Irene Aricò

Sleep disorders in children with Attention-Deficit/Hyperactivity Disorder (ADHD) recorded overnight by video-polysomnography

OBJECTIVE To outline specific sleep disturbances in different clinical subsets of Attention Deficit/Hyperactivity Disorder (ADHD) and to confirm, by means of nocturnal video-polysomnography (video-PSG), a variety of sleep disorders in ADHD besides the classically described periodic leg movement disorder (PLMD), restless legs syndrome (RLS) and sleep related breathing disorder (SRBD). METHODS Fifty-five ADHD children (47 M, 8F; mean age=8.9 y) were included: 16 had Inattentive and 39 Hyperactive/Impulsive or Combined ADHD subtype. Behavior assessment by Conners and SNAP-IV Scales, a structured sleep interview and a nocturnal video-PSG were administered. RESULTS Most children/parents reported disturbed, fragmentary sleep at night; complaints were motor restlessness (50%), sleep walking (47.6%), night terrors (38%), confusional arousals (28.5%), snoring (21.4%), and leg discomfort at night associated with RLS (11.9%). There is a significant difference (p value <0.05 or <0.001) in almost all the studied sleep variables between ADHD children and controls. International RLS Rating Scale scoring, Periodic Limb Movements during Sleep (PLMS) and Wake (PLMW) indexes, hyperactivity and opposition scores and ADHD subtype appear related. Different sleep disorders seem to address specific ADHD phenotypes and correlate with severity of symptoms as in sleep related movement disorders occurring in Hyperactive/Impulsive and Combined ADHD subtypes. Besides, an abnormality of the arousal process in slow wave sleep with consequent abnormal prevalence of disorders of arousal possibly enhanced by SRBD has also been detected in 52% of our sample. CONCLUSIONS This study underlines the opportunity to propose and promote the inclusion of sleep studies, possibly by video-PSG, as part of the diagnostic screening for ADHD. This strategy could address the diagnosis and treatment of different specific ADHD phenotypic expressions that might be relevant to childrens symptoms and contribute to ADHD severity.

Ictal and interictal EEG abnormalities in ADHD children recorded over night by video-polysomnography

In this paper we explore the prevalence of ictal and interictal epileptiform discharges (IEDs) and sleep disorders in ADHD children referred to a sleep clinic for all night video-PSG. Forty-two ADHD outpatients (35 males and 7 females) underwent video-PSG and a behavioural/neuropsychological assessment. Spearman correlation coefficients (p<0.05 criterion level) were used to assess the association between cognitive, behavioural, clinical (co-morbidity), sleep (sleep efficiency) and EEG (seizures, IEDs, localization of IEDs foci) variables. Sleep disorders were found in 86% of ADHD children; among these, 26% had RLS. 53.1% of ADHD children had IEDs (28.2% centro-temporal spikes, 12.5% frontal spikes, 9.3% temporal-occipital spikes and 2.3% generalized S-W). Nocturnal seizures were recorded in three patients: two with atypical interictal rolandic spikes and one with left frontal slow abnormalities. A significant relationship (p<0.05) emerges between nocturnal seizures and WISC-R IQ score and visual-spatial memory test and between some cognitive variables and interictal rolandic spikes. High levels of inattention, impulsivity/hyperactivity and oppositional behaviours were related (p<0.01 or 0.05) with Restless Leg Syndrome diagnosis. In conclusion, ADHD is a condition often associated with EEG epileptiform abnormalities. Seizures/IEDs presence seems to play a role on cognitive abilities, conversely sleep disorders have a stronger impact on behavioural rather than cognitive indicators.

Dopamine agonists restore cortical plasticity in patients with idiopathic restless legs syndrome.

In the present work, we aimed at assessing whether patients with idiopathic restless legs syndrome (RLS) showed alterations of sensory‐motor plasticity, an indirect probe for motor learning, within the motor cortex (M1). Previous findings suggest that learning in human M1 occurs through LTP‐like mechanisms. To test our hypothesis, we employed the paired associative stimulation (PAS) protocol by transcranial magnetic stimulation (TMS), which is able to induce LTP‐like effects in the motor cortex of normal subjects. Twelve patients with idiopathic RLS and 10 age‐ and sex‐matched control subjects were recruited. PAS protocol consisted of 0.05 Hz electrical median nerve stimulation (90 stimuli), paired with 0.05 Hz TMS (90 stimuli) over the hot spot for stimulating the abductor pollicis brevis (APB) muscle given 25 milliseconds after the onset of the electrical stimulus. Corticospinal excitability recorded in APB muscle, as indexed by MEP obtained after single stimulus, was tested before and up to 30 minutes after PAS protocol. Eight of 12 patients were studied before and after 4 weeks of dopaminergic treatment. PAS protocol increased significantly corticospinal excitability as long as 30 minutes in healthy subjects. On the contrary, PAS protocol did not change the amplitude of MEPs in patients with idiopathic RLS without treatment. PAS associative plasticity was restored after 4 weeks of dopaminergic treatment. Our data demonstrated that associative sensory‐motor plasticity, an indirect probe for motor learning, is impaired in idiopathic RLS patients but may be reverted to normal after dopaminergic treatment.

Impairment of sensory-motor integration in patients affected by RLS

Much evidence suggests that restless legs syndrome (RLS) is a disorder characterized by an unsuppressed response to sensory urges due to abnormalities in inhibitory pathways that specifically link sensory input and motor output. Therefore, in the present study, we tested sensory-motor integration in patients with RLS, measured by short latency afferent inhibition (SAI) and long latency afferent inhibition (LAI). SAI and LAI were determined using transcranial magnetic stimulation before and after 1month of dopaminergic treatment in RLS patients. Ten naïve patients with idiopathic RLS and ten healthy age-matched controls were recruited. Patients with secondary causes for RLS (e.g. renal failure, anaemia, low iron and ferritin) were excluded, as well as those with other sleep disorders. Untreated RLS patients demonstrated deficient SAI in the human motor cortex, which proved revertible toward normal values after dopaminergic treatment. We demonstrated an alteration of sensory-motor integration, which is normalized by dopaminergic treatment, in patients affected by RLS. It is likely that the reduction of SAI might contribute significantly to the release of the involuntary movements and might account for the sensory urge typical of this condition.

Nocturnal frontal lobe epilepsy presenting with restless leg syndrome-like symptoms.

We describe the case of a 22-year-old male affected by NFLE reporting paroxysmal RLS-like symptoms. The patient was referred to our Sleep Center due to nocturnal paresthesias and cramps involving the left leg and leading to sleep fragmentation. At age 4, the patient presented with secondary generalized seizures preceded by left leg discomfort, controlled on CBZ. After successive therapy discontinuation, leg symptoms built up in frequency and duration until a secondary generalized seizure re-occurred. On CBZ prompt resumption no further GM seizures occurred albeit persistence of night-time frequent cramps and paraesthesia. Sleep EEG demonstrated asymmetric interictal sharp theta on the right posterior frontal areas, whereas brain MRI results were consistent with a Taylor type right frontal cortical dysplasia. CBZ augmentation and add on therapy with LEV led to further frequency reduction of sensory symptoms.

Could combined sleep and pain evaluation be useful in the diagnosis of disorders of consciousness (DOC)? Preliminary findings

Abstract Background: The diagnosis of Disorders of Consciousness (DOC) is still challenging. Indeed, ~ 40% of patients in vegetative state (VS) are misdiagnosed, suggesting the need of more appropriate diagnostic tools. Emerging data are showing that EEG, including sleep structure evaluation and multimodal evoked potential recording could be helpful in DOC diagnosis. Moreover, pain perception evaluation could further increase diagnosis accuracy in such individuals. Methods: Fourteen individuals with DOC, due to severe brain injury, were enrolled and admitted to the Intensive Neurorehabilitation Unit of the Research Institute. All patients were evaluated by means of the Coma Recovery Scale-Revised, a 24hh-polysomnography and a Laser Evoked Potential (LEP) paradigm. Results: Clinically-defined patients in Minimally Consciousness State showed a more preserved sleep structure, physiologic hypnic figures and preserved REM/NREM sleep distribution than subjects in VS. LEP showed increased latencies and reduced amplitudes and were also detectable in patients with more structured sleep. Conclusions: The data support previous findings concerning the importance of sleep study in DOC diagnosis, with more specific neurophysiological paradigms. Interestingly, the findings shed some light on the possible correlations among global brain connectivity, sleep structure and pain perception, which are related to the activity of the wide thalamo-cortical and cortico-cortical networks underlying consciousness.

Repetitive transcranial magnetic stimulation induced slow wave activity modification: A possible role in disorder of consciousness differential diagnosis?

Slow wave activity (SWA) generation depends on cortico-thalamo-cortical loops that are disrupted in patients with chronic Disorders of Consciousness (DOC), including the Unresponsive Wakefulness Syndrome (UWS) and the Minimally Conscious State (MCS). We hypothesized that the modulation of SWA by means of a repetitive transcranial magnetic stimulation (rTMS) could reveal residual patterns of connectivity, thus supporting the DOC clinical differential diagnosis. We enrolled 10 DOC individuals who underwent a 24hh polysomnography followed by a real or sham 5Hz-rTMS over left primary motor area, and a second polysomnographic recording. A preserved sleep-wake cycle, a standard temporal progression of sleep stages, and a SWA perturbation were found in all of the MCS patients and in none of the UWS individuals, only following the real-rTMS. In conclusion, our combined approach may improve the differential diagnosis between MCS patients, who show a partial preservation of cortical plasticity, and UWS individuals, who lack such properties.

Transient awakening from vegetative state: is high-dose zolpidem more effective?

EOSINOPHILIA IS A condition in which the eosinophil count in the peripheral blood exceeds 0.45 × 10/L (450/ μl). Almost all types of blood dyscrasia have been reported for clozapine, among which agranulocytosis is the most serious. It was demonstrated that clozapine induces oxidative stress in neutrophils, which may trigger agranulocystosis. However, little is known about mechanisms underlying other types of blood dyscrasia. There are two major pathways that mediate eosinophilia: (i) cytokine-mediated increased differentiation and survival of eosinophils (extrinsic eosinophilic disorders); and (ii) mutation-mediated clonal expansion of eosinophils (intrinsic eosinophilic disorders). Systemic causes include: allergic disorders, parasitic infections, some forms of malignancy, systemic autoimmune diseases, some forms of vasculitis (e.g. Churg–Strauss syndrome), cholesterol embolism, coccidioidomycosis, interstitial nephropathy and hyperimmunoglobulin E syndrome. Drug hypersensitivity reactions are a common cause of eosinophilia, ranging from rash to severe life-threatening drug reactions with eosinophilia and systemic symptoms (DRESS). Drugs that have been shown to cause DRESS are anticonvulsants and antipsychotics. A case of rapidly developing and self-limiting clozapineinduced eosinophilia in 34-year-old man with schizophrenia is presented. He was treated with clozapine due to ineffectiveness and extrapyramidal symptoms associated with previous antipsychotics (quetiapine, olanzapine, amisulpride, aripiprazole). Before treatment with clozapine, complete blood count and regular biochemistry tests were all normal. After 22 days of treatment with clozapine (dose 200 mg/day), eosinophilia (3.18 × 10/L) was found, which rapidly increased to 7.79 × 10/L after another 4 days (dose 225 mg/day) and slowly returned to normal (0.51 × 10/L) within 16 days. There were no other signs or symptoms. Regular and additional blood tests (electrolytes, C-reactive protein, lipid profile, glucose, total bilirubin, creatinine, creatine kinase, urea, transaminases, vitamin B12, urinalysis, total immunoglobulin (Ig)E, toxocarosis and toxoplasmosis IgM antibodies) revealed no potential causes. Apart from accessory spleen, abdominal ultrasound was normal. Chest X-ray was normal. Electrocardiogram was without pathological changes. Stool ova and parasite exam and stool culture were normal. After excluding other causes, it was decided that eosinophilia was induced by clozapine, but as similar cases were previously described as self-limiting, we decided to continue clozapine with a 200-mg daily dose and clinical symptoms improved. No recurrence of eosinophilia was observed during further treatment. The patient continues to take a 200-mg daily dose of clozapine and his condition remains stable. Using the Naranjo Adverse Drug Reaction probability scale, a score of 6 was found (a probable adverse reaction to the drug). Clinicians should be cautious about clozapine-induced eosinophilia, as it may be associated with severe treatmentinduced consequences (myocarditis, colitis, pleural effusions). In some cases, treatment may be continued, but careful monitoring is always required.

Sleep Disorders Diagnosis and Management in Children with Attention Deficit/Hyperactivity Disorder (ADHD)

ADHD is an increasingly prevalent developmental disorder, especially in the western world where prevalence rates are estimated around 12%. According to both the DSM-IV and the ICD-10 it refers to three major problematic domains: attention, hyperactivity and impulsivity. Subtypes of ADHD have been coded accordingly as a predominantly hyperactive-impulsive type (H), predominantly inattentive (I) and a combined type (C). Age is an important factor in the clinical/behavioral manifestations of ADHD. Symptoms, in fact, vary according to brain maturation. The hyperactive aspects, for instance, tend to subside with age, even if longitudinal research demonstrated that over 30% of children with ADHD grow up to be adults with significant ADHD related problems. Gender also plays an important role in ADHD, with a 1:10 male prevalence in clinical samples (Cortese et al., 2006). It also appears to have a strong influence over behavioral symptoms and co-morbid disorders, which appear generally less disruptive in girls. ADHD holds a high potential for psychiatric and cognitive co-morbidity (mood, anxiety, conduct disorder and learning disability), with a nearly 50% rate of oppositional defiant conduct in males.

Sleep in Children with Psychiatric and Behavioral Problems

Sleep is commonly affected in psychiatric and behavioral pediatric disorders, contributing to children’s disability and parental burden. Difficulties initiating and maintaining sleep, often non-restorative in quality, frequent parasomnias, such as disorders of arousals, enuresis, and nightmares; sleep-related movement disorders such as bruxism, restless legs syndrome (RLS), and periodic limb movement during sleep (PLMS); snoring; and sleep apnea may all interfere with sleep consolidation and daytime performance both at school and daycare. Alterations of slow-wave sleep (SWS), both in terms of macro- and microstructural aspects, are common to almost all disorders, whereas rapid eye movement (REM) sleep is more impacted by mood and autism spectrum disorders (ASDs), often correlating with relational and emotional profiles rather than with cognitive problems. In said disorders, subjective complaints always override objective findings from all-night actigraphic or polysomnographic (PSG) recordings. In particular, sleep latency (SL) and total sleep time (TST) are severely affected only in the acute manic and psychotic phases and in early ASDs, whereas infranight awakenings and slow-wave sleep (SWS) fragmentation appear to be the hallmarks of these disorders, reflecting an impaired maturational process affecting mostly the frontal lobes and their connectivity.