Functional and radiological outcomes after bridging therapy versus direct thrombectomy in stroke patients with unknown onset: Bridging therapy versus direct thrombectomy in unknown onset stroke patients with 10-point ASPECTS.

BACKGROUND AND PURPOSE: The aim was to assess functional and radiological outcomes after bridging therapy (intravenous thrombolysis plus mechanical thrombectomy) versus direct mechanical thrombectomy (MT) in unknown onset stroke patients. METHODS: A cohort study was conducted on prospectively collected data from unknown onset stroke patients who received endovascular procedures at ≤6 h from symptom recognition or awakening time. RESULTS: Of the 349 patients with a 10-point Alberta Stroke Program Early Computed Tomography Score (ASPECTS), 248 received bridging and 101 received direct MT. Of the 134 patients with 6-9-point ASPECTS, 123 received bridging and 111 received direct MT. Each patient treated with bridging was propensity score matched with a patient treated with direct MT for age, sex, study period, pre-stroke disability, stroke severity, type of stroke onset, symptom recognition to groin time (or awakening to groin time), ASPECTS and procedure time. In the two matched groups with 10-point ASPECTS (n = 73 vs. n = 73), bridging was associated with higher rates of excellent outcome (46.6% vs. 28.8%; odds ratio 2.302, 95% confidence interval 1.010-5.244) and successful recanalization (83.6% vs. 63%; odds ratio 3.028, 95% confidence interval 1.369-6.693) compared with direct MT; no significant association was found between bridging and direct MT with regard to rate of symptomatic intracerebral hemorrhage (0% vs. 1.4%). In the two matched groups with 6-9-point ASPECTS (n = 45 vs. n = 45), no significant associations were found between bridging and direct MT with regard to rates of excellent functional outcome (44.4% vs. 31.1%), successful recanalization (73.3% vs. 76.5%) and symptomatic intracerebral hemorrhage (0% vs. 0%). CONCLUSIONS: Bridging at ≤ 6 h of symptom recognition or awakening time was associated with better functional and radiological outcomes in unknown onset stroke patients with 10-point ASPECTS.

Clinical characteristics and outcome of patients with autoimmune encephalitis: clues for paraneoplastic aetiology.

BACKGROUND AND PURPOSE: Autoimmune encephalitis (AE) represents a complex syndrome with diverse clinical manifestations and therapeutic outcomes. The aim of this study was to report the clinical characteristics and the long-term outcome of patients with paraneoplastic and idiopathic AE. METHODS: All patients with subacute encephalopathy admitted to the Neurology Department of our Institution from January 2012 to May 2019 were consecutively enrolled. Patients' serum and cerebrospinal fluid were tested for neural-specific autoantibodies by indirect immunofluorescence assays on mouse brain, rat neurons, cell-based assays and immunoblots. Outcome was assessed by the modified Rankin Scale score. RESULTS: From 107 adult patients with subacute encephalopathy, 50 patients were finally diagnosed with AE. Neural antibodies (Abs) were detected in 45/50 patients (90%). Leucine-rich glioma-inactivated protein 1 immunoglobulin G was the most frequent (6/50, 12%) Ab specific to neural surface antigens detected in adults with AE. Paraneoplastic encephalitis was diagnosed in 16/50 patients (32%). The presence of bilateral temporal lobe lesions on magnetic resonance imaging and cerebrospinal fluid restricted oligoclonal bands was associated with a higher probability to detect cancer at the time of AE diagnosis. All patients with Abs to neural surface antigens had a good outcome at last follow-up. Severe disability at AE onset and the lack of long-term immunosuppression predicted a poor outcome. CONCLUSIONS: Leucine-rich glioma-inactivated protein 1 immunoglobulin G was the most frequent Ab detected. Patients with bilateral temporal lobe lesions and oligoclonal bands have a higher probability to harbour an occult tumour. In these patients, a strict surveillance and monitoring for cancer detection is recommended.

Treatment-emergent central sleep apnoea after surgery for obstructive sleep apnoea.

Central sleep apnoea (CSA) is a lack of drive to breathe during sleep, which can occur in physiologic as well as in pathologic conditions. A particular type of CSA, defined treatment-emergent CSA (TECSA), may occur after the treatment of obstructive sleep apnoea syndrome (OSAS), either with CPAP or surgery. TECSA is transitory and seems to be related to the severity of OSAS. We describe a 51-year-old man affected by severe OSAS who developed severe, transient CSA immediately after upper airways surgery. We believe that CSA was triggered by the sudden variation in nocturnal arterial PCO2, which decreased from 52.3 mmHg before surgery to 42.0 mmHg after surgery. It is conceivable that, due to long-lasting severe OSAS, our patient lowered his chemosensitivity to PCO2. Consequently, the resolution of obstructive apnoeas and the restoration of normal nocturnal values of PCO2 may have reduced the nocturnal PCO2 to the point of being inadequate to stimulate ventilation.

Tensor veli palatini electromyography for monitoring Eustachian tube rehabilitation in otitis media.

BACKGROUND: The pathogenesis of otitis media is related to Eustachian tube dysfunction. The tensor veli palatini muscle actively opens the Eustachian tube and promotes middle-ear ventilation. This study describes a technique for paratubal electromyography that uses a surface, non-invasive electrode able to record tensor veli palatini muscle activity during swallowing. METHODS: Twenty otitis media patients and 10 healthy patients underwent tensor veli palatini electromyography. Activity of this muscle before and after Eustachian tube rehabilitation was also assessed. RESULTS: In 78.5 per cent of patients, the electromyography duration phase and/or amplitude were reduced in the affected side. The muscle action potential was impaired in all patients who underwent Eustachian tube rehabilitation. CONCLUSION: This study confirmed that Eustachian tube muscle dysfunction has a role in otitis media pathogenesis and showed that muscle activity increases after Eustachian tube rehabilitation therapy.

Evaluation of pharyngeal muscle activity through nasopharyngeal surface electromyography in a cohort of dysphagic patients with acute ischaemic stroke.

Oro-pharyngeal dysphagia is frequently present during the acute phase of stroke. The aim of the present study was to evaluate whether the recording of surface EMG using a nasopharyngeal (NP) electrode could be applied to evaluation of pharyngeal muscle activity in acute stroke patients and if this neurophysiological measure is related with clinical assessment of swallowing. Patients were examined and clinical severity was assessed with the National Institute of Health Stroke Scale (NIHSS) score; dysphagia was evaluated through bedside screening test using the Gugging Swallowing Scale (GUSS). Extension of the ischaemic lesion was measured by quantitative score, based on CT scan [Alberta Stroke Programme Early CT Score (ASPECTS)]. We analysed 70 patients; 50 were classified as dysphagic (Dys+), and 20 as non-dysphagic (Dys-). Each participant underwent a surface NP EMG recording performed with a NP electrode, made of a Teflon isolated steel catheter, with a length of 16 cm and a tip diameter of 1.5 mm. The electrode was inserted through the nasal cavity, rotated and positioned approximately 3 mm anteroinferior to the salpingo-palatine fold. At least four consecutive swallowing-induced EMG bursts were recorded and analysed for each participant. Swallowing always induced a repetitive, polyphasic burst of activation of the EMG, lasting around 0.25 to 1 sec, with an amplitude of around 100-600mV. Two parameters of the EMG potentials recorded with the NP electrode were analyzed: duration and amplitude. The duration of the EMG burst was increased in Dys+ patients with a statistically significant difference compared to Dys- patients (p < 0.001). The amplitude was slightly reduced in the Dys+ group, but statistically significant differences were not observed (p = 0,775). Nevertheless, the burst amplitude showed a significant inverse correlation with NIHSS [r(48) = -0.31; p < 0.05] and ASPECTS scores [r(48) = -0.27; p < 0.05], meaning that the burst amplitude progressively reduced with an increase of clinical severity (NIHSS) and topographic extension of brain lesions in CT (ASPECTS). These results suggest that NP recordings can give a semi-quantitative measure of swallowing difficulties originating from pharyngeal dysfunction, in fact, electromyographic findings suggest reduced pharyngeal motility.

LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population.

OBJECTIVE: A multicentre observational study was aimed to assess the prevalence of late-onset Pompe disease (LOPD) in a large high-risk population, using the dried blood spot (DBS) as a main screening tool. DESIGN/METHODS: 17 Italian neuromuscular centres were involved in the late-onset Pompe early diagnosis (LOPED) study. Inclusion criteria were: (1) age ≥5 years, (2) persistent hyperCKaemia and (3) muscle weakness at upper and/or lower limbs (limb-girdle muscle weakness, LGMW). Acid α-glucosidase (GAA) activity was measured separately on DBS by fluorometric as well as tandem mass spectrometry methods. A DBS retest was performed in patients resulted positive at first assay. For the final diagnosis, GAA deficiency was confirmed by a biochemical assay in skeletal muscle, whereas genotype was assessed by GAA molecular analysis. RESULTS: In a 14-month period, we studied 1051 cases: 30 positive samples (2.9%) were detected by first DBS screening, whereas, after retesting, 21 samples were still positive. Biochemical and molecular genetic studies finally confirmed LOPD diagnosis in 17 cases (1.6%). The median time from the onset of symptoms/signs to diagnosis was 5 years. Among those patients, 35% showed presymptomatic hyperCKaemia and 59% showed hyperCKaemia+LGMW, whereas 6% manifested with LGMW. CONCLUSIONS: LOPED study suggests that GAA activity should be accurately screened by DBS in all patients referring for isolated hyperCKaemia and/or LGMW. A timely diagnosis was performed in five patients with presymptomatic hyperCKaemia, but two had already manifested with relevant changes on muscle morphology and MRI. Consequently, enzyme replacement therapy was started in 14/17 patients, including the 2 patients still clinically presymptomatic but with a laboratory evidence of disease progression.

Drug-induced sleep endoscopy as a selection tool for mandibular advancement therapy by oral device in patients with mild to moderate obstructive sleep apnoea.

Nowadays oral appliance therapy is recognised as an effective therapy for many patients with primary snoring and mild to moderate obstructive sleep apnoea (OSA), as well as those with more severe OSA who cannot tolerate positive airway pressure (PAP) therapies. For this reason, it is important to focus on objective criteria to indicate which subjects may benefit from treatment with a mandibular advancement device (MAD). Various anthropometric and polysomnographic predictors have been described in the literature, whereas there are still controversies about the role of drug-induced sleep endoscopy (DISE) and advancement bimanual manoeuvre as predictor factors of treatment outcome by oral device. Herein, we report our experience in treatment of mild moderate OSA by oral appliance selected by DISE. We performed a single institution, longitudinal prospective evaluation of a consecutive group of mild moderate patients with obstructive sleep apnoea syndrome who underwent DISE. During sleep endoscopy, gentle manoeuvre of mandibular advancement less than 5 mm was performed. In 30 of 65 patients (46.2%) we obtained an unsuccessful improvement of airway patency whereas in 35 of 65 patients (53.8%) the improvement was successful and patients were considered suitable for oral device application. Because 7 of 35 patients were excluded due to conditions interfering with oral appliance therapy, we finally treated 28 patients. After 3 months of treatment, we observed a significant improvement in the Epworth medium index [(7.35 ± 2.8 versus 4.1 ± 2.2 (p < 0.05)], in mean AHI [(21.4 ± 6 events per hour versus 8.85 ± 6.9 (p < 0.05)] and in mean ODI [(18.6 ± 8 events per hour to 7 ± 5.8 (p < 0.05)]. We observed that the apnoea/hypopnoea index (AHI) improved by up to 50% from baseline in 71.4% of patients selected after DISE for MAD therapy. In the current study, mandibular advancement splint therapy was successfully prescribed on the basis not only of severity of disease, as determined by the subject's initial AHI, but also by DISE findings combined with results of gentle mandibular advancement manoeuvre allowing direct view of the effects of mandibular protrusion on breathing spaces in obstruction sites, and showing good optimisation of selection of patients for oral device treatment.

The detection of neural autoantibodies in patients with antiepileptic-drug-resistant epilepsy predicts response to immunotherapy.

BACKGROUND AND PURPOSE: The detection of antibodies binding neural antigens in patients with epilepsy has led to the definition of 'autoimmune epilepsy'. Patients with neural antibodies not responding to antiepileptic drugs (AEDs) may benefit from immunotherapy. Aim of this study was to evaluate the frequency of autoantibodies specific to neural antigens in patients with epilepsy and their response to immunotherapy. METHODS: Eighty-one patients and 75 age- and sex-matched healthy subjects (HS) were enrolled in the study. Two groups of patients were included: 39 patients with epilepsy and other neurological symptoms and/or autoimmune diseases responsive to AEDs (group 1) and 42 patients with AED-resistant epilepsy (group 2). Patients' serum and cerebrospinal fluid were evaluated for the presence of autoantibodies directed to neural antigens by indirect immunofluorescence on frozen sections of mouse brain, cell-based assays and a radioimmunoassay. Patients with AED-resistant epilepsy and neural autoantibodies were treated with immunotherapy and the main outcome measure was the reduction in seizure frequency. RESULTS: Neural autoantibodies were detected in 22% of patients (18/81), mostly from the AED-resistant epilepsy group (P = 0.003), but not in HS. Indirect immunofluorescence on mouse brain revealed antibodies binding to unclassified antigens in 10 patients. Twelve patients received immunotherapy and nine (75%) achieved >50% reduction in seizure frequency. CONCLUSIONS: A significant proportion of patients with AED-resistant epilepsy harbor neural-specific autoantibodies. The detection of these antibodies, especially of those binding to synaptic antigens, may predict a favorable response to immunotherapy, thus overcoming AED resistance.

Are stroke cases affected by sleep disordered breathings all the same?

Sleep disordered breathings (SDB) worsens the clinical prognosis of stroke patients. Continuous positive airway pressure (CPAP) is a promising effective treatment. Unfortunately, not all patients are compliant with CPAP, suggesting that it is not appropriate for all patients with obstructive sleep apnoea (OSA) after stroke. People with the highest likelihood of benefiting have to be identified. We present a classification of cases with stroke and SDB to be adopted in order to identify the best responders to CPAP treatment. We propose to classify patients in four subgroups: (1) patients who terminate the apnoea by arousing from sleep; these cases are those affected either by an anatomical or a functional obstruction of upper airways that may precede or are the consequence of stroke; (2) cases that alternate OSA to central sleep apnoea (CSA) cause of an altered loop gain; (3) cases in whom ischemic damages have altered the sleep microstructure (CAP); (4) cases that manifest a CSA as the direct consequence of stroke on the central neuronal drive to breath. So far, no study has investigated the consequences of stroke on sleep microstructure. In order to better elucidate these relationships, when reviewing the PSG tracings of stroke patients, the microstructure of sleep should be systematically analysed.

Hyoid myotomy without suspension: a surgical approach to obstructive sleep apnoea syndrome.

The aim of this study was to verify if hyoid myotomy without hyoid suspension is effective in surgical treatment of obstructive sleep apnoea syndrome (OSAS). We recruited six patients with OSAS, aged between 34 to 60 years, with retropalatal and retrolingual upper airway obstruction, non-obese (BMI < 27) and non-compliant to continuous positive airway pressure therapy. Pre-surgical clinical and instrumental evaluations included clinical examination, cephalometry, polysomnography (PSG) and sleep endoscopy. Surgical treatment included nasal surgery, uvulopalatopharyngoplasty, tonsillectomy and hyoid myotomy without hyoid suspension. Follow-up evaluations were performed with serial PSGs, performed early (one week after surgery), and at 1, 6 and 18 months after surgery. We observed that surgery was followed by immediate normalisation of breathing parameters evaluated by PSG that persisted after 18 months. Thus, hyoid myotomy without suspension combined with nasal and palatal surgery may be considered a valid treatment of non-obese OSAS patients with retrolingual and retropalatal collapse. Furthermore, we suggest that hyoid bone suspension, binding it to mandibular or to thyroid cartilage, might be unnecessary in selected cases.

Aminoacylase I deficiency due to ACY1 mRNA exon skipping.

Aminoacylase 1 (ACY1) deficiency is a rare inborn error of metabolism of which less than 20 observations have been described. Patients exhibit urinary excretion of specific N-acetyl amino acids and manifest a heterogeneous clinical spectrum including intellectual disability, motor delay, seizures, moderate to severe mental retardation, absent speech, growth delay, muscular hypotonia and autistic features. Here, we report the case of ACY1 enzyme deficiency in a 6-year-old girl presenting severe intellectual disability, motor retardation, absence of spontaneous locomotor activity and severe speech delay. Urinary excretion of N-acetylated amino acids was present. Mutational analysis of ACY1 gene identified the new homozygous c.1001_1001+5del6 mutation, which alters the mRNA transcription leading to exon 13 skipping and inclusion of a premature stop codon (p.Lys308Glufs*7). A quantitative fluorescent multiplex-polymerase chain reaction (QFM-PCR) assay has been set up and confirmed homozygosity of the mutation in the patient's DNA. Biochemical analysis showed absence of ACY1 enzyme activity in the patient's fibroblasts. The structure of the mutated protein has been defined by homology modeling (HM). Our data endorse the hypothesis of a link between this inborn error of metabolism and the neurological manifestations observed in patients with ACY1 deficiency.

The role of drug-induced sleep endoscopy in the diagnosis and management of obstructive sleep apnoea syndrome: our personal experience.

Nowadays, drug-induced sleep endoscopy (DISE) is performed widely and its validity and reliability has been demonstrated by several studies; in fact, it provides clinical information not available by routine clinical inspection alone. Its safety and utility are promising, but still needs to be improved to reach the level of excellence expected of gold standard tests used in clinical practice. Our study compares the results of clinical and diagnostic evaluation with those of sleep endoscopy, evaluating the correlation between clinical indexes of routine clinical diagnosis and sites of obstruction in terms of number of sites involved, entity of obstruction and pattern of closure. This study consists in a longitudinal prospective evaluation of 138 patients who successfully underwent sleep endoscopy at our institution. Patients were induced to sleep with a low dose of midazolam followed by titration with propofol. Sedation level was monitored using bispectral index monitoring. Our results suggest that the multilevel complete collapse was statistically significantly associated with higher apnoea hypopnea index values. By including partial sites of obstruction greater than 50%, our results also suggest that multilevel collapse remains statistically and significantly associated with higher apnoea hypopnoea index values. Analyzing BMI distribution based on number of sites with complete and partial obstruction there was no significant difference. Finally, analyzing Epworth Sleepiness Score distribution based on number of sites with complete obstruction, there was a statistically significant difference between patients with 3-4 sites of obstruction compared to those with two sites or uni-level obstruction. In conclusion, our data suggest that DISE is safe, easy to perform, valid and reliable, as previously reported. Furthermore, we found a good correlation between DISE findings and clinical characteristics such as AHI and EPS. Consequently, adequate assessment by DISE of all sites of obstruction is very important, not only in patients with low-moderate AHI and EPS, but also in patients with a high AHI or/and high EPS, in particular to plan multilevel surgery that in these latter situations is more demanding since success may be harder to achieve.

Children who develop type 1 diabetes early in life show low levels of carnitine and amino acids at birth: does this finding shed light on the etiopathogenesis of the disease?

BACKGROUND: Children and adolescents with overt type 1 diabetes (T1D) have been found to show an altered carnitine profile. This pattern has not previously been analyzed in neonates before onset of the disease. MATERIALS AND METHODS: Fifty children who developed T1D during the first 6 years of life, born and living in the Tuscany and Umbria Regions of Italy, were identified and 200 controls were recruited into the study. All newborns were subjected to extended neonatal screening by mass spectrometry at 48-72 h of life. Four controls for each of the 50 index cases were taken randomly and blinded in the same analytical batch. The panel used for neonatal screening consists of 13 amino acids, free carnitine, 33 acyl-carnitines and 21 ratios. All Guthrie cards are analyzed within 2 days of collection. RESULTS: Total and free carnitine were found to be significantly lower in neonates who later developed T1D compared with controls. Moreover, the concentrations of the acyl-carnitines - acetyl-L-carnitine (C2), proprionylcarnitine (C3), 3-hydroxyisovalerylcarnitine (C5OH), miristoylcarnitine (C4), palmitoylcarnitine (C16) and stearoylcarnitine (C18) - were also significantly low in the cases vs controls. Furthermore, total amino-acid concentrations, expressed as the algebraic sum of all amino acids tested, showed a trend toward lower levels in cases vs controls. CONCLUSIONS: We found that carnitine and amino-acid deficit may be evident before the clinical appearance of T1D, possibly from birth. The evaluation of these metabolites in the neonatal period of children human leukocyte antigen genetically at 'risk' to develop T1D, could represent an additional tool for the prediction of T1D and could also offer the possibility to design new strategies for the primary prevention of the disease from birth.

Seizure-induced brain lesions: a wide spectrum of variably reversible MRI abnormalities.

Introduction MRI abnormalities in the postictal period might represent the effect of the seizure activity, rather than its structural cause. Material and Methods Retrospective review of clinical and neuroimaging charts of 26 patients diagnosed with seizure-related MR-signal changes. All patients underwent brain-MRI (1.5-Tesla, standard pre- and post-contrast brain imaging, including DWI-ADC in 19/26) within 7 days from a seizure and at least one follow-up MRI, showing partial or complete reversibility of the MR-signal changes. Extensive clinical work-up and follow-up, ranging from 3 months to 5 years, ruled out infection or other possible causes of brain damage. Seizure-induced brain-MRI abnormalities remained a diagnosis of exclusion. Site, characteristics and reversibility of MRI changes, and association with characteristics of seizures were determined. Results MRI showed unilateral (13/26) and bilateral abnormalities, with high (24/26) and low (2/26) T2-signal, leptomeningeal contrast-enhancement (2/26), restricted diffusion (9/19). Location of abnormality was cortical/subcortical, basal ganglia, white matter, corpus callosum, cerebellum. Hippocampus was involved in 10/26 patients. Reversibility of MRI changes was complete in 15, and with residual gliosis or focal atrophy in 11 patients. Reversibility was noted between 15 and 150 days (average, 62 days). Partial simple and complex seizures were associated with hippocampal involvement (p=0.015), status epilepticus with incomplete reversibility of MRI abnormalities (p=0.041). Conclusions Seizure or epileptic status can induce transient, variably reversible MRI brain abnormalities. Partial seizures are frequently associated with hippocampal involvement and status epilepticus with incompletely reversible lesions. These seizure-induced MRI abnormalities pose a broad differential diagnosis; increased awareness may reduce the risk of misdiagnosis and unnecessary intervention.

Psychological functioning measures in patients with primary insomnia and sleep state misperception.

OBJECTIVE: Sleep state misperception (SSM) is a term used in the International Classification of Sleep Disorders to indicate people who mistakenly perceive their sleep as wakefulness. SSM is a form of primary insomnia. The aim of this study was to record psychological functioning measures (anxiety, depression, ability to feel pleasure, obsessive-compulsive traits) in a population of patients with primary insomnia and to evaluate the relationship between these measures and the patients' perception of their sleep. MATERIALS AND METHODS: Seventy-six consecutive patients with primary insomnia were enrolled: 34 men and 42 women, mean age 53.9 ± 13.1. Sleep study included the following: Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Berlin's Questionnaire and home-based polysomnography. Psychometric evaluation included the following: Self-Administered Anxiety Scale, Beck's Depression Inventory, Maudsley's Obsessive Compulsive Inventory, Snaith-Hamilton Pleasure Scale, Eating Attitude Test. RESULTS: All patients with insomnia had psychometric scores higher than the general population, but very few patients, in both groups, had anxiety or depression scores consistent with severe mood or anxiety disorders. Comparisons between subjective and objective scores confirmed that most sleep parameters were underestimated. Patients with SSM had lower anxiety scores as compared to patients without SSM. CONCLUSIONS: The study did not succeed in identifying any predictor of sleep misperception. We speculate that a group of patients, rather than being extremely worried by their insomnia, may have a sort of agnosia of their sleep.

Propranolol concentrations after oral administration in term and preterm neonates.

OBJECTIVE: While propranolol pharmacokinetics has been extensively studied in adults, this study reports the first evaluation of propranolol pharmacokinetics in term and preterm neonates. METHODS: Propranolol concentrations were measured in four term and 32 preterm newborns treated with oral propranolol at the dose of 0.5 or 0.25 mg/kg every 6 h by serial dried blood spots. RESULTS: The levels of propranolol, although with high inter-individual variability, were proportional with the administered dose. Pharmacokinetic parameters evaluated at the steady state in newborns treated with 0.5 mg/kg/6 h showed values of maximal (71.7 ± 29.8 ng/mL), minimal (42.2 ± 20.8 ng/mL) and average concentration (60.8 ± 25.0 ng/mL), time of maximal concentration (2.6 ± 0.9 h) and area under the time-concentration curve (364.7 ± 150.2 ng/mL/h) similar to those observed in adults. In both dosing groups, elimination half-life was significantly longer (14.9 ± 4.3 and 15.9 ± 6.1 h), and apparent total body clearance (27.2 ± 13.9 and 31.3 ± 13.3 mL/kg/min) lower than those reported in adults, suggesting a slower metabolism in newborns. No differences were observed between newborns with different gestational age or different sex. CONCLUSIONS: Neonates treated with propranolol-exhibited drug concentrations proportional with the dose, with significant long half-life.

Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene.

Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. Fabry disease (FD) is an X-linked lysosomal storage disorder with a heterogeneous spectrum of clinical manifestations that are caused by the deficiency of α-galactosidase A (α-Gal-A) activity. Although useful for diagnosis in males, enzyme activity is not a reliable biochemical marker in heterozygous females due to random X-chromosome inactivation, thus rendering DNA sequencing of the α-Gal-A gene, alpha-galactosidase gene (GLA), the most reliable test for the confirmation of diagnosis in females. The spectrum of GLA mutations is highly heterogeneous. Many polymorphic GLA variants have been described, but it is unclear if haplotypes formed by combinations of such variants correlate with FD, thus complicating molecular diagnosis in females with normal α-Gal-A activity. We tested 67 female probands with clinical manifestations that may be associated with FD and 110 control males with normal α-Gal-A activity. Five different combinations of GLA polymorphic variants were identified in 14 of the 67 females, whereas clearcut pathogenetic alterations, p.Met51Ile and p.Met290Leu, were identified in two cases. The latter has not been reported so far, and both mutant forms were found to be responsive to the pharmacological chaperone deoxygalactonojirimycin (DGJ; migalastat hydrochloride). Analysis of the male control population, as well as male relatives of a suspected FD female proband, permitted the identification of seven different GLA gene haplotypes in strong linkage disequilibrium. The identification of haplotypes in control males provides evidence against their involvement in the development of FD phenotypic manifestations.

Recurrent subarachnoid bleeding and superficial siderosis in a patient with histopathologically proven cerebral amyloid angiopathy.

A 68-year-old man with a history of hypertension presented with recurrent subarachnoid bleeding. Brain MRI showed superficial siderosis, and diagnostic cerebral angiograms did not show any intracranial vascular malformation or arterial aneurism. Post mortem neuropathological examination of the brain was consistent with a diagnosis of cerebral amyloid angiopathy. Clinicians should be aware that cerebral amyloid angiopathy should be considered in patients with unexplained recurrent subarachnoid bleeding, even in cases without familial clustering or transthyretin variant.