Andrea Bernardini

Bio: Andrea Bernardini is an academic researcher from University of Udine. The author has contributed to research in topics: Genome-wide association study & Obstructive sleep apnea. The author has an hindex of 4, co-authored 11 publications receiving 70 citations.

Epidemiology of paraneoplastic neurological syndromes: a population-based study

Abstract: The epidemiology of paraneoplastic neurological syndromes (PNS) remains to be defined. We present here the first population-based incidence study and report the clinical spectrum and antibody profile of PNS in a large area in Northeastern Italy. We performed a 9-year (2009–2017) population-based epidemiological study of PNS in the provinces of Udine, Pordenone and Gorizia, in the Friuli-Venezia Giulia region (983,190 people as of January 1, 2017). PNS diagnosis and subgroups were defined by the 2004 diagnostic criteria. Age- and sex-adjusted incidence rates were calculated. We identified 89 patients with a diagnosis of definite PNS. Median age was 68 years (range 26–90), 52% were female. The incidence of PNS was 0.89/100,000 person-years. PNS incidence rates increased over time from 0.62/100,000 person-years (2009–2011), 0.81/100,000 person-years (2012–2014) to 1.22/100,000 person-years (2015–2017). The prevalence of PNS was 4.37 per 100,000. Most common PNS were limbic encephalitis (31%), cerebellar degeneration (28%) and encephalomyelitis (20%). Among antibody (Ab)-positive cases, most frequent specificities included: Yo (30%), Hu (26%), and Ma2 (22%), while the most frequent associated tumors were lung (17%) and breast cancer (16%), followed by lymphoma (12%). PNS developed in 1 in every 334 cancers in our region. Statistically significant associations were observed between cancer type and Ab-specificity (P < 0.001), and between neurological syndrome and Ab-specificity (P < 0.001). This first population-based study found an incidence of PNS that approximates 1/100,000 person-years and a prevalence of 4/100,000. Moreover, the incidence of PNS is increasing over time, probably due to increased awareness and improved detection techniques.

Neurologic Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review.

Abstract: OBJECTIVE To define the clinical characteristics, management, and outcome of neurologic immune-related adverse events (n-irAEs) of immune checkpoint inhibitors (ICIs). METHODS Systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS A total of 694 articles were identified. Two hundred fifty-six articles, with 428 individual patients, met the inclusion criteria. Reports regarding neuromuscular disorders (319/428, 75%) were more frequent than those on CNS disorders (109/428, 25%). The most common n-irAEs reports were myositis (136/428, 32%), Guillain-Barre syndrome and other peripheral neuropathies (94/428, 22%), myasthenic syndromes (58/428, 14%), encephalitis (56/428, 13%), cranial neuropathies (31/428, 7%), meningitis (13/428, 3%), CNS demyelinating diseases (8/428, 2%), and myelitis (7/428, 2%). Other CNS disorders were detected in 25/428 (6%) patients. Compared with the whole sample, myasthenic syndromes were significantly more Ab positive (33/56, 59%; p < 0.001). Anti-programmed cell death protein 1/programmed cell death ligand 1 was more frequent in myasthenic syndromes (50/58, 86%; p = 0.005) and less common in meningitis (2/13, 15%; p < 0.001) and cranial neuropathies (13/31, 42%; p = 0.005). Anti-cytotoxic T-lymphocyte antigen-4 ICIs were more frequent in meningitis (8/13, 62%; p < 0.001) and less common in encephalitis (2/56, 4%; p = 0.009) and myositis (12/136, 9%; p = 0.01). Combination of different ICIs was more frequent in cranial neuropathies (12/31, 39%; p = 0.005). Melanoma was more frequent in patients with peripheral neuropathies (64/94, 68%; p = 0.003) and less common in encephalitis (19/56, 34%; p = 0.001). The highest mortality rate was reached in myasthenic syndromes (28%). CONCLUSION Considering the increasing use of ICI therapy in the forthcoming future, this information can be valuable in assisting neurologists and oncologists in early n-irAEs diagnosis and treatment.

Stroke-Like Presentation of Paraneoplastic Cerebellar Degeneration: a Single-Center Experience and Review of the Literature

Abstract: Paraneoplastic cerebellar degeneration (PCD) is usually thought to have a subacute progression over several weeks. We report herein incidence and clinical features of hyperacute onset PCD, a vertebrobasilar stroke mimic. We performed a retrospective analysis of all suspected PCD cases referred to the Udine University Hospital between 2009 and 2017. Our center provides the only neuroimmunology laboratory for three provinces of the Friuli-Venezia Giulia region, Italy (983,190 people as of January 1, 2017). Inclusion criteria were (1) abrupt onset of neurological symptoms; (2) initial consideration of a vascular etiology; (3) final diagnosis of “definite PCD.” We also carried out a systematic review of the literature in order to identify previous stroke-like PCD cases. Between 2009 and 2017, 24 patients received a final diagnosis of PCD. The age-standardized incidence rate of PCD was 0.22/100,000 person-years. Two cases (8.3%) had a stroke-like onset, with an incidence of 0.02/100,000 person-years. Additionally, 10 previously reported stroke-like PCD cases were identified. Among all cases (n = 12), 67% were female; median age was 51 years (range, 22–69). An associated cancer was discovered in all cases. Brain imaging was normal in most (75%) of the patients. Cerebrospinal fluid (CSF) analysis showed inflammatory alterations in 73% of the cases. Cancer treatment was more effective than immunotherapy in improving the neurological syndrome. Typical patients with hyperacute PCD are middle-aged women with normal brain imaging, inflammatory markers in CSF, and cancer. Surgery of the underlying cancer is probably the best treatment. PCD must be considered in the differential diagnosis of acute-onset ataxia and/or vertigo.

Timing use of novel anti-epileptic drugs: is earlier better?

Abstract: Introduction: Epilepsy is one of the most common neurological disorders. The goal of pharmacologic therapy remains complete freedom from seizures with minimal side effects. Despite advancements and the development of third-generation antiepileptic drugs (AEDs), a third of patients with epilepsy remain refractory to pharmacotherapy. Areas covered: The present manuscript is based on an extensive Internet and PubMed search from 2004 to 2019. It is focused on the third-generation AEDs (e.g. lacosamide, eslicarbazepine, perampanel, and brivaracetam). Expert opinion: Newer antiepileptic drugs are increasingly used. However, how early in the course of epilepsy third-generations AEDs should be used is still unclear. Third-generation AEDs may offer better tolerability, milder adverse effects, less drug interactions and improved pharmacokinetic characteristics compared to the conventional AEDs. For this reason, the third-generation AEDs may be used earlier and earlier in epileptic patients. Further head-to-head comparisons are needed to determine the exact position of third-generation AEDs relative to conventional AEDs.

Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes

Abstract: Objective The contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS. Methods A panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project. Results The panel proposed to substitute “classical syndromes” with the term “high-risk phenotypes” for cancer and introduce the concept of “intermediate-risk phenotypes.” The term “onconeural antibody” was replaced by “high risk” (>70% associated with cancer) and “intermediate risk” (30%–70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided. Conclusions The proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.

30 years of second-generation antiseizure medications: impact and future perspectives.

Abstract: Since 1989, 18 second-generation antiseizure medications have reached the market, resulting in a greatly increased range of treatment options for patients and prescribers. 30 years have passed and now is the time for an appraisal of the effect of these medications on clinical outcomes. Every antiseizure medication needs to be assessed individually, but overall second-generation drugs are less likely to cause pharmacokinetic interactions than their older counterparts. Some second-generation antiseizure medications have shown advantages in tolerability and safety, particularly in the treatment of older patients and women of childbearing potential. Disappointingly, however, none of these medications appear to be more efficacious than first-generation antiseizure medications, highlighting the need for novel strategies in epilepsy drug development. Although second-generation antiseizure medications have not substantially reduced the proportion of patients with pharmacoresistant epilepsy, their availability has enabled more opportunities to tailor treatment choice to the characteristics of the individual.

Central nervous system complications associated with immune checkpoint inhibitors

Abstract: Objective To describe the spectrum and outcome of central nervous system complications associated with immune checkpoint inhibitors (CNS-ICI). Methods Patients with CNS-ICI were identified and their characteristics compared with ICI-related peripheral neuropathy (PN-ICI). Results We identified 19 patients with CNS-ICI. The patients were receiving nivolumab (n=8), pembrolizumab (n=6), a combination of ipilimumab-nivolumab (n=3), ipilimumab-durvalumab (n=1), or atezolizumab (n=1). Underlying malignancies included non-small-cell lung cancer (n=8), melanoma (n=3), and other less common tumours (n=8). Neurological phenotypes were limbic encephalitis (n=8), meningoencephalitis (n=4) and cerebellitis (n=4). Two patients developed isolated confusion and one parkinsonism. Associated autoantibodies included onconeural (Ma2, n=7; Hu, n=1), astrocytic (glial fibrillar acidic protein, n=2) and neuronal surface (contactin-associated protein-like 2, n=1) specificities. ICIs were withheld and corticosteroid treatment was given in all cases. Five patients received intravenous immunoglobulin, two rituximab, one plasmapheresis and one infliximab. Overall, six patients died. Readministration of ICI was attempted in three patients, without further relapses. Non-small-cell lung cancer was significantly more frequent in patients with CNS-ICI (p Conclusion Three main clinical phenotypes characterise CNS complications of ICIs, each with distinct immunological background, disease course and response to treatment. Other clinical manifestations (including parkinsonism and steroid-responsive confusion) are also possible. Underlying cancers, antibody prevalence and outcome appear different from those of patients with PN-ICI.

Neurologic Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review.

Abstract: OBJECTIVE To define the clinical characteristics, management, and outcome of neurologic immune-related adverse events (n-irAEs) of immune checkpoint inhibitors (ICIs). METHODS Systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS A total of 694 articles were identified. Two hundred fifty-six articles, with 428 individual patients, met the inclusion criteria. Reports regarding neuromuscular disorders (319/428, 75%) were more frequent than those on CNS disorders (109/428, 25%). The most common n-irAEs reports were myositis (136/428, 32%), Guillain-Barre syndrome and other peripheral neuropathies (94/428, 22%), myasthenic syndromes (58/428, 14%), encephalitis (56/428, 13%), cranial neuropathies (31/428, 7%), meningitis (13/428, 3%), CNS demyelinating diseases (8/428, 2%), and myelitis (7/428, 2%). Other CNS disorders were detected in 25/428 (6%) patients. Compared with the whole sample, myasthenic syndromes were significantly more Ab positive (33/56, 59%; p < 0.001). Anti-programmed cell death protein 1/programmed cell death ligand 1 was more frequent in myasthenic syndromes (50/58, 86%; p = 0.005) and less common in meningitis (2/13, 15%; p < 0.001) and cranial neuropathies (13/31, 42%; p = 0.005). Anti-cytotoxic T-lymphocyte antigen-4 ICIs were more frequent in meningitis (8/13, 62%; p < 0.001) and less common in encephalitis (2/56, 4%; p = 0.009) and myositis (12/136, 9%; p = 0.01). Combination of different ICIs was more frequent in cranial neuropathies (12/31, 39%; p = 0.005). Melanoma was more frequent in patients with peripheral neuropathies (64/94, 68%; p = 0.003) and less common in encephalitis (19/56, 34%; p = 0.001). The highest mortality rate was reached in myasthenic syndromes (28%). CONCLUSION Considering the increasing use of ICI therapy in the forthcoming future, this information can be valuable in assisting neurologists and oncologists in early n-irAEs diagnosis and treatment.