Thalamic altered spontaneous activity and connectivity in obstructive sleep apnea syndrome.

BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) syndrome is a sleep disorder characterized by excessive snoring, repetitive apneas, and nocturnal arousals, that leads to fragmented sleep and intermittent nocturnal hypoxemia. Morphometric and functional brain alterations in cortical and subcortical structures have been documented in these patients via magnetic resonance imaging (MRI), even if correlational data between the alterations in the brain and cognitive and clinical indexes are still not reported. METHODS: We examined the impact of OSA on brain spontaneous activity by measuring the fractional amplitude of low-frequency fluctuations (fALFF) in resting-state functional MRI data of 20 drug-naïve patients with OSA syndrome and 20 healthy controls matched for age, gender, and body mass index. RESULTS: Patients showed a pattern of significantly abnormal subcortical functional activity as compared to controls, with increased activity selectively involving the thalami, specifically their intrinsic nuclei connected to somatosensory and motor-premotor cortical regions. Using these nuclei as seed regions, the subsequent functional connectivity analysis highlighted an increase in patients' thalamocortical connectivity at rest. Additionally, the correlation between fALFF and polysomnographic data revealed a possible link between OSA severity and fALFF of regions belonging to the central autonomic network. CONCLUSIONS: Our results suggest a hyperactivation in thalamic diurnal activity in patients with OSA syndrome, which we interpret as a possible consequence of increased thalamocortical circuitry activation during nighttime due to repeated arousals.

Increasing volume and complexity of pediatric epilepsy surgery with stable seizure outcome between 2008 and 2014: A nationwide multicenter study.

OBJECTIVE: The objective of the study was to assess common practice in pediatric epilepsy surgery in Italy between 2008 and 2014. METHODS: A survey was conducted among nine Italian epilepsy surgery centers to collect information on presurgical and postsurgical evaluation protocols, volumes and types of surgical interventions, and etiologies and seizure outcomes in pediatric epilepsy surgery between 2008 and 2014. RESULTS: Retrospective data on 527 surgical procedures were collected. The most frequent surgical approaches were temporal lobe resections and disconnections (133, 25.2%) and extratemporal lesionectomies (128, 24.3%); the most frequent etiologies were FCD II (107, 20.3%) and glioneuronal tumors (105, 19.9%). Volumes of surgeries increased over time independently from the age at surgery and the epilepsy surgery center. Engel class I was achieved in 73.6% of patients (range: 54.8 to 91.7%), with no significant changes between 2008 and 2014. Univariate analyses showed a decrease in the proportion of temporal resections and tumors and an increase in the proportion of FCDII, while multivariate analyses revealed an increase in the proportion of extratemporal surgeries over time. A higher proportion of temporal surgeries and tumors and a lower proportion of extratemporal and multilobar surgeries and of FCD were observed in low (<50surgeries/year) versus high-volume centers. There was a high variability across centers concerning pre- and postsurgical evaluation protocols, depending on local expertise and facilities. SIGNIFICANCE: This survey reveals an increase in volume and complexity of pediatric epilepsy surgery in Italy between 2008 and 2014, associated with a stable seizure outcome.

Epilepsy surgery of "low grade epilepsy associated neuroepithelial tumors": A retrospective nationwide Italian study.

OBJECTIVE: To analyze the attitude and results of Italian epilepsy surgery centers in the surgical management of "low grade epilepsy associated neuroepithelial tumors" (LEATs). METHODS: We conducted a retrospective study enrolling 339 consecutive patients with LEATs who underwent surgery between January 2009 and June 2015 at eight Italian epilepsy surgery centers. We compared demographic, clinical, pathologic, and surgical features of patients with favorable (Engel class I) and unfavorable (Engel class II, III, and IV) seizure outcome. In addition, we compared patients with tumor-associated focal cortical dysplasia (FCD) and patients with solitary tumors to identify factors correlated with FCD diagnosis. RESULTS: Fifty-five (98.2%) of 56 patients with medically controlled epilepsy were seizure-free after surgery, compared to 249 (88.0%) of 283 patients with refractory epilepsy. At multivariate analysis, three variables independently predict unfavorable seizure outcome in the drug-resistant group. Age at surgery is largely the most significant (p = 0.001), with an odds ratio (OR) of 1.04. This means that the probability of seizure recurrence grows by 4% for every waited year. The resection site is also significant (p = 0.039), with a relative risk (RR) of 1.99 for extratemporal tumors. Finally, the completeness of tumor resection has a trend toward significance (p = 0.092), with an RR of 1.82 for incomplete resection. Among pediatric patients, a longer duration of epilepsy was significantly associated with preoperative neuropsychological deficits (p < 0.001). A statistically significant association was observed between FCD diagnosis and the following variables: tailored surgery (p < 0.001), temporal resection (p = 0.001), and surgical center (p = 0.012). SIGNIFICANCE: Our nationwide LEATs study gives important insights on factors predicting seizure outcome in refractory epilepsy and determining variability in FCD detection. Timely surgery, regardless of pharmacoresistance and oriented to optimize epileptologic, neuropsychological, and oncologic outcomes should be warranted.

Novel POLG mutations and variable clinical phenotypes in 13 Italian patients.

POLG gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA (mtDNA) replication and repair. Mutations in POLG have been linked to a spectrum of clinical phenotypes, resulting in autosomal recessive or dominant mitochondrial diseases. These mutations have been associated with heterogeneous phenotypes, presenting with varying severity and at different ages of onset, ranging from the neonatal period to late adult life. We screened 13 patients for POLG mutations. All patients underwent a complete neurological examination, and in most of cases, muscle biopsy was performed. We detected 15 different variations in 13 unrelated Italian patients. Two mutations were novel and mapped in the pol domain (p.Thr989dup and p.Ala847Thr) of the enzyme. We also report new cases carrying controversial variations previously described as incompletely penetrant or a variant of unknown significance. Our study increases the range of clinical presentations associated with mutations in POLG gene, underlining some peculiar clinical features, such as PEO associated with corneal edema, and epilepsy, severe neuropathy with achalasia. The addition of two new substitutions, including the second report of an in-frame duplication, to the growing list of defects increases the value of POLG genetic diagnosis in a range of neurological presentations.

Rhabdomyolysis in an elderly multitreated patient: multiple drug interactions after statin withdrawal.

Rhabdomyolysis precipitated by multitherapy is most frequently described during statin treatment, due to impairment of statin clearance by drugs sharing cytochrome P450 biotransformation pathway. Modulation of membrane transporters for drug efflux, operated by substrates, can also affect drugs' tissue levels. We report rhabdomyolysis in an elderly patient, in multitreatment with different potentially myotoxic medications, taking place seven months after atorvastatin discontinuation. Affected by ischaemic heart disease, arterial hypertension and dementia-related behaviour disturbances, the patient was receiving angiotensin 2-receptor inhibitors, beta-blockers, vasodilators, diuretics, salycilates, allopurinol, proton pump inhibitors, antipsychotics and antidepressants. He had taken atorvastatin for 14 years, with constantly normal creatine-kinase plasma levels. Two months after addition of the antianginal drug ranolazine, creatine-kinase mildly increased and atorvastatin was withdrawn. Nonetheless, creatine-kinase progressively rose, with severe weakness and rhabdomyolysis developing seven months later. Muscle biopsy showed a necrotizing myopathy with no inflammation or autoimmune changes. After ranolazine withdrawal, creatine-kinase and myoglobin returned to normal levels and strength was restored. Several psychotropic and cardiovascular medications prescribed to the patient share either cytochrome P450 biotransformation and permeability-glycoprotein efflux transport. In the event of cardiovascular/neuropsychiatric polypharmacy in geriatric patients, the risk of muscle severe adverse effects from pharmacokinetic drug-drug interaction should be considered beyond the direct myotoxicity of statins.

Altered cortical and subcortical local coherence in obstructive sleep apnea: a functional magnetic resonance imaging study.

Obstructive sleep apnea (OSA) syndrome is the most common sleep-related breathing disorder, characterized by excessive snoring and repetitive apneas and arousals, which leads to fragmented sleep and, most importantly, to intermittent nocturnal hypoxaemia during apneas. Considering previous studies about morphovolumetric alterations in sleep apnea, in this study we aimed to investigate for the first time the functional connectivity profile of OSA patients and age-gender-matched healthy controls, using resting-state functional magnetic resonance imaging (fMRI). Twenty severe OSA patients (mean age 43.2 ± 8 years; mean apnea-hypopnea index, 36.3 h(-1) ) and 20 non-apneic age-gender-body mass index (BMI)-matched controls underwent fMRI and polysomnographic (PSG) registration, as well as mood and sleepiness evaluation. Cerebro-cerebellar regional homogeneity (ReHo) values were calculated from fMRI acquisition, in order to identify pathology-related alterations in the local coherence of low-frequency signal (<0.1 Hz). Multivariate pattern classification was also performed using ReHo values as features. We found a significant pattern of cortical and subcortical abnormal local connectivity in OSA patients, suggesting an overall rearrangement of hemispheric connectivity balance, with a decrease of local coherence observed in right temporal, parietal and frontal lobe regions. Moreover, an increase in bilateral thalamic and somatosensory/motor cortices coherence have been found, a finding due possibly to an aberrant adaptation to incomplete sleep-wake transitions during nocturnal apneic episodes, induced by repetitive choke sensation and physical efforts attempting to restore breathing. Different hemispheric roles into sleep processes and a possible thalamus key role in OSA neurophysiopathology are intriguing issues that future studies should attempt to clarify.

Supratentorial neurenteric cyst associated with a intraparenchymal subependymoma.

Neurenteric cyst is a rare developmental lesion that very infrequently is localised supratentorially. Intraparenchymal subependymoma is an even more rare benign tumour. The authors report the case of a 45-year-old gentleman with a background of drug resistant epilepsy. An MRI was performed which showed a left frontal cystic lesion with a solid component. Histopathology confirmed a type C neurenteric cyst associated with an intraparenchymal subependymoma. Following enlargement of the lesion and worsening of symptoms he was referred to our institution for further management. A frontotemporal craniotomy was performed for excision of the lesion but recurrence occurred within 1 year. The lesion was further excised and 19 months post re-excision the patient is seizure free with no evidence of recurrence on MRI.

Transient periodic lateralised epileptiform discharges (PLEDs) following internal carotid artery stenting.

Background. Periodic lateralised epileptiform discharges (PLEDs) are EEG patterns consisting of periodic or pseudoperiodic unilateral, focal or hemispheric epileptiform discharges at a rate of 1-2 Hz. PLEDs may be triggered by acute brain injuries or systemic metabolic changes such as fever, hyperglycaemia or electrolyte imbalance and may result in disturbance of consciousness and/or neurological deficits. Case report. A 58-year-old female with a history of focal epilepsy and deep brain haematoma presented with acute change in awareness, associated with EEG evidence of PLEDs, three days after a left internal carotid artery stenting procedure. Clinical examination, laboratory testing and MRI were unchanged with respect to pre-stenting investigations. Conclusion. In this patient, PLEDs may have been triggered by local haemodynamic changes due to reperfusion after stenting in a previously damaged brain area.

The ethics of pain clinical trials on persons lacking judgment ability: much to improve.

AIM: People lacking judgmental ability (newborn infants [NIs] and persons with mental impairment [PMI]) are reported to receive less analgesic treatments than people who can give adequate informed consent. We performed the present study to assess whether this also happens in clinical trials that should statutorily guarantee basic patients' rights. We examined those trials in which patients undergo painful minor procedures (PMP) because these procedures are frequent and severely stressful for NI and PMI. MATERIALS AND METHODS: We performed a Medline search to retrieve the studies published in 2009 and 2010, in which NI and PMI underwent PMP. RESULTS: We retrieved 46 studies that exposed NI to PMP; only in 14.2% of the studies, a validated analgesic treatment was administered to the control group. We retrieved only one article where PMP was performed in PMI for clinical reasons (venipuncture); in 13 more studies, pain was experimentally provoked by noxious stimuli such as heat, electricity, or arm mobilization. All these studies were not performed to evaluate a possible analgesic strategy but to assess PMI's pain responsiveness and no analgesia was used. CONCLUSION: PMI and NI enrolled in clinical trials as controls rarely receive analgesia; and few studies exist to find out analgesic treatments shaped on PMI's exigencies. These data raise concern about the actual guarantees for persons lacking judgmental ability enrolled in potentially painful trials. We also recommend more effort to find out analgesic treatments tailored to the specific exigencies of PMI.

Autonomic activity and baroreflex sensitivity in patients submitted to carotid stenting.

Arterial baroreflex and cardiac autonomic control play important roles in hemodynamic instability after carotid artery stenting (CAS). Spontaneous baroreflex sensitivity (BRS), heart rate variability (HRV) and blood pressure variability (BPV) are established tools for the assessment of arterial baroreflex and cardiac autonomic activity. Aim of the study was to evaluate cardiac autonomic activity (by means of HRV, BPV and BRS) after CAS and to explore the impact of internal carotid artery stenosis on BRS changes after CAS. 37 patients (68±10.45 years) with internal carotid stenosis underwent CAS. HRV, BPV and BRS were measured in all subjects before and at 1 and 72h after CAS. ANOVA was performed to compare BRS, HRV and BPV parameters before and after CAS. Spearman analysis was performed to determine a possible correlation between carotid stenosis degree (or carotid plaque diameter) and BRS changes (ΔBRS). LF/HF (index of sympatho-vagal balance) decreased during postoperative period, in comparison with baseline (2.32±1.70 vs 1.65±1.40, p<0.05). There was a significant negative correlation between carotid stenosis degree and ΔBRS (r=-0.35, p=0.03) and between carotid plaques thickness and ΔBRS (r=-0.36, p=0.02). CAS procedure may cause an alteration of carotid wall mechanical properties, increasing baroreflex sensitivity. BRS does not increase in all the patients, because arterial wall damage and nerve destruction determined by atherosclerotic plaque may reduce ΔBRS.

A novel point mutation in the mitochondrial tRNA((Trp)) gene produces late-onset encephalomyopathy, plus additional features.

BACKGROUND: Mitochondrial diseases due to mitochondrial tRNA genes mutations are usually multisystem disorders with infantile or adult onset. OBJECTIVE: To identify the molecular defect underlying a mitochondrial encephalomyopathy. METHODS/PATIENTS: Case report of a 51year-old woman presenting with late-onset myoclonic epilepsy plus additional features. Proband's mother presented hypothyroidism and diabetes. RESULTS: Muscle biopsy showed mitochondrial changes. Respiratory chain activities were reduced. The novel G5538A mutation was identified in different tissues DNAs from the proband and from her mother. CONCLUSION: We were able to identify a novel mtDNA tRNA((Trp)) gene pathogenic mutation.

Hypnotizability-related EEG alpha and theta activities during visual and somesthetic imageries.

Hypnotizability is a cognitive multidimensional trait that involves peculiar imagery characteristics. Subjects with high- (Highs) and low (Lows)-susceptibilities to hypnosis have shown different levels of skill at visual and somesthetic-guided imageries performed during upright stance. The aim of this experiment is to study the modulation of the EEG alpha and theta band amplitude during guided visual and somesthetic imageries in Highs and Lows, as these rhythms are responsive to the cognitive activities involved in mental imagery. Our results show that, at variance with standing subjects, subjects in both groups in a semi-reclined position report higher vividness and lower effort for visual than for somesthetic imagery. EEG patterns however are different between the two groups. Highs exhibit a more widespread alpha desynchronization and slightly different EEG patterns during visual and somesthetic imageries, while Lows show segregated alpha- and theta-desynchronization, without any difference between the tasks. Our results indicate that different, hypnotizability-related cognitive strategies, that are revealed by differences in EEG modulation, are responsible for the similar subjective experience associated with visual and somesthetic imageries in Highs and Lows. In addition, in both groups higher order mental representation of different sensory modalities might be subserved by a unique integrated neural network.

Intracranial and intraspinal hemorrhage following spinal anesthesia.

Spinal anesthesia (SA), accounting for more than 50% of regional anesthesias in the spinal region, is generally perceived as simple and safe. Our purpose is to increase awareness of hemorrhagic complications following SA. A 69-year-old male without either coagulation disorders or anticoagulant/antiplatelet therapy developed acute radiculopathy, and severe mental confusion after SA for prostatectomy. CT showed intracranial subarachnoid and intraventricular acute hemorrhage. Cerebral angiography was negative. MRI showed subarachnoid and subdural hematoma in the dorsolumbar spine. Seven-year follow-up showed permanent cognitive and radicular damage. Multiple attempts for SA most likely caused spinal vessels rupture, either directly or indirectly by inducing differential pressure changes between cerebrospinal fluid and intravascular spaces; however, definite mechanisms have not been completely understood. Patients undergoing spinal puncture must report any neurological abnormality, which may result in irreversible damage. Cases of altered consciousness require an extensive neuroradiological evaluation. Proper competency of physicians responsible for spinal puncture is mandatory.

Postictal serum nucleotidases activities in patients with epilepsy.

Adenosine, a potent anticonvulsant, can be produced in the body by the hydrolysis of adenine nucleotides through the action of ecto- or soluble nucleotidases. Changes in nucleotide hydrolysis occur after pentylenetetrazol-induced epileptic events. We evaluated serum ATP, ADP and AMP hydrolysis rates and soluble nucleotide phosphodiesterase (PDEase) activity at 5, 10, 15, 30 and 60 min, and 12h following an epileptic event. Fifteen patients (seven female, eight male; mean age 15.5 years) were included in the study. The type of seizure was generalized in four patients and was localization related in the remaining 11. There were no differences in adenine nucleotide hydrolysis rates between patients and healthy subjects in the interictal stage. In comparison with controls, ATP, ADP and AMP hydrolysis rates were significantly increased at 5 min (53+/-1.4%, 79.2+/-2.8% and 37.0+/-2.6%, respectively) and up to 30 min following the epileptic event. In contrast to ADP and AMP, ATP hydrolysis remained significantly increased at 60 min (71.4+/-1.6%), returning to the basal level after 12h. Serum PDEase activity was also significantly higher in the patients than in healthy subjects, peaking at 15 min (61+/-2.9%) and remaining significantly increased up to 60 min (4.6+/-1.2%) following the epileptic episode. Globally, the variations in the postictal serum ADP hydrolysis rate almost overlapped those of AMP hydrolysis, whereas changes in the ATP hydrolysis rate overlapped those of PDEase activity. The clinical significance of this elevation in postictal soluble serum nucleotidase activity remains to be clarified. However, it is possible to hypothesize that the higher nucleotidase activity might play a role in the modulation of epileptic events.

Obstructive sleep apnea syndrome: a cause of acute delirium.

Delirium is a transient global disorder of cognition related to a variety of structural or functional neural disorders. Descriptions and characterizations of delirium associated with obstructive sleep apnea syndrome (OSAS) are rare. We describe a 52-year-old man with severe OSAS associated with sudden onset of delirium and with a fluctuating nighttime course, prolonged for several days. The delirium disappeared after treatment with continuous positive airway pressure (CPAP). The patient remained free of symptoms under CPAP during a follow-up of 8 years.

Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study.

STUDY OBJECTIVES: To verify the existence of a symptomatic form of restless legs syndrome (RLS) secondary to multiple sclerosis (MS) and to identify possible associated risk factors. DESIGN: Prospective, multicenter, case-control epidemiologic survey. SETTINGS: Twenty sleep centers certified by the Italian Association of Sleep Medicine. PATIENTS: Eight hundred and sixty-one patients affected by MS and 649 control subjects. INTERVENTIONS: N/A. MEASURES AND RESULTS: Data regarding demographic and clinical factors, presence and severity of RLS, the results of hematologic tests, and visual analysis of cerebrospinal magnetic resonance imaging studies were collected. The prevalence of RLS was 19% in MS and 4.2% in control subjects, with a risk to be affected by RLS of 5.4 (95%confidence interval: 3.56-8.26) times greater for patients with MS than for control subjects. In patients with MS, the following risk factors for RLS were significant: older age; longer MS duration; the primary progressive MS form; higher global, pyramidal, and sensory disability; and the presence of leg jerks before sleep onset. Patients with MS and RLS more often had sleep complaints and a higher intake of hypnotic medications than patients with MS without RLS. RLS associated with MS was more severe than that of control subjects. CONCLUSIONS: RLS is significantly associated with MS, especially in patients with severe pyramidal and sensory disability. These results strengthen the idea that the inflammatory damage correlated with MS may induce a secondary form of RLS. As it does in idiopathic cases, RLS has a significant impact on sleep quality in patients with MS; therefore, it should be always searched for, particularly in the presence of insomnia unresponsive to treatment with common hypnotic drugs.