Nerve ablation after bronchial thermoplasty and sustained improvement in severe asthma.

BACKGROUND: Bronchial thermoplasty (BT) is a non-pharmacological intervention for severe asthma whose mechanism of action is not completely explained by a reduction of airway smooth muscle (ASM). In this study we analyzed the effect of BT on nerve fibers and inflammatory components in the bronchial mucosa at 1 year. METHODS: Endobronchial biopsies were obtained from 12 subjects (mean age 47 ± 11.3 years, 50% male) with severe asthma. Biopsies were performed at baseline (T0) and after 1 (T1), 2 (T2) and 12 (T12) months post-BT, and studied with immunocytochemistry and microscopy methods. Clinical data including Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Questionnaire (ACQ) scores, exacerbations, hospitalizations, oral corticosteroids use were also collected at the same time points. RESULTS: A statistically significant reduction at T1, T2 and T12 of nerve fibers was observed in the submucosa and in ASM compared to T0. Among inflammatory cells, only CD68 showed significant changes at all time points. Improvement of all clinical outcomes was documented and persisted at the end of follow up. CONCLUSIONS: A reduction of nerve fibers in epithelium and in ASM occurs earlier and persists at one year after BT. We propose that nerve ablation may contribute to mediate the beneficial effects of BT in severe asthma. TRIAL REGISTRATION: Registered on April 2, 2013 at ClinicalTrials.gov Identifier: NCT01839591 .

Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial.

BACKGROUND: A neuroprotective effect of lithium in amyotrophic lateral sclerosis (ALS) has been recently reported. We performed a multicenter trial with lithium carbonate to assess its tolerability, safety, and efficacy in patients with ALS, comparing 2 different target blood levels (0.4-0.8 mEq/L, therapeutic group [TG], vs 0.2-0.4 mEq/L, subtherapeutic group [STG]). METHODS: The study was a multicenter, single-blind, randomized, dose-finding trial, conducted from May 2008 to November 2009 in 21 Italian ALS centers. The trial was registered with the public database of the Italian Agency for Drugs (http://oss-sper-clin.agenziafarmaco.it/) (EudraCT number 2008-001094-15). RESULTS: As of October 2009, a total of 171 patients had been enrolled, 87 randomized to the TG and 84 to the STG. The interim data analysis, performed per protocol, showed that 117 patients (68.4%) discontinued the study because of death/tracheotomy/severe disability, adverse events (AEs)/serious AEs (SAEs), or lack of efficacy. The Data Monitoring Committee recommended stopping the trial on November 2, 2009. CONCLUSIONS: Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that therapeutic (0.4-0.8 mEq/L) vs subtherapeutic (0.2-0.4 mEq/L) lithium carbonate did not differ in the primary outcome of efficacy (survival/loss of autonomy) in ALS. Both target levels led to dropouts in more than 30% of participants due to patient-perceived lack of efficacy and AEs.

Creutzfeldt-Jakob disease with a novel extra-repeat insertional mutation in the PRNP gene.

The authors investigated two unrelated patients with Creutzfeldt-Jakob disease (CJD) with clinical features of sporadic CJD (sCJD) carrying one extra octapeptide repeat in the prion protein (PrP) gene (PRNP). A synaptic type PrP distribution throughout the cerebral gray matter and plaque-like PrP deposits in the subcortical gray structures were detected immunocytochemically. The different patterns of PrP deposition were associated with distinct types of protease-resistant PrP, similar to type 1 and type 2 of sCJD. The features suggest that this insertion is a pathogenic mutation.

Risk of sporadic amyotrophic lateral sclerosis associated with seropositivity for herpesviruses and echovirus-7.

We examined the association between risk of sporadic amyotrophic lateral sclerosis (ALS) and seroprevalence of antibodies to echovirus-7 (echo-7) and herpesviruses 6, 7, and 8 through a population-based case-control study. We enrolled in a northern Italy area 20 newly diagnosed ALS cases and 20 referents. Risk of ALS was higher in subjects seropositive for echo-7 when we used the immunofluorescent assay, while little increase was noted with the neutralization test. Considering the different characteristics of these two serological assays, these results suggest an association between disease risk and infection with enterovirus (EV) family members (not specifically echo-7). ALS risk was slightly associated with seropositivity of human herpesvirus-6 (odds ratio: 3.2; p = 0.102) and more strongly with human herpesvirus-8 seropositivity (odds ratio: 8.4; p = 0.064), though these point estimates were statistically unstable due to the limited number of observed cases. The findings of this study warrant further investigation in larger studies of the possible etiologic role of EV or herpesvirus infection in sporadic ALS.

Mutations in the RYR1 gene in Italian patients at risk for malignant hyperthermia: evidence for a cluster of novel mutations in the C-terminal region.

Mutations in the ryanodine receptor type 1 (RYR1) gene are associated with Malignant Hyperthermia (MH) and Central Core Disease (CCD). We report here on the molecular analysis of the RYR1 gene in Italian families referred as potential cases of MH or in patients with CCD or multicore/minicore myopathy. Of a total of 20 individuals with mutations in the RYR1 gene, 14 were part of a group of 47 MH susceptible (MHS) patients, 4 of 34 individuals diagnosed as MH equivocal (MHE), and 2 were patients diagnosed with minicore myopathy and CCD, respectively. Mutations were found to segregate with the MHS or MHE phenotype within the families of the probands. A discordance between phenotype and genotype was observed in a family where a mutation detected in an MHS proband was also found in the father who had been diagnosed MH normal (MHN) at the IVCT. In addition to known mutations, seven novel mutations were found, five of which occurred in exons encoding the C-terminal region of RYR1. These results indicate that the C-terminal region of RYR1 represents an additional hot spot for mutations in patients with MH, similar to what has been reported for patients with CCD.

Clinical and molecular studies of 73 Italian families with autosomal dominant cerebellar ataxia type I: SCA1 and SCA2 are the most common genotypes.

We clinically and genetically evaluated 73 Italian families with autosomal dominant cerebellar ataxia (ADCA) type I. Spinocerebellar ataxia (SCA) type 1 was the most common genotype (SCA1), accounting for 41% of cases (30 families), SCA2 was slightly less frequent (29%, 21 families), and the remaining families were negative for the SCA1, SCA2, and SCA3 mutations. Among the positively genotyped families, SCA1 was found most frequently in families from northern Italy (50%), while SCA2 was the most common mutation in families from the southern part of the country (56%). Slow saccades and decreased deep tendon reflexes were observed significantly more frequently in SCA2 patients, while increased deep tendon reflexes and nystagmus were more common in SCA1. In SCA1 and SCA2 families there was a significant inverse correlation between expansion size and age at onset. Analysis of triplet repeat numbers in parent-offspring pairs showed greater meiotic instability, which was associated with an earlier onset of the disease in SCA2 families than in SCA1 families.

Clinical and genetic study of a family with spinocerebellar ataxia type 1 (SCA1) and beta-thalassemia.

We report a family affected by autosomal dominant ataxia, in which numerous members also showed microcytosis. Genetic analysis demonstrated a CAG expansion in the SCA1 locus in five members, while all subjects with microcytosis revealed a C-T substitution at codon 39 of the beta-globin gene. A pure cerebellar syndrome with prominent gait ataxia characterized the first stages of the neurological disease. The fully developed disease included additional clinical findings such as dysarthria and dysphagia, and instrumental signs of axonal involvement of the peripheral nerves. Ophthalmoplegia was not observed. The coexistence of hereditary spinocerebellar degeneration and erythropathies or hemoglobinopathies has been previously described. We discuss the possible linkages between these two pathologies.

Precocious loss of physiological sleep in a case of Creutzfeldt Jakob disease: a serial polygraphic study.

Creutzfeldt-Jakob disease (CJD) is a prion-related subacute encephalopathy producing widespread neuronal degeneration and spongiform pathological changes, especially in the neocortex. Progressive dementia, motor signs and electroencephalographic (EEG) alterations characterize the full stage of the disease. A series of eight 24-hour polygraphic recordings were carried out in the last 3 months of life of a 68-year-old female patient affected by CJD that was confirmed neuropathologically. Genetic classification demonstrated this patient to have a sporadic form of the disease. The polygraphic recordings demonstrated three types of EEG findings, as follows: 1) sustained pseudoperiodic discharges (SPD), characterized by long-lasting diffuse sequences of slow sharp waves or di- or triphasic slow waves recurring at 0.5- to 1.5-second intervals; 2) discontinuous pseudoperiodic discharges (DPD), consisting of runs of pseudoperiodic discharges (PD)(phase A) cyclically replaced at about 1-minute intervals with semi-rhythmic theta-delta activities (phase B); 3) non-rapid eye movement (NREM) sleep-like pattern, with dominant 0.5- to 4-Hz activities, less rhythmic than the EEG of phase B. Only these three EEG patterns occurred spontaneously during the repeated polygraphic sessions. The NREM sleep-like pattern was found only in the first recording, whereas the following polygraphic sessions were occupied exclusively by SPD or by a DPD pattern. SPD was associated with either a relatively high level of vigilance (along the first three recordings) or a state of alert-appearing silent immobility (following the fourth recording). During DPD, the patient was unable to accomplish any voluntary movement and fluctuated between levels of greater arousal (phase A) and lesser arousal (phase B). Just as in stage 2 coma, the fluctuations between phases A and B of DPD were synchronous with phasic modifications of muscle activity and neurovegetative functions. In particular, reinforcement of muscle tone and myoclonic spasms coincided with phase A, whereas heart rate deceleration and respiratory pauses or decrease in flow were synchronous with phase B. As EEG evolved toward the disappearance of DPD and finally to flatness, the phase-locked coordination among arousal, somatic and vegetative activities was progressively impaired and was replaced with an uncontrolled exaggeration of cardiorespiratory activity. The genetic, neuropathological and polysomnographic differences between CJD and another prion disease, fatal familial insomnia, are discussed.

Panencephalopathic type of Creutzfeldt-Jakob disease with neuropathologic features similar to Pick's disease.

The panencephalopathic type of Creutzfeldt-Jakob disease is characterized by a serious degeneration of the white matter in addition to the other pathological features of the classic Creutzfeldt-Jakob disease. The clinical and neuropathological findings of a new case are described in a woman aged 62, who died after a year of illness. The brain appeared seriously affected by atrophy and white matter degeneration. Microscopically, it showed a marked cortical spongiosis, with gemistocytic astrogliosis and degeneration of the white matter of both hemispheres. Although a serious loss of nerve cells was evident, some residual neurons with a ballooned aspect were found in the fronto-temporal cortex. Other neurons presented argyrophilic inclusions similar to Pick bodies. By means of immunohistochemical techniques and monoclonal antineurofilaments antibodies some neurons with swollen cytoplasm and enlargement of the first tract of the neurites were detected in the basal layers of the frontal and temporal cortex. These abnormal features were due to the accumulation of phosphorylated 200 Kd neurofilaments. The relations between Creutzfeldt-Jakob and Pick's diseases are analyzed on the basis of the neuropathological findings. There is evidence from the immunohistochemical data of an interference in the axonal transport of neurofilaments.

Creutzfeldt-Jakob disease presenting as Wernicke-Korsakoff syndrome.

A 47-year-old man began to suffer from progressive truncal ataxia and mental alterations typical of Wernicke-Korsakoff syndrome. He showed confusional state, hallucinations, delirium of jealousy and a serious impairment of recent memory. The symptomatology lasted 13 months, but only in the last weeks was it complicated by myoclonias. Triphasic pseudoperiodic sharp-waves characterized the EEG-recordings only in the final stage. Macroscopic examination of the brain showed marked atrophy of the mammillary bodies and superior vermis. However, the histological features were consistent with Creutzfeldt-Jakob disease (CJD) with focal accentuation of the changes in the latter structures. This case supports the hypothesis that CJD-changes begin focally in the CNS and, subsequently, spread along neuronal pathways, probably via central axons. Only in the final stage does the pathological process involve most parts of the gray matter. A focal accentuation of the CJD process in the cerebello-mammillo-thalamic system caused in this case a Wernicke-Korsakoff-like syndrome.

Tangier disease: central nervous system impairment in a case of syringomyelia-like syndrome.

A neuroradiological investigation of the central nervous system (CNS) in a case of Tangier disease presenting as a syringomyelia-like syndrome is reported. No syringomyelinic cavities were found. However, MRI showed cervical spinal cord atrophy and scattered foci of greater density with T2 weighted images in the white matter of the frontal, parietal and occipital lobes. Cerebral and cervical spinal cord involvement in the course of Tangier disease is now shown for the first time. The authors postulate that the MRI detected alterations are related to the underlying illness.

Recovery from herpes simplex encephalitis: selective impairment of specific semantic categories with neuroradiological correlation.

The clinical, neuropsychological and neuroradiological features of two patients affected by herpes simplex virus type 1 (HSV-1) encephalitis are described. An experimental study for the assessment of naming, recognition and description displayed in one patient a persistent significant impairment in naming living things. The other patient showed a failing "semantic memory" for the same categories, although a significant impairment emerged only for plants. In both patients, the late neuroradiological sequelae were localised mainly in the inferior and middle gyri of the left temporal lobe and in the left-side insula. In one patient, the right-side insula was also involved. The selective cerebral damage induced by HSV-1 is stressed and a correlation between the neuroradiological and neuropsychological findings is attempted. The stereotyped anatomical and neuropsychological changes lead to the belief that the virus may recognise, within the limbic system, particular cellular "strains" on the basis of their molecular specificity.

Acute confusional migraine: clinical and electroencephalographic aspects.

Twelve patients with episodes of acute confusional migraine (ACM) are reported. Prolonged agitation and mental confusion characterized the headache attacks, occurring mostly among adolescents. The ictal EEG showed diffuse, slow abnormalities and a peculiar pattern known as FIRDA (frontal intermittent rhythmic delta activity). Neuroradiologic examinations and laboratory tests were unremarkable. After the acute stage, EEG gradually tended to show normalization. Apart from the noticeable similarities to the "juvenile head trauma syndrome", the authors assume that ACM represents a peculiar clinical form among the different types of migraine associated with disorders of higher mental functions.

Acute confusional migraine attacks resolved by sleep: lack of significant abnormalities in post-ictal polysomnograms.

We observed acute confusional migraine (ACM) attacks in two adolescents, and in both cases the episodes ended when the patients fell asleep spontaneously. Laboratory and neuroradiologic examinations were unremarkable. The post-ictal polysomnograms displayed a regular quality and duration of the physiologic components of sleep. Random posterior slow waves occurred only during the nocturnal awakenings and REM periods. The observation that sleep may resolve migraine attacks is emphasized. ACM is characterized by peculiar and relatively quickly reversible clinical manifestations and EEG abnormalities. The lack of significant abnormalities in post-ictal polysomnograms corresponds to a functional integrity of the brainstem structures involved in the global organization of sleep and may represent a useful laboratory feature in the diagnosis of ACM.

Neuropathy in Tangier disease: A clinicopathologic study and a review of the literature.

A new case of Tangier disease is described. It is the 33rd case in world literature and only the 2nd in Italy. A 52-year-old man showed a widely spread neuropathy with facial diplegia, bilateral wasting of hand muscles and dissociated loss of pain and temperature sensation sparing the distal parts of the lower limbs. Clinical and laboratory data were typical of Tangier disease. A histological and ultrastructural study of the patient's superficial peroneal nerve and brevis peroneus muscle was carried out. A revision of the clinical and neuropathological aspects of the neuropathy of Tangier disease allowed our case to be included within a particular neurological description. Four patients with similar clinical characteristics had been noted previously. Clinical, morphological and biochemical data suggest the hypothesis that there are two different neuropathic forms of Tangier disease.

Comparative in vitro study of the pro-apolipoprotein A-I to apolipoprotein A-I converting activity between normal and Tangier plasma.

We examined the ability of the plasma of a 52-yr-old male Tangier patient to effect the conversion of radiolabeled pro-apolipoprotein A-I (apo A-I), isolated from hepatoma cell culture media, into mature apo A-I. The conversion was assessed by amino-terminal sequence analysis, isoform patterns with two-dimensional gel electrophoresis, and a rapid assay based on the different solubilities of intact pro-apo A-I and its hexapeptide prosegment in 10% trichloroacetic acid. We found that the converting activity of Tangier plasma was comparable to that exhibited by control normolipidemic plasma and that in both cases pro-apo A-I was correctly processed at the Gln-Asp bond. After ultracentrifugal fractionation of Tangier plasma at d = 1.21 g/ml, the pro-apo A-I-to-mature apo A-I converting activity was mainly recovered in the middle fraction of d = 1.225 g/ml and was at least 10-fold more effective than the top and bottom fractions. In contrast, in normal plasma the activity was only present in the top and bottom fractions. It has been previously established that in Tangier plasma the pro-apo A-I/apo A-I ratio is significantly higher than normal (1 vs. 0.02). Our studies suggest that this abnormal ratio is not the result of a reduced converting enzyme activity and may relate to differences in turnover rates between Tangier and normal plasma apolipoproteins.

On the variability of the human flocculus and paraflocculus accessorius.

42 human cerebelli were examined macroscopically in order to ascertain the general morphological, conformation of the flocculus and accessory paraflocculus, as well as their variability. The flocculus had a mean number of 14.2 +/- 0.3 (s.e.) folia and 7.0 +/- 0.4 (s.e.) subfolia arranged in a rosette-like cluster of relatively constant shape. The coefficient of variability of the number of folia and subfolia was respectively 22.1% and 47.4%. The accessory paraflocculus had a mean number of 4.2 +/- 0.2 (s.e.) folia and 2.0 +/- 0.2 (s.e.) subfolia, with a variability coefficient of respectively 50.2% and 102.8% which was more than double that of the flocculus. In fact the conformation of the accessory paraflocculus varied from a single small flattened lamella to a rosette-like cluster of folia similar in shape and size to those of the flocculus. There was no correlation between the variability of the flocculus and accessory paraflocculus. The possible reason for this marked variability is discussed in the light of the phylogenetic evolution of the structures examined.