Efficacy and Safety of Rescue Treatment with Plasma Exchange in Patients with Acute Inflammatory Neurological Disorders: A Single Center Experience.

BACKGROUND: Therapeutic plasma exchange (TPE) is a highly effective rescue treatment for patients with acute exacerbation of neuroimmunological disease that removes circulating autoantibodies and inflammatory components from the bloodstream. The aims of this study are to explore the safety and the effectiveness of TPE in patients with autoimmune neurological disorders. METHODS: We retrospectively evaluated the frequency of adverse events (AEs) and the effectiveness of TPE using the modified Ranking Scale (mRS) in patients with acute neurological flares who underwent TPE at the University Hospital of Palermo. RESULTS: Of 59 patients, the majority underwent TPE due to multiple sclerosis (MS) relapse. In 23.7% of cases, TPE was performed before obtaining a definite diagnosis due to the severity of the clinical presentation. After TPE, the mRS score was globally reduced (p < 0.0001), and this effect was marked in patients with MS, Guillain-Barré syndrome, and myasthenia gravis crisis but not in those with paraneoplastic syndromes. Circulating pathogenetic antibodies, younger age, and the early use of TPE were factors strongly associated with TPE effectiveness. The overall safety profile of TPE was satisfactory with an AE frequency of 15%. CONCLUSIONS: These results highlight the early use of TPE in patients with circulating pathogenetic antibodies as well as its favorable safety profile.

Tocilizumab treatment in MOGAD: a case report and literature review.

Myelin oligodendrocyte glycoprotein-immunoglobulin G associated disease (MOGAD) is an autoimmune demyelinating disorder of the central nervous system (CNS) which usually occurs with recurrent optic neuritis, transverse myelitis, acute disseminating encephalomyelitis, or brainstem encephalitis. To date, the anti-CD 20 drug rituximab (RTX) is employed in MOGAD although some authors reported the efficacy of Tocilizumab (TCZ) in refractory patients. We present the case of a woman affected by refractory MOGAD who was treated with TCZ after therapy with RTX had failed to prevent relapses. We also conducted a current literature review on TCZ use in MOGAD. A 57-year-old Caucasian woman affected by MOGAD with severe motor impairment and cognitive dysfunction was treated from 2020 to February 2022 with RTX. However, she experienced progressive clinical and cognitive worsening associated with white matter lesions mimicking leukodystrophy. In February 2022, the patient started therapy with TCZ administered with improvement of cognitive performance, walking ability, and brainstem functions. During TCZ, our patient reached the condition of NEDA-3 (no relapse, no increase in disability, no MRI activity on neuroimaging follow-up performed in September 2023). Moreover, the patient experienced paucisymptomatic SARS-CoV-2 infection that did not modify TCZ schedule. To date, there are few evidence on the efficacy and safety of TCZ in MOGAD. However, all the reviewed cases showed that TCZ represents an effective therapy in drug-resistant MOGAD. Our case highlights the efficacy of TCZ in drug resistant MOGAD and strengthens previous reports of TCZ safety and efficacy in MOGAD.

A Rapid and Simple Multiparameter Assay to Quantify Spike-Specific CD4 and CD8 T Cells after SARS-CoV-2 Vaccination: A Preliminary Report.

mRNA and Adenovirus vaccines for COVID-19 are used to induce humoral and cell-mediated immunity, with the aim to generate both SARS-CoV-2 B and T memory cells. In present study, we described a simple assay to detect and quantify Spike-specific CD4+ and CD8+ T cell responses induced by vaccination in healthy donors and in subjects with B cell compart impairment, in which antibody response is absent due to primary immunodeficiencies or CD20 depleting therapy. We detect and quantified memory T cell immune responses against SARS-CoV-2 evocated by vaccination in both groups, irrespective to the humoral response. Furthermore, we identified TNF-α as the main cytokine produced by T memory cells, after antigen-specific stimulation in vitro, that could be considered, other than IFN-γ, an additional biomarker of induction of T memory cells upon vaccination. Further studies on the vaccine-induced T cell responses could be crucial, not only in healthy people but also in immunocompromised subjects, where antigen specific T cells responses play a protective role against SARS-CoV-2.

The Role of Nutritional Lifestyle and Physical Activity in Multiple Sclerosis Pathogenesis and Management: A Narrative Review.

Studies on the role of nutritional factors and physical activity (PA) in the pathogenesis of multiple sclerosis (MS) go back a long time. Despite the intrinsic difficulty of studying their positive or negative role in MS, the interest of researchers on these topics increased during the last few decades, since the role of diet has been investigated with the perspective of the association with disease-modifying drugs (DMD). The association of DMD, diets, and PA might have an additive effect in modifying disease severity. Among the various diets investigated (low-carbohydrate, gluten-free, Mediterranean, low-fat, fasting-mimicking, and Western diets) only low-carbohydrate, Mediterranean, and fast-mimicking diets have shown both in animal models and in humans a positive effect on MS course and in patient-reported outcomes (PROs). However, the Mediterranean diet is easier to be maintained compared to fast-mimicking and low-carbohydrate diets, which may lead to detrimental side effects requiring careful clinical monitoring. Conversely, the Western diet, which is characterized by a high intake of highly saturated fats and carbohydrates, may lead to the activation of pro-inflammatory immune pathways and is therefore not recommended. PA showed a positive effect both in animal models as well as on disease course and PROs in humans. Training with combined exercises is considered the more effective approach.

Four cases of progressive multifocal leukoencephalopathy in iatrogenic immunocompromised patients.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by John Cunningham Virus (JCV). We report four PML cases in immunocompromised patients, respectively treated with (1) Natalizumab, (2) Rituximab, (3) autologous stem-cell transplantation, and (4) Tacrolimus. All patients underwent neurological examination, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), JCV-DNA research on biological samples, and lymphocytes subpopulation study. All cases presented with motor, behavioural, and cognitive disorders. Visual, sensitive, and cerebellar deficits developed in three cases. MRI revealed widespread progressive demyelinating areas with active borders; three patients presented contrast enhancement. One patient developed inflammatory reconstitution syndrome (IRIS). At MRS, all cases presented decreased N-acetyl-aspartate (NAA) and three cases showed increased choline (Cho). In one patient, plasma and urine tested positive for JCV-DNA, while cerebrospinal fluid (CSF) analysis confirmed JCV in two patients. The fourth patient had a low JCV-DNA blood titer and brain biopsy showed subacute necrosis. Two patients had abnormal lymphocyte subpopulations. Three patients underwent therapy with Mirtazapine, one of whom received Mefloquine in add-on. No clinical response was registered. Clinical onset, MRI and MRS were highly suggestive of PML in all patients, despite three cases presented contrast enhancement. In three cases JCV-DNA detection in biological samples confirmed the diagnosis. The fourth patient fulfilled diagnosis of "presumptive PML". Our data confirm the importance to complete the diagnostic workup despite the presence of findings not completely consistent with classical PML. We hypothesize that atypical characteristics could due to the clinical conditions leading to PML.

Characteristics and treatment of Multiple Sclerosis-related trigeminal neuralgia: An Italian multi-centre study.

BACKGROUND: The prevalence of trigeminal neuralgia (TN) in Multiple Sclerosis (MS) patients is higher than in the general population and its management can be particularly challenging. Our aim is to describe the characteristics, treatment and prognostic factors of MS-related TN in a retrospective multicentre study. METHODS: Neurologists members of the RIREMS group (Rising Researchers in MS) enrolled MS patients with a TN diagnosis and filled out a spreadsheet comprising their clinical data. RESULTS: Population consisted of 298 patients. First-choice preventive treatments were carbamazepine and oxcarbazepine. A surgical procedure was performed in 81 (30%) patients, most commonly gamma knife stereotactic radiosurgery (37%), followed by microvascular decompression (22%) and radiofrequency thermocoagulation (21%); one third of patients underwent at least two procedures. Surgery was associated with higher disability, male sex and longer interval between MS and TN onset. Patients (77%) who stayed on at least one preventive medication at most recent follow-up, after a mean period of 8 years, had a higher disability compared to the untreated group. Furthermore, patients with higher disability at TN onset were less likely to discontinue their first preventive medication due to pain remission, had bilateral TN more frequently and underwent surgical interventions earlier. CONCLUSION: MS patients with a higher disability at TN onset and with a longer interval between MS and TN onset had differing clinical features and outcomes: pain was more frequently bilateral, surgery was more frequent and anticipated, and preventive medication discontinuation due to pain remission was less common.

Association between multiple sclerosis, cancer risk, and immunosuppressant treatment: a cohort study.

BACKGROUND: The association between multiple sclerosis (MS) and cancer has long been investigated with conflicting results. Several reports suggest an increased cancer risk among MS patients treated with immunosuppressant (IS) drugs. METHODS: We performed a cohort study including MS patients recruited at the Neurological Department of the University of Palermo. Mean follow-up period was ten years for the whole cohort. We calculated cancer incidence among patients treated with IS. Incidence rates were compared in the cohort by calculating the relative risk according to length and dose of exposure to IS. Cancer incidence among MS patients was compared to cancer incidence in the general population of Sicily in similar age groups. RESULTS: On an overall cohort of 531 MS patients (346 women and 185 men) exposed to IS, we estimated a crude incidence rate for cancer of 2.26% (2.02% in women, 2.7% in men). Cancer risk was higher compared to rates observed among an equal number of patients not exposed to IS, and to the risk in the general population in Sicily at similar age groups (adjusted HR: 11.05; CI 1.67-73.3; p = 0.013). CONCLUSION: The present study showed a higher cancer risk in MS patients associated only to previous IS exposure. Studies on long-term outcomes are essential to evaluate the possibility that treatment options that need to be considered for a long time-period may modify risk for life threatening diseases.

Natalizumab Discontinuation and Treatment Strategies in Patients with Multiple Sclerosis (MS): A Retrospective Study from Two Italian MS Centers.

INTRODUCTION: Natalizumab (NTZ) discontinuation can be followed by multiple sclerosis (MS) disease reactivation. Currently no disease-modifying drug (DMD) has been shown to be able to abolish disease reactivation. The aims of the current study were: (1) to determine the frequency of MS reactivation after NTZ discontinuation; (2) to evaluate predictors of reactivation risk, and (3) to compare the effect of different treatments in reducing this risk. METHODS: Data from 132 patients with MS followed-up for 2 years before NTZ treatment and 1 year after interruption were collected from two Italian MS centers and retrospectively evaluated. RESULTS: Overall, 72 of 132 patients (54.5%) had relapses after NTZ discontinuation and 60 of 125 patients (48%), who had magnetic resonance imaging, had radiological reactivation. Rebound was observed in 28 of 132 patients (21.2%). A higher number of relapses in the 2 years before NTZ treatment, a longer washout period, and a lower number NTZ infusions correlated with reactivation and rebound. Untreated patients (n = 37) had higher clinical and radiological activity and rebound in comparison to patients receiving DMDs. Moreover, a lower risk of relapses was found in patients treated with second-line therapies (NTZ and fingolimod) than in those treated with first-line therapies (interferon beta, glatiramer acetate, teriflunomide, azathioprine). Interestingly, no disease reactivation in off-label treatment (rituximab, autologous hematopoietic stem cell transplantation) was observed. CONCLUSION: NTZ discontinuation is a risk for MS reactivation and rebound. An alternative treatment should be promptly resumed mainly in patients with a previous very active disease course and with a shorter NTZ therapy. Second-line therapies demonstrate superiority in preventing relapses after NTZ discontinuation.

Tumor diagnosis preceding Alzheimer's disease onset: is there a link between cancer and Alzheimer's disease?

Studies reporting an inverse association between Alzheimer's disease (AD) and cancer are scant. Available data are mostly based on ancillary findings of mortality data or obtained from studies evaluating frequency of neoplasms in AD patients independently if they occurred before or after AD. Moreover, some studies estimated frequencies of neoplasms in demented individuals, who were not necessarily AD patients. We estimated frequency of tumors preceding the onset of AD in AD patients and compared it to that of age- and gender-matched AD-free individuals. Occurrence of tumors preceding AD onset was assessed through a semi-structured questionnaire. Tumors were categorized as benign, malignant, or of uncertain classification and as endocrine-related or not. Odds ratios (OR), used as measure of the association between the two diseases, were adjusted for tumor categories and known risk factors for AD and tumors. We included 126 AD patients and 252 matched controls. Tumor frequency before AD onset was 18.2% among cases and 24.2% among controls. There was a suggestive trend of an overall inverse association between the two diseases (adjusted OR 0.6; 95% CI 0.4-1.1; p = 0.11). Risk for neoplasms was significantly reduced only for women (adjusted OR, 0.5; 95% CI 0.3-0.9; p = 0.03) and for endocrine related tumors (adjusted OR, 0.5; 95% CI 0.2-1; p = 0.04). Our study confirms the inverse association reported in previous epidemiological studies. Though our findings might be explained by processes playing an opposite role in tumors development and neurodegeneration, they are also suggestive for a possible role of estrogen.

MRI abnormalities following repeated and incoming seizures.

Neuroimaging, an important diagnostic tool frequently used in the evaluation of patients with epilepsy, has mainly the aim to identify structural abnormalities needing a treatment and to contribute to the definition of the aetiology. Brain magnetic resonance imaging (MRI) in epilepsy is more sensitive than computerized tomography (CT) scan for detecting abnormalities. Status epilepticus (SE) and repeated incoming seizures may determine extensive and transient or long lasting pronounced MRI changes. We describe a case of a 41-year-old woman with a history of brain neoplasm, whose contrast-enhanced MRI images following repeated and incoming seizures were characterized either by reversible and irreversible abnormalities.

Leprosy: report of a case with severe peripheral neuropathy.

Leprosy (Hansen's disease) is a chronic granulomatous infectious disease, caused by Mycobacterium leprae, with cutaneous and neurological manifestations. Leprosy is very rare in Europe but some cases are reported, especially among people coming from endemic areas. Here, we report a case of Hansen's disease and emphasize the importance of a prompt diagnosis and treatment also in non-endemic areas.

Progressive necrotic encephalopathy following tacrolimus therapy for liver transplantation.

Previously described neurologic damage induced by immunosuppressive treatments includes transient or reversible central nervous system involvement. We describe a 57-year-old man who underwent liver transplantation and was started on immunosuppressive therapy with tacrolimus (FK506). Six months later, he started complaining of a progressive motor and sensory impairment of the left side, together with cognitive impairment. Brain MRI showed an enlarging lesion of the white matter with peripheral contrast enhancement. PET study indicated severe hypometabolism in the right hemisphere and spectroscopic MRI showed a peak of choline and relative reduction of other metabolites. Findings of CSF examinations and cultures, serology, and molecular techniques were normal. Tacrolimus treatment was stopped. A cerebral biopsy of the lesion showed a sub acute necrotizing process. In the following months, cognitive status of the patient tended to improve although he remained hemiplegic, while serial MRI confirmed the tendency to the recovery of the lesion that was still present 1 year after. The present observation describes a progressive encephalopathy associated with immune suppression with an unusual feature and permanent brain damage.

Diabetes preceding Parkinson's disease onset. A case-control study.

OBJECTIVE: To assess the association between diabetes preceding Parkinson's disease (PD) and PD. METHODS: PD individuals were matched to PD free individuals randomly selected from people in the same municipality as the cases. Occurrence of diabetes preceding PD onset among cases and controls was assessed through a structured questionnaire. Information regarding current and past medical treatment and other variables was also collected. We used univariate and multivariate logistic models to calculate crude and adjusted odds ratios (OR). Covariates are adjusted for included education, smoking habit, alcohol and coffee consumption. RESULTS: 318 PD individuals (165 women, 153 men) and 318 matched controls were included in the study. PD patients had a mean age at interview of 66.7 years. Mean age at PD onset was 60.8 years and mean PD duration 5.9 years. We found an inverse association between PD and diabetes preceding PD onset in all groups stratified by gender, age at PD onset, body mass index (BMI), smoking habit, alcohol and coffee consumption. Multivariate analysis yielded the same findings after controlling for the variables (adjusted OR 0.4; 95% CI, 0.2-0.8). CONCLUSIONS: Our findings provide additional support for a potential link between diabetes and PD.

Parkinson's disease and cancer: insights for pathogenesis from epidemiology .

Epidemiological evidence suggests a reduced incidence of many common types of cancers in individuals with Parkinson's disease (PD). Parkinson's disease and cancer are two diseases that result from an excessive signaling by one of two forces driving cells to opposite directions. PD results from the excessive death of dopaminergic neurons in the substantia nigra pars compacta (SNc) in the brain, while uncontrolled growth is the key property of cancer. Parkinson's disease is a complex disorder, probably due in most of the cases to the interaction of environment and genes. Many genes responsible for familial forms of PD are supposed to have a supportive role in regulating or maintaining the cell cycle, a fact that allows us to assume their interaction in tumorigenesis. Understanding the nature of these processes may help researchers find new and more efficacious therapeutic approaches for both diseases.

How many parkinsonian patients are suitable candidates for deep brain stimulation of subthalamic nucleus? Results of a questionnaire.

We used a CAPSIT-based questionnaire to estimate the percentage of parkinsonian patients suitable for subthalamic nucleus (STN) deep brain stimulation (DBS) in a movement disorders clinic. We found that out of 641 consecutive PD patients only 1.6% fulfilled strict STN-DBS criteria. When we applied more flexible criteria, the percentage of eligibility increased to 4.5%. Most patients (60%) were ineligible because they did not satisfy multiple questionnaire items. Items related to disease severity were responsible for the largest number of exclusions. This knowledge will help make decisions on resource allocation in centres wishing to start DBS surgery.

Search for genetic factors associated with susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is a cell-mediated autoimmune disease characterized by type-1 cytokine production. Environmental and individual genetic background might influence this response particularly in cytokine gene polymorphisms. We evaluated whether polymorphisms of interleukin (IL)-10, IL-12, and tumor necrosis factor (TNF)-alpha genes, which might play a role in MS pathogenesis, are associated with MS susceptibility. Genotype frequencies for all the analyzed polymorphisms were not differently distributed between cases and controls. It is reasonable to suppose that the cytokine single-nucleotide polymorphisms (SNPs) studied must be considered against a larger genetic background involving other functional SNPs of Th1 regulator elements such as IL-21 and IL-23.

Implications for estrogens in Parkinson's disease: an epidemiological approach.

Evidence from experimental and epidemiological studies suggests a role of sex hormones in the pathogenic process leading to neurodegenerative diseases, (i.e., Alzheimer's and Parkinson's disease). The effects of sexual steroid hormones are complex and vary with the events of women's fertile life. Estrogens are supposed to influence dopamine synthesis, metabolism, and transport; however, there is no consensus regarding the direction, locus, and mechanism of the effect of estrogens on the dopaminergic system. A neuroprotective effect of estrogens has been demonstrated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-animal models of Parkinson's disease (PD). Epidemiological studies indicate gender differences regarding the onset and the prognosis of PD. Most of the analytical studies explored the relationship between PD and exogenous estrogens. Only three studies investigated the role of endogenous estrogens in the risk of developing PD. These studies reported an increased risk of PD in conditions causing an early reduction in endogenous estrogens (early menopause, reduced fertile life length). Longer cumulative length of pregnancies has also been associated with an increased PD risk. A lack of consensus still exists on the effect of the type of menopause (surgical vs. natural) on PD risk. Finally, the effect of postmenopausal estrogen replacement therapy is still debated. Inconsistencies across studies are in part explained by the complexity of the mechanisms of action of sexual hormones and by the paucity of analytical studies.

DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral sclerosis complex.

DJ-1 gene mutations have been found to cause early-onset Parkinson's disease. We report a family from southern Italy with three brothers affected by early-onset parkinsonism, dementia, and amyotrophic lateral sclerosis. Molecular analysis of the DJ-1 gene in two living patients showed a novel homozygous mutation in exon 7 (E163K) and a new homozygous mutation (g.168_185dup) in the promoter region of the gene. Both mutations cosegregated with the disease and were detected in a heterozygous state in the patients' mother and their healthy siblings. Our findings expand the spectrum of clinical presentations associated with mutations in DJ-1 gene.

Prevalence and risk factors of post-polio syndrome in a cohort of polio survivors.

OBJECTIVE: To investigate frequency and associated factors of post polio syndrome (PPS) in an Italian cohort of people with prior poliomyelitis. METHODS: We screened subjects admitted for poliomyelitis at the paediatric hospital of the University of Palermo during the time frame 1945-1960. Patients who developed PPS were identified through a structured questionnaire and a neurologic examination. PPS diagnosis was made according to specified diagnostic criteria. Frequency of PPS was calculated in the selected cohort of polio survivors. The association with the investigated risk factors (sex, age at onset of polio, extension and severity of polio, education, associated diseases, cigarette smoking, trauma, polio vaccination) was analysed by the calculation of the odds ratio. RESULTS: Forty-eight participants met the adopted diagnostic criteria for PPS, giving a prevalence of 31.0%. The prevalence rate was significantly higher in women than in men (p=0.02). Logistic regression analyses revealed a significant inverse association with onset of poliomyelitis at over 12 months of age (OR 0.33; CI 0.14-0.79) a higher degree of education (OR 0.20; CI 0.07-0.79), and a significant association with the presence of other diseases (OR 9.86; CI 3.69-26.34). CONCLUSIONS: In our survey one-third of patients with prior poliomyelitis had PPS. Higher age at onset of poliomyelitis is inversely associated with PPS. The association with other diseases may indicate that a chronic physical stress, particularly in already weak motor units, can contribute to the development of signs and symptoms of PPS. Our results also suggest the impact of socio-economic conditions on the risk of PPS.

Tumor diagnosis preceding Parkinson's disease: a case-control study.

Lower cancer risk in Parkinson's disease (PD) patients compared to the general population has been reported. However, most of the studies were based on death certificates. We designed a case-control study to estimate the association of tumor preceding PD onset and PD. PD patients were matched by age and gender to PD-free individuals, randomly selected from the municipalities of residence of cases. Occurrence of tumors preceding PD onset was assessed through a structured questionnaire. Neoplasms were categorized as benign, malignant, or of uncertain classification, and endocrine-related or not. Odds ratios (OR) were calculated using conditional logistic regression and adjusted for tumor categories and risk factors. We included 222 PD patients. Frequency of cancer was 6.8% for cases, 12.6% for controls. PD patients had a decreased risk for neoplasms (adjusted OR, 0.4; 95% confidence interval [CI], 0.2-0.7). Risk was reduced only for women (adjusted OR, 0.3; 95% CI, 0.1-0.7). PD patients had a decreased risk both for malignant (adjusted OR, 0.6; 95% CI, 0.1-2.5) and nonmalignant neoplasms (adjusted OR, 0.3; 95% CI, 0.1-0.7). Still, risk was decreased for endocrine-related tumors (adjusted OR, 0.3; 95% CI, 0.1-0.9) and non-endocrine-related tumors (adjusted OR, 0.4; 95% CI, 0.1-0.9). Our study confirms the inverse association between PD and neoplasms reported in previous epidemiologic studies.