ABSTRACTBackgroundAdvanced cell therapeutics are emerging as potentially effective treatments for chronic neurological diseases, including secondary progressive multiple sclerosis (SPMS). Here we report the results of a phase I trial in which good manufacturing practice-grade foetal allogeneic human neural stem cells (hNSCs) were implanted via intracerebroventricular (ICV) injection in 15 individuals with active and non-active SPMS.MethodsThis is a phase I, open-label, multicentre, dose-escalation, international study. The primary objective was to assess the feasibility, safety, and tolerability of ICV injections of allogeneic hNSCs in patients affected by SPMS over a study follow up of 12 months. We also evaluated the number and type of adverse events (AEs) leading to a maximum tolerated dose, the general health status, and mortality. The secondary objectives were the therapeutic benefit of allogeneic hNSCs using assessment scales, magnetic resonance imaging (MRI), and laboratory and neurophysiologic parameters.FindingsFifteen unrelated SPMS patients were enrolled and treated between 2018 and 2020. The participants had a median age of 49.8 years. Their mean extended disability status scale (EDSS) at enrolment was 7.6, the mean disease duration was 22 years, and mean time from diagnosis to progression was 10.1 years. Neither treatment-related deaths nor serious AEs were reported during the study (1 year follow up after treatment). All the other AEs were classified as non-serious and were associated to non-study concomitant therapy or other medical conditions not connected to the experimental treatment. During the study, none of the participants worsened in the progression of their SPMS as shown by the evaluation scales implemented to assess their progress. Laboratory and neurophysiologic parameters showed no clinically significant variations. MRI follow-up showed non-clinically significant type 1, 2, and 3 changes.InterpretationThe intracerebroventricular injection of foetal allogeneic hNSCs in people with SPMS is feasible, tolerated and safe. Study participants displayed a substantial clinical stability during the 12-month follow-up. The absence of relevant adverse reactions (Ars) arising from the transplantation of hNSCs indicates a short-term neutral balance between benefits and risks and suggests a concrete, though perspective therapeutic possibility for SPMS patients. Further studies are needed to confirm and extend the findings herein and evaluate the actual therapeutic potential of advanced cell therapeutics for a condition where the lack of effective disease modifying therapies is a major unmet clinical need.

OBJECTIVE:To assess whether arterial hypertension (AH) is an independent risk factor for chronic symmetric polyneuropathy (CSP) in the elderly.BACKGROUND:A strong relationship has been detected between AH and distal symmetric polyneuropathy in insulin-dependent and non-insulin-dependent diabetes. However, the correlation between AH and polyneuropathy caused by other clinical conditions has not yet been studied.METHODS:Four thousand one hundred and ninety-one subjects aged > or = 55 years seen in office consultations by 25 general practitioners (GPs) from two separate areas in Italy were interviewed, using a pretested semistructured questionnaire covering conditions commonly associated with neuropathy and symptoms of peripheral nerve disease. A neurologist later visited individuals with > or = 2 symptoms of polyneuropathy and a diagnosis of CSP was made in the presence of bilateral, fairly symmetric impairment of at least two among strength, sensation and tendon reflexes. AH was ascertained when known to the GP and/or if the patient was being treated with antihypertensive drugs.RESULTS:One hundred and fifty one subjects had CSP (3.6%). Diabetes was the commonest associated condition (18%). AH was present in 47 patients with CSP (31%). The odds ratio (OR) of AH in patients with CSP was 4.5 [95% confidence interval (CI) 3.1-6.6]. The OR of AH was 3.2 (95% CI 1.5-6.9) in patients with diabetes, and 5.7 (95% CI 3.6-9.3) in those without diabetes. The OR of AH was 4.8 (95% CI 4.4-5.2) after adjusting for the commonest risk factors for CSP.CONCLUSION:AH may be an independent risk factor for CSP in the elderly.

An algorithm has been structured as a guided reading of the international league against epilepsy (ILAE) syndromic classification to be used in clinical practice by less experienced physicians in newly diagnosed patients. The algorithm followed the original structure of the classification, which identifies major syndromic groups, subgroups, and specific syndromes. Validation required two raters, a resident and a board-certified neurologist, to apply the algorithm with different techniques (direct or recorded interview, medical record consultation) to 19 children and 18 adults with epilepsy with information available at the time of diagnosis. The two raters’ diagnoses were compared with those of the caring physicians, and cases where disagreement arose were discussed in conference to achieve consensus. The κ statistic was used as a measure of inter-rater agreement. Caring physicians and both raters agreed in 51% of cases. Substantial agreement (κ=0.75) was obtained between the resident and the neurologist on major diagnostic groups and subgroups, mostly in adults. Agreement with the caring physician was slightly more satisfactory for the resident (κ=0.67) than for the neurologist (κ=0.60). Agreement was better with direct or indirect interview than with record consultation, and improved further after discussion. Agreement was obtained after discussion in 32% of cases, in some of which the caring physician agreed on the resident’s diagnosis. Agreement was less satisfactory for specific syndromes. On this basis, an algorithm of the ILAE classification is a fairly reliable instrument only for making a broad syndromic classification of epilepsy at the time of diagnosis. The limits of the algorithm tend mostly to reflect the intrinsic limitations of the classification itself.

Summary: Purpose: The social implications of epilepsy are ill‐defined, and there are no comparative findings from different countries. A multicenter cohort study has recently been completed on the risk of morbidity and accidents. The main social issues in the study population (patients with epilepsy and control subjects) are investigated and correlated to the clinical features of the disease.

"Central core disease" (CCD) is a rare disease of infancy and childhood and represents the prototypic member of a group of muscular disorders known as "congenital, benign (non progressive) myopathies". It is very uncommon to diagnose cases affected by CCD in youth and adulthood. The disease is mainly familial with a dominant autosomal pattern of inheritance, but sporadic cases are known to occur. The candidate gene has been localized on chromosome 19q13.1, and is allelic with RYR-1 ("ryanodine receptor" [calcium release channel gene]), the gene responsible of the susceptibility to malignant hyperthermia. In some familial cases of CCD a susceptibility to malignant hyperthermia was also recognized. The diagnosis is only made based on muscular biopsy, which documents some peculiar morphological abnormalities, i.e. focal losses of oxidative enzyme activities, exclusively in type I muscular fibres. The basis for the loss of such activities is represented by an almost total absence of mitochondria and sarcoplasmic reticulum in those focal regions of muscle fibres. Cores may be "structured" and "unstructured" based on the reactivity with myosin ATPases, which ultrastructurally means preservation or destruction of myofilaments. Both structured and unstructured cores qualify this disease in the same way. The authors have observed two cases of CCD in patients in their non infantile age. Both diagnoses were accomplished by means of muscular biopsy, and the results of their studies in both cases are herein presented and discussed.

Focal lesions of increased signal within cerebral white matter on T2-weighted MR images have been reported in migraine patients. The percentage of this finding ranged from 12 to 47%, varying broadly. Furthermore the origin and the nature of cerebral lesions remain uncertain. We enrolled 80 (58F, 22M, mean age 33.8+/-11.1 years) consecutive migraine patients (MP) to ascertain MRI focal cerebral hyperintensity. Fifty (34F, 16M, mean age 37.5+/-16.8) tension headache patients (THP) were included as control group. Antiphospholipid antibodies (ACA, LAG), protein C and S, antithrombin III were titrated in patients who showed MRI cerebral focal hyperintensity lesions in both groups. Furthermore they underwent to evoked potentials (VEP, SEP, BAEP) and carotid ultrasonography examinations. Twenty-two (27.5%) and 15 (30%) patients showed MRI lesions in migraine and tension-type headache group, respectively One female migrainous patient showed a little aneurism of the left middle cerebral artery. No alteration of coagulation parameters and instrumental examinations as well as serum antiphospholipid antibodies presence were detected in MP and TH patients with MRI focal cerebral hyperintensity. However these patients, particularly those with tension-type headache, were significantly older and more hypertensive than patients without cerebral lesions. Furthermore THP showed more carotid intima thickness. Neuroimaging finding of focal high signal within cerebral white matter is fairly common in migraine and tension-type headache patients but if is not produced by derangement of coagulation parameters. Risk factors for cerebrovascular diseases such as hypertension, dyslipidemia and age could account for this finding in older patients.

To assess the prognosis of the Guillain-Barre syndrome and identify the main prognostic indicators, 297 patients with Guillain-Barre syndrome recruited through a network of Italian centres were followed up for 24 months or until clinical recovery, whichever was earliest. For each patient the time to plateau, improvement, clinical recovery, or death was calculated, and prognostic indicators (age, sex, antecedent events, disability at admission and nadir electrophysiological patterns) and treatments were noted. The mean duration of follow-up was 309 days. During this period, 212 patients (71%) recovered, 48 (16%) had residua and 33 (11%) died. The mean times to nadir improvement and clinical recovery were 12, 28 and 200 days. Using life-tables and survival curves, the cumulative probability of achieving the plateau of symptoms was 73% by 1 week and 98% by 4 weeks. Improvement started during the first week in 36% of cases and within 4 weeks in 85%. The rates of clinical recovery at 1 and 4 weeks, 6, 12 and 24 months were 4, 24, 57, 70 and 82%, respectively. The chance of recovery was significantly affected by age, antecedent gastroenteritis, disability, electrophysiological signs of axonopathy, latency to nadir and duration of active disease. The main treatments did not seem to affect the chance of recovery.

Patients treated with interferon alfa can develop autoantibodies and autoimmune diseases. We describe two patients who developed myasthenia gravis with abnormal levels of serum anti-acetylcholine receptor antibodies during interferon alfa-2b treatment for malignancies. One of these patients had myopathic findings on EMG and focal deficiency of cytochrome c oxidase on muscle biopsy.

The prevalence and general characteristics of chronic symmetric symptomatic polyneuropathy were assessed in two elderly populations living in Varese, northern Italy, and San Giovanni Rotondo, southern Italy. We interviewed 4,191 subjects (3,027 in Varese and 1,164 in San Giovanni Rotondo), 55 years and older, seen in office consultations by 27 general practitioners, A neurologist examined 734 patients who had two or more symptoms of polyneuropathy, A diagnosis of possible polyneuropathy (screening neuropathic symptoms and one of the following findings: bilateral impairment of strength; bilateral impairment of sensation; bilateral impairment of deep tendon reflexes) was made in 213 patients (7.0%) in Varese and 94 (8.1%) in San Giovanni Rotondo. Probable polyneuropathy (screening symptoms and at least two of the physical findings) was present in 111 Varese patients (3.7%) and 40 San Giovanni Rotondo patients (3.4%). The age- and sex-adjusted prevalence rate of probable polyneuropathy was 3.6 per 100 in Varese and 3.3 per 100 in San Giovanni Rotondo, The disease was more prevalent in women in Varese and in men in San Giovanni Rotondo and was significantly correlated with age in Varese, Diabetes was found in association with probable polyneuropathy in 43.7% of patients. Muscle cramps and distal paresthesia were the main symptoms. In general, polyneuropathy was mild to moderate, impairment of deep tendon reflexes and sensation being the most common findings.

We describe clinical, morphological and biochemical findings of a patient with reducing body myopathy (RBM). This 15-year-old patient was affected by severe limb-girdle progressive myopathy with asymmetric distribution. Muscle biopsy showed many fibers with cytoplasmic polymorphic masses, which stained dark purple with modified Gomori's trichrome, associated with proliferation of cytoplasmic bodies. Cytoplasmic polymorphic masses showed marked reducing activity with menadione-nitro blue tetrazolium reaction. Ultrastructurally, there was great amount of highly electron-dense tubular-filamentous structures of 16-17 nm in diameter. Immunohistochemistry showed that many fibers were positive for desmin. Sodium dodecyl sulfate-electrophoresis disclosed an increase in two bands of approximately 53 and 70 kDa, and Western blot demonstrated that the 53-kDa band was desmin. It was not possible to characterize the 70-kDa protein further.

An epidemiological survey has been conducted during a 3-month period in the Regional Hospital of S. Giovanni Rotondo, a small city in Southern Italy. A total of 1,878 patients aged 12 years and over admitted to the hospital were randomized during the study period. Each patient was asked 7 specific questions focusing on symptoms most likely due to polyneuropathy. The sensitivity and specificity of the screening procedure were tested separately and found to be high. All cases who gave affirmative answers to at least 2 questions were carefully investigated in search of a polyneuropathy. Of the 20 cases which gave an affirmative answer to 2 or more questions, 19 (1 % or 10 cases per 1,000 hospital population) had a neurological examination fitting with the diagnosis of polyneuropathy. There were 3 males and 16 females with a median age of 61 years. Diabetes was the commonest associated disorder. The disease ran a mild course in 12 cases and was severe in only 1. The screening model used in the current study seems a valuable and simple approach for case ascertainment in epidemiological investigations of polyneuropathy.