Pathophysiology of Rett syndrome

Rett syndrome is a distinct clinical entity with an unknown cause. In previous publications we stressed the age related sequential appearance of pathognomonic symptoms of Rett syndrome and suggested the early central monoaminergic deficiency disorder as the pathophysiology. In this report we present a series of cinefilms made of one patient at different ages which clearly show the age dependent changes of motor disturbances. Furthermore, the record of sleep-wakefulness rhythm and the series of polysomnography of another patient who was on L-DOPS are presented. The results of sleep studies again confirm the early involvement of the noradrenergic and serotonergic systems and relatively early development of postsynaptic supersensitivity of the dopaminergic system. The possibility of the involvement of the cholinergic system is also suggested. The summary of the sensory evoked potentials (SEP) performed on six patients is also presented and the pathomechanism of cortical involvement is discussed. Based on these new and past findings, we confirm our speculation on the pathophysiology. The basic mechanism is probably the deficient states of the monoaminergic systems occurring at a very early developmental stage. These derangements occurring at an early stage cause serious abnormality in the higher centers during development. The striking age dependent clinical manifestations and measurable physiological parameters are the reflexion of the underlying patho-physiology of Rett syndrome.     

Rett syndrome—An early catecholamine and indolamine deficient disorder?

The results of clinical and polysomnographical examinations on 11 Japanese Rett syndrome cases were summarized to substantiate further our previous results regarding the pathophysiology of the disease. It was concluded that the disease starts early in infancy and takes a progressive course. Each characteristic symptom appears in an orderly sequence which is thought to reflect the sequential systemic involvement of certain neuronal systems. Based on the characteristic symptoms and signs, and polysomnographical studies, we speculated that the initial lesion was the locus coeruleus with a hypoactive noradrenergic system combined with other hypoactive monoaminergic systems, including those of serotonin and dopamine, occurring along with the early developmental course. In later stages, hyperfunction possibly due to postsynaptic supersensitivity of the dopamine system causes the characteristic symptoms of the Rett syndrome.     

Beyond standard polysomnography: Advantages and indications for use of extended 10–20 EEG montage during laboratory sleep study evaluations

PurposeStandard polysomnography (PSG) typically utilizes 4–6 channels of electroencephalography (EEG), which is inadequate to evaluate focal epileptiform activity. Though technical capability has long existed for more extensive EEG recording, few sleep laboratories have utilized this technique. The objective of this study was to determine the utility of combining PSG with 18-channel EEG in select patients with paroxysmal nocturnal events or other symptoms concerning for sleep disorders, nocturnal seizures or both.MethodsConsecutive combined PSG–EEG studies (n = 237) were performed between 10/1/2005 and 8/1/2009. Demographics, referral source, indications, and results were reviewed and analyzed.ResultsOf the 237 consecutive combined PSG–EEG studies performed, 93% revealed the presence of a primary sleep disorder, 38% were shown to have abnormal EEGs, and 37% had both. Among the 221 subjects (93%) shown to have sleep disorders, the majority of these cases were obstructive sleep apnea (OSA) 89%, followed by periodic limp movements of sleep (PLMS) 22% and rapid eye movement behavior disorder (RBD) 6%. Significantly more patients with known epilepsy were diagnosed with OSA then were patients without a seizure history.ConclusionsCombined PSG–EEG, utilizing 18-channel EEG, is an under-utilized technique which can assist in diagnosing paroxysmal nocturnal events, and differentiate between the presence of a primary sleep disorder, seizure activity, or both. Our study further illustrates the importance of considering sleep disorders in epilepsy patients.     

Clinical features of the early stage of the Rett syndrome.

Our previous reports have pointed out that the Rett syndrome (RS) starts from early infancy with autistic behavior and muscle hypotonia, and we have raised the hypothesis in regard to the pathophysiology that RS can be an early developmental disorder of the monoaminergic and indolamine systems. This paper presents the reanalysis of early motor and behavioral features performed on 16 patients. The most frequent complaint was developmental delay, but 2 cases were presented with autistic behaviors. Development showed delay even from head control. Crawling was particularly difficult. Muscle hypotonia was present in all cases. Early autistic behaviors were seen in high degree and the most frequent was the pervasive lack of social association. Autistic behaviors characterizing older autism were seen in various degrees. These findings reconfirm our previous reports and hypothesis. Furthermore, it can be suggested that the onset may even be in the fetal stage and that lesions of specific neuronal systems occurring in early ontogeny could result in specific abnormality in the higher system which manifest later in development, after these structures reach certain levels of maturation.     

Natural history of Rett syndrome

Rett syndrome is a unique neurodevelopmental disorder, with onset of hypotonia, autistic tendency, and abnormalities of fine finger movements and gross movements of the arms in early infancy. Clinical features include specific age-dependent symptoms. Studies of early and late signs correlated locomotive dysfunction to language disability and stereotypy to regression of higher cortical functions. Studies of sleep parameters revealed early hypofunction of brainstem aminergic neurons and late occurrence of hypofunction of dopaminergic neurons, followed by receptor supersensitivity. The syndrome's pathophysiology suggests that early hypofunction of aminergic neurons interferes with the development of higher neuronal systems. Particular symptoms surface at different ages throughout the natural course of Rett syndrome, with regressional and static periods.     

EEG and evoked potentials in infantile neuronal ceroid-lipofuscinosis

Sixteen children with infantile neuronal ceroid-lipofuscinosis (INCL), age range 0.5 to 5.4 years, were studied using EEG, electroretinograms (ERG), visual evoked potentials (VEP) and somatosensory evoked potentials (SEP).
Electroencephalography was the first of these examinations to reveal abnormalities, however the EEG may be normal at the preclinical stage. The first abnormality to appear was an attenuated reaction to passive eye opening and closing which was followed by disturbances in background activity and diminution in amplitude, and by disappearance of sleep spindles. The gradual disappearance of posterior rhythm reactivity and of sleep spindles suggests that thalamic dysfunction progresses with time. EEG inactivity appeared by the age of 3 years. Evoked potentials were normal in the early stages of the disease. SEP showed abnormalities at Stage 2 (1.7 years), while ERG and VEP abnormalities appeared at Stage 3 (by the age of 2.5 years). All neurophysiologies! reactions examined were abolished by the age of 4 years. Follow-up EEG gives important hints as to the early diagnosis of INCL. Progression of the disease can be followed by evoked potentials which may also be helpful in the differential diagnostics.     

CAP variables and arousals as sleep electroencephalogram markers for primary insomnia.

OBJECTIVE: Polysomnographic (PSG) measures consistently reflect poor sleep quality and effective treatment in insomniac patients. METHODS: The PSG findings of 47 patients (18 M and 29 F, 42.5+/-10 years) meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for a diagnosis of primary insomnia were compared with those of 25 age- and gender-balanced healthy subjects (controls) without sleep complaints. After one adaptation night to the sleep lab, each patient underwent two randomized double-blind PSG recordings. Twenty-four patients followed a placebo-drug sequence and 23 a drug-placebo succession. Active treatment consisted of widely used hypnotic drugs, i.e. zolpidem, triazolam, zopiclone, brotizolam. Conventional PSG measures, electroencephalogram (EEG) arousals and CAP variables (including phase A subtypes) were quantified and statistically analyzed. RESULTS: Compared to controls, insomniac patients under placebo showed a significant increase of CAP rate, subtypes A1 and A2, EEG arousals, nocturnal wakefulness and stage 1, associated with reduced values of total sleep time and slow wave sleep (stages 3 and 4). In insomniac patients, sleep quality was significantly improved by hypnotic treatment. Compared to placebo, active medication significantly reduced CAP rate, subtypes A1 and A2, but had only marginal effects on subtypes A3 and on EEG arousals. Under hypnotic treatment total sleep time, nocturnal awakenings, stage 1 and slow wave sleep recuperated normal values. The most significant correlation between sleep quality and PSG variables was found for CAP rate (P<0.0001). CONCLUSIONS: PSG investigation extended to CAP variables and EEG arousals can be an important procedure for the diagnosis of primary insomnia and evaluation of treatment efficacy.     

Human sleep EEG analysis using the correlation dimension.

Sleep electroencephalograms (EEG) were analyzed by non-linear analysis. Polysomnography (PSG) of nine healthy male subjects was analyzed and the correlation dimension (D2) was calculated. The D2 characterizes the dynamics of the sleep EEG, estimates the degrees of freedom, and describes the complexity of the signal. The mean D2 decreased from the awake stage to stages 1, 2, 3 and 4 increased during rapid eye movement (REM) sleep. The D2 during each REM sleep stage were high and those during each slow wave sleep stage were low, respectively, for each sleep cycle. The mean D2 of the sleep EEG in the second half of the night was significantly higher than those in the first half of the night. Significant changes were also observed during sleep stage 2, but were not seen during REM sleep and sleep stages 3 and 4. The D2 may be a useful method in the analysis of the entire sleep EEG.     

抑郁症及其亚型的睡眠脑电图研究

目的 探讨抑郁症患者睡眠脑电图的异常改变以及抑郁闰不同亚型之间的差异。方法 采用日本光电ＲＭ－６０００多导生理记录仪,对１８例抑郁症患者和１９名健康人进行睡眠脑电图检查。结果 与对照组比较,抑郁症组出现明显的醒觉时间增多、睡眠总时间减少、晒起时间增加、睡眠效率下降、睡眠维持率下降、第一阶段睡眠百分比增加、快速眼球运动（ＲＥＭ）潜代期缩短和ＲＥＭ密度增加,经统计学处理差异均有显著性（Ｐ〈０．０５）。     

A rule-based automatic sleep staging method

In this paper, a rule-based automatic sleep staging method was proposed. Twelve features including temporal and spectrum analyses of the EEG, EOG, and EMG signals were utilized. Normalization was applied to each feature to eliminating individual differences. A hierarchical decision tree with fourteen rules was constructed for sleep stage classification. Finally, a smoothing process considering the temporal contextual information was applied for the continuity. The overall agreement and kappa coefficient of the proposed method applied to the all night polysomnography (PSG) of seventeen healthy subjects compared with the manual scorings by R&K rules can reach 86.68% and 0.79, respectively. This method can integrate with portable PSG system for sleep evaluation at-home in the near future.     

MeCP2+/- mouse model of RTT reproduces auditory phenotypes associated with Rett syndrome and replicate select EEG endophenotypes of autism spectrum disorder

Impairments in cortical sensory processing have been demonstrated in Rett syndrome (RTT) and Autism Spectrum Disorders (ASD) and are thought to contribute to high-order phenotypic deficits. However, underlying pathophysiological mechanisms for these abnormalities are unknown. This study investigated auditory sensory processing in a mouse model of RTT with a heterozygous loss of MeCP2 function. Cortical abnormalities in a number of neuropsychiatric disorders, including ASD are reflected in auditory evoked potentials and fields measured by EEG and MEG. One of these abnormalities, increased latency of cortically sourced components, is associated with language and developmental delay in autism. Additionally, gamma-band abnormalities have recently been identified as an endophenotype of idiopathic autism. Both of these cortical abnormalities are potential clinical endpoints for assessing treatment. While ascribing similar mechanisms of idiopathic ASD to Rett syndrome (RTT) has been controversial, we sought to determine if mouse models of RTT replicate these intermediate phenotypes. Mice heterozygous for the null mutations of the gene MeCP2, were implanted for EEG. In response to auditory stimulation, these mice recapitulated specific latency differences as well as select gamma and beta band abnormalities associated with ASD. MeCP2 disruption is the predominant cause of RTT, and reductions in MeCP2 expression predominate in ASD. This work further suggests a common cortical pathophysiology for RTT and ASD, and indicates that the MeCP2+/- model may be useful for preclinical development targeting specific cortical processing abnormalities in RTT with potential relevance to ASD.     

Electroencephalogram abnormalities in patients with NREM parasomnias

ObjectiveElectroencephalographic (EEG) changes in patients with NREM parasomnias (NRP) occur in sleep architecture as changes in slow wave sleep or cyclic pattern, which are not considered abnormal. However, abnormalities in EEG in these patients have recently been reported, indicating that EEG patterns in NRPs are not definitive. Moreover, most of the polysomnography (PSG) findings in NRP patients were reported in the adult population requiring data from pediatric population to avoid bias in conclusion.MethodsIn sum, 39 patients with a NRP were undergone comprehensive assessments including a PSG with additional EEG montages. EEG recordings were evaluated in patients without a history of epilepsy and further compared between pediatric and adult patients.ResultsTwenty-three (59%) of the patients were pediatric and 77% were male. The mean age was 18.4 (±13.1) years. Of the patients, 19 (49%) had somnambulism, 13 (33%) had confusional arousal and seven (18%) had sleep terrors. Macrostructure of sleep detected by PSG was normal in all patients. After excluding 11 (28%) patients with a positive history of epilepsy, seven (25%) of 28 showed EEG abnormalities within K-complexes in NREM-II stage, six of whom were pediatric patients compared to only one adult (p < 0.05).ConclusionThis study showed that patients with NRP may display EEG abnormalities in NREM-II stage. These abnormalities were more frequent in pediatric patients compared to adults. In NRP patients, utmost care should be taken in EEG evaluations to prevent false diagnosis of epilepsy.     

Effect of alpha-methyldopa administration during pregnancy on the development of a child's sleep

A male infant was born to a mother who had been suffering from primary hyperaldosteronism with the administration of alpha-methyldopa (MD) during pregnancy. His behavioral development, especially that of sleep, was studied by means of sleep-awake rhythm and polysomnography recordings (PSG) from 2 months to 2 years and 5 months of age. His daily sleep-awake rhythm showed some abnormal pattern. As to the PSG, the proportion of each sleep stage was normal and the two types of body movements (BM) showed various patterns. A paradoxical increase was seen in the twitch movement of some muscles. MD affects the catecholamine system in the CNS and human sleep. Since the sleep-awake rhythm and BM are thought to be related to the monoaminergic system in the CNS, we assume that his behavior and sleep disorders are the effects of the maternal MD administration during pregnancy.     

MAO-A and COMT polymorphisms and gene effects in narcolepsy.

Narcolepsy presents one of the tightest associations with a specific HLA antigen (DQB1*0602) but there is strong evidence that non-HLA genes also confer susceptibility. Recent observations have implicated the hypocretin/orexin system in narcolepsy in both humans and animals. In addition, the implication of monoaminergic systems in the pathophysiology of narcolepsy is well established and a significant association between the monoamine oxydase-A (MAO-A) gene and human narcolepsy has recently provided a possible genetic link. We investigated polymorphisms of MAO-A and catechol-O-methyltransferase (COMT) in 97 Caucasians with well-defined narcolepsy-cataplexy and sought for genotypic effects on disease symptoms. No evidence of association between genotype or allele frequencies of both MAO-A or COMT gene and narcolepsy was found. However, a sexual dimorphism and a strong effect of COMT genotype on disease severity were found. Women narcoleptics with high COMT activity fell asleep twice as fast as those with low COMT activity during the multiple sleep latency test (MSLT) while the opposite was true for men. COMT genotype also strongly affected the presence of sleep paralysis and the number of REM sleep onsets during the MSLT. In agreement with well-documented pharmacological results in canine narcolepsy, this study reports the first genetic evidence for the critical involvement of the dopaminergic and/or noradrenergic systems in human narcolepsy.     

Sleep-wake mechanisms and drug discovery: sleep EEG as a tool for the development of CNS-acting drugs

Sleep laboratory investigations constitute a unique noninvasive tool to analyze brain functioning, Polysomnographic recordings, even in the very early phase of development in humans, are mandatory in a developmental plan of a new sleep-acting compound. Sleep is also an interesting tool for the development of other drugs acting on the central nervous system (CNS), Indeed, changes in sleep electroencephalographic (EEG) characteristics are a very sensitive indication of the objective central effects of psychoactive drugs, and these changes are specific to the way the drug acts on the brain neurotransmitter systems. Moreover, new compounds can be compared with reference drugs in terms of the sleep EEG profile they induce. For instance, cognitive enhancers involving cholinergic mechanism have been consistently demonstrated to increase rapid eye movement (REM) sleep pressure, and studying drug-induced slow wave sleep (SWS) alteration is a particularly useful tool for the development of CNS compounds acting at the 5-HT(2A/C) receptor, such as most atypical antipsychotics and some antidepressant drugs. The sleep EEG profile of antidepressants, and particularly their effects on REM sleep, are specific to their ability to enhance noradrenergic or serotonergic transmission, it is suggested that the effects of noradrenergic versus serotonergic reuptake inhibition could be disentangled using specific monoamine depletion tests and by studying drug effects on sleep microsiructure.     

Changes of somatosensory evoked potential accompanying ischaemia and hypoxia in cats

Changes of evoked potential accompanying haemorrhagic hypotension and hypoxia were investigated on cats to evaluate the usefulness of SEP as a monitor in an intensive care unit (ICU), and the following results were obtained. Positive-negative diphasic potential was elicited at posterior sigmoid gyrus(PSG) by contralateral superficial radial nerve stimulation. This potential was recorded at the restricted area of the posterior border of PSG and regarded as primary somatosensory evoked potential. In the initial stage of haemorrhagic hypotension, both positive and negative components of SEP occasionally increased in amplitude. In profound hypotension in which CBF fell to less than the critical level of 30 ml 100 g-1 min-1, the latency was retarded and the amplitude was decreased. At CBE less than 10 ml 100 g-1 min-1, SEP disappeared. Within the range of CBF between 10 and 30 ml 100 g-1 min, a close correlation was noted between CBF and SEP amplitude. Transient increase of SEP amplitude was also observed during hypoxia induced by inhalation of nitrogen gas. (3) In normal state SEP was decreased in amplitude by conditioning stimulation of the nucleus lateralis posterior (LP nucleus) of the thalamus. This might be explained by the fact that intracortical inhibitory interneurons were activated by stimulation of LP nucleus. After haemorrhagic hypotension and hypoxia, however, the inhibitory effect on SEP elicited by LP nucleus stimulation attenuated or disappeared. Because of the initial impairment of the inhibitory interneurons by ischaemia and hypoxia, the amplitude of SEP might increase transiently. In conclusion, the authors thought that SEP might be less useful than EEG in ICU, because of its insensible change to hypoxia and ischaemia.     

Early-infantile epileptic encephalopathy with suppression-bursts, Ohtahara syndrome; its overview referring to our 16 cases.

Ohtahara syndrome (OS) is characterized by frequent tonic spasms, with or without clustering, of early onset within a few months of life, and a suppression-burst (S-B) pattern in electroencephalography (EEG). Tonic spasms occur in not only waking but also sleeping state in most cases. Partial seizures are observed in about one-third of cases. Brain imagings reveal structural abnormalities including malformations, notably asymmetric lesions in most cases.S-B pattern is persistently observed regardless of circadian cycle. Bursts of 1-3s duration alternate with nearly flat suppression phase of 2-5s at an approximately regular rate; 5-10s of burst-burst interval. Some asymmetry in S-B is noted in about two-thirds of cases. Ictal EEG of tonic spasms shows principally desynchronization with or without initial rapid activity. Tonic spasms appear concomitant with bursts.Characteristic age-dependent evolution from OS to West syndrome (WS) in many cases, and further from WS to Lennox-Gastaut syndrome (LGS) in some, proceed concomitantly with EEG transition from S-B to hypsarrhythmia at around age 3-6 months, and further from hypsarrhythmia to diffuse slow spike-waves at around age 1.Under the inclusive concept of the age-dependent epileptic encephalopathy, OS, WS, and LGS have common characteristics such as age preference, frequent minor generalized seizures, and continuous massive epileptic EEG abnormality. Mutual transition suggests the same pathophysiology among three syndromes and the age factor should be considered as the common denominator responsible for the manifestation of each of their own specific clinico-electrical features. Namely, these syndromes may be the age-specific epileptic reaction to various non-specific exogenous brain insults, acting at the specific developmental stages.     

The neurobiology of narcolepsy.

Narcolepsy is characterized by excessive sleepiness and abnormal manifestations of rapid eye movement (REM) sleep. Neurochemical studies of human and canine narcolepsy have demonstrated disturbed monoaminergic and cholinergic function and suggest that deficits of noradrenaline availability in specific brain regions may account for much of its disordered pathophysiology. Genetic susceptibility to narcolepsy is closely linked to a specific region of the major histocompatibility complex on chromosome 6 and an important direction for future research will be to unravel the relationship between this gene region and the neurochemical abnormalities of narcolepsy.