

Conclusions: The website is a tool to address PwMS information needs on the role of MRI. It could be used by neurologists to facilitate communication with PwMS.
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http://dx.doi.org/10.1007/s00415-020-09864-7DOI Listing
August 2020

Symptomatic cerebrospinal fluid escape.

AIDS 2019 12;33 Suppl 2:S159-S169

Department of Infectious Diseases.

: Cerebrospinal fluid (CSF) viral escape is defined by detectable HIV-RNA in CSF despite undetectable or lower-than-CSF level in plasma of patients receiving combination antiretroviral therapy (cART). This condition may occasionally be associated with neurological problems, consisting of new and progressive cognitive decline and/or focal symptoms and signs, defining the 'symptomatic CSF escape'. Brain MRI usually shows diffuse white matter hyperintensities that recall the presentation of HIV encephalopathy in the precART era. However, patients develop symptomatic CSF escape with relatively high CD4 cell counts and suppressed or low systemic virus replication. In addition, the frequent CSF pleocytosis and the pathological demonstration of CD8 T-cell brain infiltrates in some cases of symptomatic escape indicate that inflammation is an important component in the pathogenesis of this condition. Low nadir CD4 cells are common, likely reflecting the establishment of a HIV reservoir in the central nervous system (CNS). CSF escape seems to result from reactivation of CNS infection when cART potency is lowered, because of low patient's adherence, drug resistance, or use of drug combinations that are poorly effective in the CNS and cART optimization is key to revert escape and neurological disease in the great majority of cases.
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http://dx.doi.org/10.1097/QAD.0000000000002266DOI Listing
December 2019

Four cases of natalizumab-related PML: a less severe course in extended interval dosing?

Neurol Sci 2019 Oct 7;40(10):2119-2124. Epub 2019 Jun 7.

Regional Multiple Sclerosis Center, ASST - Spedali Civili di Brescia, Via Ciotti 154, 25018, Montichiari, Brescia, Italy.

Background: Progressive multifocal leukoencephalopathy (PML) is a severe adverse event of natalizumab (NTZ). The administration of NTZ with extended interval dosing (EID) has been proposed as a strategy to potentially reduce the incidence of PML while maintaining its therapeutic efficacy.

Methods: In the current paper, we describe 4 cases of NTZ-PML in EID included in the Italian PML cohort.

Results: The patients developed PML after at least 38 NTZ infusions. Their John Cunningham virus (JCv) index was > 1.5, and patients had not previously used immunosuppressant. Two patients were asymptomatic at PML onset, while two had mild motor impairment of the right hand and anomia, respectively. All of them had undetectable viral load but one (37 JCv copies/ml). In all patients, MRI revealed unilobar lesions with deferred contrast enhancement suggestive of immune reconstitution. The clinical course ended with a favorable clinical outcome (ΔEDSS up to 1).

Conclusions: Although PML in EID seems to occur less frequently than in conventional dosing regimen, strict monitoring of high-risk patients contributed to the indolent course observed in the four described cases, characterized by a prolonged pre-symptomatic phase, paucisymptomatic onset, low JCv load, less severe functional impairment during immune reconstitution, and a mild disability burden.
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http://dx.doi.org/10.1007/s10072-019-03959-4DOI Listing
October 2019

Should frequent MRI monitoring be performed in natalizumab-treated MS patients? A contribution to a recent debate.

Mult Scler 2020 09 30;26(10):1227-1236. Epub 2019 May 30.

Regional Multiple Sclerosis Center, ASST Spedali Civili di Brescia, Via Ciotti, 154, Montichiari 25018, Brescia, Italy.

Background: Brain magnetic resonance imaging (MRI) is the most effective surveillance tool for the detection of asymptomatic progressive multifocal leukoencephalopathy (PML). However, the optimal frequency for routine MRI surveillance is under-investigated.

Objective: To understand whether, upon their first MRI appearance, PML lesions present a difference in volume when comparing patients who frequently underwent MRI surveillance (3/4 months) with those who were assessed at longer intervals (6/12 months) and to understand the impact of the volume of lesions on clinical outcome.

Methods: The data of patients included in the Italian PML cohort were retrospectively analysed. Patients who had all the pre-diagnostic MRI scans available ( = 37) were included. The volume of PML lesion was calculated by manually outlining the PML lesion.

Results: Compared with patients who underwent MRI examination at least every 4 months, patients who were assessed less frequently had a lesion of significantly higher volume (median: 2567 (883-3583) vs. 664 mm (392-963)  = 0.006) and suffered a higher rate of disability (median: 2.25 expanded disability status scale points (-2.5 to 8) vs. 0.5 (-1 to 2.5)  = 0.004).

Conclusion: The positive clinical outcome of patients undergoing frequent MRI surveillance and the small volume of the PML lesion upon first appearance justify a frequent surveillance using MRI in patients at high risk of PML.
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http://dx.doi.org/10.1177/1352458519854162DOI Listing
September 2020

Immune profiling of a patient with alemtuzumab-associated progressive multifocal leukoencephalopathy.

Mult Scler 2019 07 9;25(8):1196-1201. Epub 2019 Apr 9.

Centro di Ricerca Emato-oncologica AIL (CREA), Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy.

A 31-year-old woman affected by multiple sclerosis (MS) experienced generalized tonic-clonic seizures 2 months after the second alemtuzumab cycle. Positive JC virus (JCV)-DNA in cerebrospinal fluid (CSF) and lesion iconography at magnetic resonance imaging (MRI) were suggestive of progressive multifocal leukoencephalopathy (PML). After 1 month, during full-blown immune reconstitution inflammatory syndrome, JCV-DNA became negative and symptoms gradually improved. New T- and B-cell output and T- and B-cell diversity were low and lymphocytes poorly responded to stimulation. This is the first case of an alemtuzumab-treated patient with clinical symptoms and radiological features compatible with PML. The lack of large T- and B-cell diversity, necessary for JCV recognition, is likely to have concurred to PML insurgence.
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http://dx.doi.org/10.1177/1352458519832259DOI Listing
July 2019

Value of structured reporting in neuromuscular disorders.

Radiol Med 2019 Jul 9;124(7):628-635. Epub 2019 Mar 9.

Neuroradiology Department, IRCCS C. Mondino Foundation, Pavia, Italy.

Objective: To assess whether structured reports (SRs) of MRI in patients with inherited neuromuscular disorders (IND) provide more clinically relevant information than non-structured reports (NSRs) and whether neuroradiologists' expertise affects completeness of reports.

Material And Methods: Lower limbs' MRI reports of patients with IND produced by neuroradiologists with different level of expertise (> 15 years vs. < 15 years of experience in reading IND-MRI) before and after implementation of a SR template were included. Reports were assessed for the presence of 9 key features relevant for IND management. Reports and images were evaluated by neurologists who assessed: disease-specific muscular involvement pattern; presence of sufficient information to order the appropriate genetic/diagnostic tests; presence of sufficient information to make therapeutic decision/perform biopsy and necessity to review MRI images. Mann-Whitney and Fisher's exact tests were used to compare the number of key features for NSR and SR and neurologists' answers for reports produced by neuroradiologists with different experience.

Results: Thirty-one SRs and 101 NSRs were reviewed. A median of 8 and 6 key features was present in SR and NSR, respectively (p value < 0.0001). When reports were produced by less expert neuroradiologists, neurologists recognized muscular involvement pattern, had sufficient information for clinical decision-making/perform biopsy more often with SR than NSR (p values: < 0.0001), and needed to evaluate images less often with SR (p value: 0.0001). When reports produced by expert neuroradiologists were evaluated, no significant difference in neurologists' answers was observed.

Conclusion: SR of IND-MRI contained more often clinically relevant information considered important for disease management than NSR. Radiologist's expertise affects completeness of NSR reports.
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http://dx.doi.org/10.1007/s11547-019-01012-0DOI Listing
July 2019

Early diagnosis of progressive multifocal leucoencephalopathy: longitudinal lesion evolution.

J Neurol Neurosurg Psychiatry 2019 03 2;90(3):261-267. Epub 2018 Nov 2.

Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Objective: Early diagnosis of natalizumab-related progressive multifocal leucoencephalopathy (NTZ-PML) in multiple sclerosis has been deemed a major priority by the regulatory agencies but has yet to become a reality. The current paper aims to: (1) investigate whether patients with NTZ-PML pass through a prolonged presymptomatic phase with MRI abnormalities, (2) estimate the longitudinal PML lesion volume increase during the presymptomatic phase and (3) estimate the presymptomatic phase length and its impact on therapy duration as a risk stratification parameter.

Methods: All Italian patients who developed NTZ-PML between 2009 and 2018 were included. The data of patients with available prediagnostic MRI were analysed (n=41). Detailed clinical and neuroradiological information was available for each participant.

Results: (1) PML lesions were detectable in the presymptomatic phase in 32/41 (78%) patients; (ii) the lesion volume increased by 62.8 % for each month spent in the prediagnostic phase; (3) the prediagnostic phase length was 150.8±74.9 days; (4) PML MRI features were detectable before the 24th month of therapy in 31.7 % of patients in our cohort.

Conclusions: Considering the latency of PML clinical manifestation, the presymptomatic phase length supports the usefulness of MRI surveillance every 3-4  months. Early diagnosis could prompt a better outcome for patients due to the relationship between lesion volume and JC virus infection. The insight from this study might also have an impact on risk stratification algorithms, as therapy duration as a parameter of stratification appears to need reassessment.
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http://dx.doi.org/10.1136/jnnp-2018-319208DOI Listing
March 2019

PET Evaluation of Late Cerebral Effect in Advanced Radiation Therapy Techniques for Cranial Base Tumors.

Curr Radiopharm 2018 ;11(2):86-91

Vita-Salute San Raffaele University and Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy.

Background And Objective: Even though the benefits of radiation therapy are well established, it is important to recognize the broad spectrum of radiation-induced changes, particularly in the central nervous system. The possible damage to the brain parenchyma may have clinical consequences and in particular cognitive impairment might be one of the major complications of radiotherapy. To date, no studies have investigated the effects of focal radiation therapy on brain structure and function together with the assessment of their clinical outcomes at a long follow-up.

Methods: In this prospective study, we evaluated in six patients the possible brain late effects after radiation therapy, using a standardized neuropsychological battery, MRI and 18F-FDG PET using SPM and semi-quantitative methods, in patients affected by cranial base tumors who underwent gamma knife or tomotherapy.

Results: Neuropsychological examinations showed no cognitive impairment after the treatment. In all patients, both MRI assessment and 18F-FDG-PET did not reveal any local or distant anatomical and metabolic late effects.

Conclusion: The present study support the safety of advanced radiation therapy techniques. 18F-FDGPET, using SPM and semi-quantitative methods, might be a valuable tool to evaluate the cerebral radiotoxicity in patients treated for brain neoplasms.
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http://dx.doi.org/10.2174/1874471011666180525134301DOI Listing
October 2018

Triggered intravoxel incoherent motion MRI for the assessment of calf muscle perfusion during isometric intermittent exercise.

NMR Biomed 2018 06 10;31(6):e3922. Epub 2018 Apr 10.

Istituto di Bioimmagini e Fisiologia Molecolare, Consiglio Nazionale delle Ricerche, Segrate, Italy.

The main aim of this paper was to propose triggered intravoxel incoherent motion (IVIM) imaging sequences for the evaluation of perfusion changes in calf muscles before, during and after isometric intermittent exercise. Twelve healthy volunteers were involved in the study. The subjects were asked to perform intermittent isometric plantar flexions inside the MRI bore. MRI of the calf muscles was performed on a 3.0 T scanner and diffusion-weighted (DW) images were obtained using eight different b values (0 to 500 s/mm ). Acquisitions were performed at rest, during exercise and in the subsequent recovery phase. A motion-triggered echo-planar imaging DW sequence was implemented to avoid movement artifacts. Image quality was evaluated using the average edge strength (AES) as a quantitative metric to assess the motion artifact effect. IVIM parameters (diffusion D, perfusion fraction f and pseudo-diffusion D*) were estimated using a segmented fitting approach and evaluated in gastrocnemius and soleus muscles. No differences were observed in quality of IVIM images between resting state and triggered exercise, whereas the non-triggered images acquired during exercise had a significantly lower value of AES (reduction of more than 20%). The isometric intermittent plantar-flexion exercise induced an increase of all IVIM parameters (D by 10%; f by 90%; D* by 124%; fD* by 260%), in agreement with the increased muscle perfusion occurring during exercise. Finally, IVIM parameters reverted to the resting values within 3 min during the recovery phase. In conclusion, the IVIM approach, if properly adapted using motion-triggered sequences, seems to be a promising method to investigate muscle perfusion during isometric exercise.
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http://dx.doi.org/10.1002/nbm.3922DOI Listing
June 2018

Diagnostic and Prognostic Value of JC Virus DNA in Plasma in Progressive Multifocal Leukoencephalopathy.

Clin Infect Dis 2018 06;67(1):65-72

Department of Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy.

Background: Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by the polyomavirus JC (John Cunningham; JCV) that affects patients with impaired immune systems. While JCV-DNA detection in cerebrospinal fluid (CSF) is diagnostic of PML, the clinical significance of plasma JCV-DNA is uncertain.

Methods: We retrospectively analyzed plasma samples from PML patients that were drawn close to disease onset and from controls without PML. In PML patients, we compared plasma JCV-DNA detection and levels to clinical and laboratory parameters, and patient survival.

Results: JCV-DNA was detected in plasma of 49/103 (48%) patients with PML (20/24, 83%, human immunodeficiency virus [HIV] negative; 29/79, 37%, HIV-positive) and of 4/144 (3%) controls without PML (0/95 HIV-negative; 4/49, 8%, HIV-positive), yielding a diagnostic sensitivity and specificity of 48% and 97% (83% and 100% in HIV-negative; 37% and 92% in HIV-positive), respectively. Among 16 PML patients with undetectable CSF JCV-DNA, 4 (25%) had detectable plasma JCV-DNA. Plasma JCV-DNA levels were independently associated with CSF levels (P < .0001) and previous corticosteroid treatment (P = .012). Higher plasma JCV-DNA levels were associated with disease progression in HIV-negative patients (P = .005); in HIV-positive patients, there was an increased risk of progression only in those treated with combination antiretroviral therapy (cART; P < .0001).

Conclusions: Testing JCV-DNA in plasma might complement PML diagnosis, especially when CSF is unavailable or JCV-DNA not detectable in CSF. In addition, JCV-DNA plasma levels could be useful as a marker of disease progression in both HIV-negative and cART-treated, HIV-positive PML patients.
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http://dx.doi.org/10.1093/cid/ciy030DOI Listing
June 2018

PML in a person with multiple sclerosis: Is teriflunomide the felon?

Neurology 2018 01 6;90(2):83-85. Epub 2017 Dec 6.

From University of Cagliari (L.L., G.F., J.F., G.C., M.G.M., E.C.); IRCCS San Raffaele Hospital (S.G.), Milan; and Binaghi Hospital (M.A.B., F.C.), ATS Sardegna, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000004804DOI Listing
January 2018

Adult leukoencephalopathies with prominent infratentorial involvement can be caused by Erdheim-Chester disease.

J Neurol 2018 Feb 4;265(2):273-284. Epub 2017 Dec 4.

Unit of Neurodegerative and Neurometabolic Rare Diseases, IRCCS Foundation "Carlo Besta" Neurological Institute, Milan, Italy.

Background: Leukoencephalopathies with prominent involvement of cerebellum and brainstem, henceforward called prominent infratentorial leukoencephalopathies (PILs), encompass a variety of inherited and acquired white matter diseases. Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis likely under-diagnosed as cause of adult PIL.

Methods: We reviewed the clinical and laboratory information of ten consecutive sporadic adult patients with PIL of unknown origin, who were investigated for ECD.

Results: There were seven males and three females; mean age at clinical onset was 49.6 years (range 38-59); cerebellar ataxia with or without other neurological symptoms was the only or the main clinical manifestation; diabetes insipidus was present in three individuals. Eight patients had white matter focal supratentorial abnormalities, in addition to the infratentorial white matter changes. Six out of eight patients had spinal cord lesions. Thoraco-abdominal CT showed periaortic sheathing in two patients, whole-body FDG-PET revealed increased glucose uptake in the long bones of the legs in five patients, brain FDG-PET showed overt infratentorial hypermetabolism in one patient. In eight patients, ECD was confirmed by bone scintigraphy, pathological data, or both. Two ECD patients treated with vemurafenib showed a marked improvement of neurological symptoms and brain MRI abnormalities at 1 year follow-up.

Conclusions: Symptoms of PIL can be the only clinical manifestation of ECD. Adult patients with PIL of unknown origin should undergo investigations aimed at unveiling ECD, including bone scintigraphy and whole-body FDG-PET. The early diagnosis allows starting disease-modifying therapies of an otherwise life-threatening disease.
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http://dx.doi.org/10.1007/s00415-017-8692-8DOI Listing
February 2018

To do or not to do? plasma exchange and timing of steroid administration in progressive multifocal leukoencephalopathy.

Ann Neurol 2017 Nov 31;82(5):697-705. Epub 2017 Oct 31.

Multiple Sclerosis Centre, Spedali Civili, Montichiari, Brescia, Italy.

Objective: To retrospectively analyze the effect of plasma exchange (PLEX; yes = PLEX , no = PLEX ) and steroids administration timing (prophylactically [proST] or therapeutically [therST]) on the longitudinal clinical course of patients with natalizumab-related progressive multifocal leukoencephalopathy (PML) and full-blown immune reconstitution inflammatory syndrome (PML-IRIS).

Methods: Clinical and radiological data of 42 Italian patients with PML were analyzed. Patient's data are available until 12 months after PML diagnosis. PLEX and steroids treatment as time-dependent covariates were entered in: (1) a Cox model to investigate their impact on full-blown PML-IRIS latency; (2) an analysis of variance ANOVA to investigate their impact on IRIS duration; and (3) a linear mixed model to assess their impact on the longitudinal clinical course (measured by means of Expanded Disability Status Scale [EDSS]).

Results: Treatment with PLEX was not associated to PML-IRIS latency (hazard ratio [HR] = 1.05; p = 0.92), but once IRIS emerged, its duration was significantly longer in patients who underwent PLEX (101 vs 54 days in PLEX and PLEX patients; p = 0.028). Receiving proST versus therST was not associated to IRIS latency (HR = 0.67; p = 0.39) or duration (p = 0.95). Patients who underwent proST had a significantly higher EDSS increase during PML (0.09 EDSS points per month; p = 0.04) as compared to those who had therST.

Interpretation: This study highlights that: (1) caution on the use of PLEX should be considered as the current data do not support a beneficial effect of PLEX and (2) caution on the early use of steroids is suggested because their prophylactic use to prevent full-blown PML-IRIS seems to negatively impact on the longitudinal disability course. Ann Neurol 2017;82:697-705.
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http://dx.doi.org/10.1002/ana.25070DOI Listing
November 2017

Is maraviroc useful in multiple sclerosis patients with natalizumab-related progressive multifocal leukoencephalopathy?

J Neurol Sci 2017 Jul 12;378:233-237. Epub 2017 May 12.

Multiple Sclerosis Centre, Spedali Civili di Brescia, Via Ciotti 154, 25018 Montichiari, Brescia, Italy. Electronic address:

Background: Despite the recent advances in the understanding of natalizumab (NTZ) related progressive multifocal leukoencephalopathy (PML) and its associated immune reconstitution inflammatory syndrome (PML-IRIS), the therapeutic options are still under investigated. In this context, the beneficial use of maraviroc is still an anecdotal observation.

Objective: To evaluate the impact of maraviroc in modifying the course of PML preventing IRIS or blunting IRIS manifestations.

Methods: Three patients with NTZ PML included in the Italian dataset of PML were treated with maraviroc. Their longitudinal clinical and radiological course was described in detail.

Results: The three patients were characterized by a steady clinical worsening not controlled by maraviroc. All the three patients manifested PML-IRIS, which emerged, respectively, at 62, 64 and 90days post NTZ withdrawal. This is in accordance with the data of the Italian dataset. Clinical and radiological stabilization of PML-IRIS occurred only after corticosteroids administration.

Conclusion: In these three cases, maraviroc did not show any clear effect in modulating the clinical course of PML preventing IRIS. Moreover, once PML-IRIS emerged, the clinical stabilization was achieved only with the use of corticosteroids. Thus, the use of maraviroc should be regarded with extreme caution due the potential adverse events associated with its use.
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http://dx.doi.org/10.1016/j.jns.2017.05.018DOI Listing
July 2017

Muscle MRI in neutral lipid storage disease (NLSD).

J Neurol 2017 Jul 13;264(7):1334-1342. Epub 2017 May 13.

Department of Neurology, San Filippo Neri Hospital, Rome, Italy.

Neutral lipid storage disease (NLSD) is a rare inherited disorder of lipid metabolism resulting in lipid droplets accumulation in different tissues. Skeletal muscle could be affected in both two different form of disease: NLSD with myopathy (NLSD-M) and NLSD with ichthyosis (NLSD-I). We present the muscle imaging data of 12 patients from the Italian Network for NLSD: ten patients presenting NLSD-M and two patients with NLSD-I. In NLSD-M gluteus minimus, semimembranosus, soleus and gastrocnemius medialis in the lower limbs and infraspinatus in the upper limbs were the most affected muscles. Gracilis, sartorius, subscapularis, pectoralis, triceps brachii and sternocleidomastoid were spared. Muscle involvement was not homogenous and characteristic "patchy" replacement was observed in at least one muscle in all the patients. Half of the patients showed one or more STIR positive muscles. In both NLSD-I cases muscle involvement was not observed by T1-TSE sequences, but one of them showed positive STIR images in more than one muscle in the leg. Our data provides evidence that muscle imaging can identify characteristic alterations in NLSD-M, characterized by a specific pattern of muscle involvement with "patchy" areas of fatty replacement. Larger cohorts are needed to assess if a distinct pattern of muscle involvement exists also for NLSD-I.
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http://dx.doi.org/10.1007/s00415-017-8498-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502068PMC
July 2017

Late onset of neutral lipid storage disease due to novel PNPLA2 mutations causing total loss of lipase activity in a patient with myopathy and slight cardiac involvement.

Neuromuscul Disord 2017 May 17;27(5):481-486. Epub 2017 Jan 17.

Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Catholic University of the Sacred Heart, pz Buonarroti 30, Milan 20145, Italy; Department of Psychology, Catholic University of the Sacred Heart, Largo Gemelli, 1, Milan 20123, Italy. Electronic address:

Neutral lipid storage disease with myopathy (NLSDM) presents with skeletal muscle myopathy and severe dilated cardiomyopathy in nearly 40% of cases. NLSDM is caused by mutations in the PNPLA2 gene, which encodes the adipose triglyceride lipase (ATGL). Here we report clinical and genetic findings of a patient carrying two novel PNPLA2 mutations (c.696+4A>G and c.553_565delGTCCCCCTTCTCG). She presented at age 39 with right upper limb abduction weakness slowly progressing over the years with asymmetric involvement of proximal upper and lower limb muscles. Cardiological evaluation through ECG and heart echo scan was normal until the age 53, when mild left ventricular diastolic dysfunction was detected. Molecular analysis revealed that only one type of PNPLA2 transcript, with exon 5 skipping, was expressed in patient cells. Such aberrant mRNA causes the production of a shorter ATGL protein, lacking part of the catalytic domain. This is an intriguing case, displaying severe PNPLA2 mutations with clinical presentation characterized by slight cardiac impairment and full expression of severe asymmetric myopathy.
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http://dx.doi.org/10.1016/j.nmd.2017.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424884PMC
May 2017

Natalizumab-Related Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis: Findings from an Italian Independent Registry.

PLoS One 2016 20;11(12):e0168376. Epub 2016 Dec 20.

Multiple Sclerosis Centre, Spedali Civili di Brescia, Via Ciotti, Montichiari, Brescia, Italy.

Background: The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV).

Objective: To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions.

Methods: An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated.

Results: Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium-enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values<0.01).

Conclusion: Our findings support that early PML diagnosis, limited CNS involvement and initial signs of immune restoration are associated with a better outcome and higher survival rate, and confirm the utility of MRI as a surveillance tool for NTZ-treated patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168376PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172579PMC
June 2017

Deconstructing IgG4-related disease involvement of midline structures: Comparison to common mimickers.

Mod Rheumatol 2017 Jul 13;27(4):638-645. Epub 2016 Sep 13.

a Unit of Medicine and Clinical Immunology, Ospedale San Raffaele , Milan , Italy.

Objective: A series of destructive and tumefactive lesions of the midline structures have been recently added to the spectrum of IgG4-related disease (IgG4-RD). We examined the clinical, serological, endoscopic, radiological, and histological features that might be of utility in distinguishing IgG4-RD from other forms of inflammatory conditions with the potential to involve the sinonasal area and the oral cavity.

Methods: We studied 11 consecutive patients with erosive and/or tumefactive lesions of the midline structures referred to our tertiary care center. All patients underwent serum IgG4 measurement, flow cytometry for circulating plasmablast counts, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4 + plasma cells/HPF for calculation of the IgG4+/IgG + plasma cell ratio.

Results: Five patients with granulomatosis with polyangiitis (GPA), three with cocaine-induced midline destructive lesions (CIMDL), and three with IgG4-RD were studied. We found no clinical, endoscopic, or radiological findings specific for IgG4-RD. Increased serum IgG4 and plasmablasts levels were not specific for IgG4-RD. Rather, all 11 patients had elevated blood plasmablast concentrations, and several patients with GPA and CIMDL had elevated serum IgG4 levels. Storiform fibrosis and an IgG4+/IgG + plasma cell ratio >20% on histological examination, however, were observed only in patients with IgG4-RD.

Conclusions: Histological examination of bioptic samples from the sinonasal area and oral cavity represents the mainstay for the diagnosis of IgG4-RD involvement of the midline structures.
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http://dx.doi.org/10.1080/14397595.2016.1227026DOI Listing
July 2017