Apneic preterms and methylxanthines: arousal deficits, sleep fragmentation and suppressed spontaneous movements.

OBJECTIVE: To determine if apneic preterm infants currently treated with methylxanthines develop evidence of sleep deprivation from cumulative arousal and motor activational effects. STUDY DESIGN: Sleep, wake, arousal and actigraphic movements were monitored in extubated clinically stable premature infants (N=37). Neonates were free of other medications for >72 h and were grouped based on methylxanthine exposure: >5 days with caffeine (n=14), >5 days theophylline (n=13) or no prior exposure (n=10). RESULT: Duration of methylxanthine treatment predicted increased arousals, wakefulness and actigraphic movements, and decreased active sleep. Recording from 1200 to 0500 hours, methylxanthine-treated groups showed reductions in all arousal parameters: waking state, number of wake epochs, brief arousals and composite arousal index, and shorter fast-burst, sleep-related motility than untreated controls. CONCLUSION: In apneic preterms, chronic methylxanthine treatment appears to produce sleep deprivation secondary to the stimulatory action of methylxanthines on arousal and motor systems.

Undetectable levels of CSF hypocretin-1 (orexin-A) in two prepubertal boys with narcolepsy.

We report on two prepubertal narcoleptic boys with undetectable levels of hypocretin-1 (orexin-A) in their cerebrospinal fluid (CSF). The disease onset times were 6 and 8 years, and CSF was collected 8 and 20 months after the onset, respectively. The initial symptoms were excessive daytime sleepiness, cataplexy and disrupted nocturnal sleep. Both subjects are DRB1*1501 and DQB1*0602 positive. The measurement of CSF hypocretin-1 is valuable for the decisive diagnosis of narcolepsy and for selecting the type of treatment in prepubertal children. Our results suggest that a significant degree of hypocretin deficiency is already present at the disease onset.

Paroxysmal discharges on EEG in young autistic patients are frequent in frontal regions.

EEGs were recorded in 86 autistic patients during sleep. Epileptic discharges were observed in 37 cases (43%). Twenty-seven (73%) of these 37 cases had localized spikes, 8 had multiple spike foci, one had generalized spikes, and one had both multiple spike foci and generalized spikes. Forty-seven epileptic discharge foci were registered in 36 cases, the exception being one with generalized spikes. Thirty-six (76.6%) of the registered 47 epileptic discharge foci were in the frontal region, one (2.1%) in the temporal region, 7 (14.1%) in the centro-parietal region, and 3 (6.4%) in the occipital region. Twenty (55.6%) of the 36 frontal spikes were at midline (11 at Fz and 9 at Cz), 8 on the left side, and 8 on the right side. The dipole of midline spikes was in the deep midline frontal region. These results suggest that frontal dysfunctions are important in the mechanism of symptoms in autism.

Mechanical ventilation care in severe childhood neurological disorders.

Forty-five patients underwent long-term life-sustaining mechanical ventilation care in the Child Neurology Ward, National Center Hospital for Mental, Nervous and Muscular Disorders from 1990 to 2000. Twenty patients had chronic respiratory insufficiency due to neuromuscular disorders, nine of whom underwent home mechanical ventilation care. Nineteen of the 45 patients had chronic respiratory insufficiency due to progressive central nervous system disorders, three of whom underwent home mechanical ventilation care. Six patients with chronic respiratory insufficiency due to the sequelae of transient events were on ventilation, two of whom underwent home mechanical ventilation care. In some patients, especially ones with neuromuscular disorders, mechanical ventilation care is very useful for improving their daily activity and quality of life. In other patients, however, mechanical ventilation care is merely a means of prolonging life without visible improvement of their quality of life. As medical resources are limited, home mechanical ventilation care is a recommended method for patients who need life-sustaining mechanical ventilation care. Considering an individual or social consensus, the indication of long-term life-sustaining mechanical ventilation care for chronic respiratory insufficiency due to severe childhood neurological disorders should be further discussed.

Diagnosis of Alexander disease in a Japanese patient by molecular genetic analysis.

Alexander disease is a leukodystrophy that is neuropathologically characterized by the presence of numerous Rosenthal fibers in astrocytes. Recently, mutations in the gene encoding glial fibrillary acidic protein (GFAP) were identified in patients with Alexander disease. We sequenced the GFAP gene of a Japanese girl who presented with typical symptoms of Alexander disease but in whom the diagnosis was not proven by histopathology. We identified a missense mutation, R239C, which is identical to the mutation previously reported to be most frequent. As was the case in previously described patients, our patient was also heterozygous for the de novo mutation. Interestingly, despite the fact that this is a de novo mutation, R239C was found to be common in different ethnic groups, implying that the site is a "hot spot" for mutagenesis. Molecular genetic analysis now makes the antemortem diagnosis of Alexander disease possible.

[Efficacy of anticonvulsants on acute encephalitis with refractory, repetitive partial seizures (AERRPS)].

The first purpose of this study is to propose a new clinical entity, acute encephalitis with refractory, repetitive partial seizures (AERRPS), which satisfy the following five criteria: 1. a prolonged acute phase of more than 2 weeks; 2. partial seizures of the same seminology persisting from the acute phase to the convalescence; 3. seizures frequently evolving into convulsive status especially during the acute phase; 4. marked intractableness of seizures; 5. exclusion of related disorders such as known viral encephalitis or metabolic disorders. The second purpose is to evaluate the efficacy of therapeutic agents on AERRPS. We reviewed 21 cases reported previously, as well as one patient seen by us. Based on the data, we recommend that patients with AERRPS should be under a high dose intravenous barbiturate during the acute phase, followed by a high dose of phenobarbital or phenytoin in the convalescence. Clonazepam, zonisamide, and potassium bromide were sometimes effective during the recovery phase.

[Three cases of Costello syndrome presenting with intractable epilepsy and profound psychomotor retardation/regression].

We report three cases of Costello syndrome (CS) presenting with intractable epilepsy and profound psychomotor retardation/regression. Previous reports on CS described mild to moderate psychomotor retardation, and epilepsy in only 8% of the cases. The details of these neurological complications have not been reported so far. All the present cases had intractable epilepsies and profound psychomotor retardation/regression. Two of them had symptomatic localization-related epilepsies and the other had Lennox-Gastaut syndrome following West syndrome. Unusual complication of profound psychomotor retardation/regression in our cases seems to be caused by intractable epilepsy. It should be noted that CS patients with epilepsy may have more severe central nervous symptoms than those previously reported.

[Life-sustaining mechanical ventilation care for children with progressive or degenerative brain disorders].

In the past 10 years, we have treated 25 patients with chronic respiratory insufficiency due to a progressive or degenerative brain disorder. Ten patients died and the other 15 survived. Five of the former and 12 of the latter received life-sustaining mechanical ventilation care. Even in the terminal stage of progressive or degenerative brain disorders, patients can survive for a longer period than previously, if life-sustaining mechanical ventilation care is given. In Japan we do not have a guideline for medical indication or decision-making for children with progressive or degenerative brain disorders. Whenever we see such patients, we have great difficulty in making a decision. It may therefore be necessary to discuss whether we should have such a guideline.

A severely brain-damaged case of 3-hydroxyisobutyric aciduria.

We report a male case of 3-hydroxyisobutyric aciduria (3HiB-uria) with severe brain damage. He had mild asphyxia at birth. He needed tube feeding for a month. He showed mild dysmorphic features, including low set ears, a long philtrum and micrognathia. At 4 months of age he had acute encephalopathy. Thereafter, severe brain damage remained and mechanical ventilation care was needed all day. After he had been admitted to our hospital at 3 years of age, repeated organic acid analysis of urine confirmed the diagnosis of 3HiB-uria. This patient had been previously diagnosed as having cerebral palsy and sequelae of acute encephalopathy.

Single-photon emission computed tomography of the brain in autism: effect of the developmental level.

Brain single-photon emission computed tomography was performed in 22 autistic and 10 nonautistic disabled patients. The regional cerebral blood flow in both laterotemporal and dorso-medio-lateral frontal areas decreased significantly in the autistic group compared with in nonautistic group. In the autistic group, the regional cerebral blood flow was significantly higher in the right temporal and right parietal lobes than that in the left ones. Inversely, the regional cerebral blood flow in the frontal and occipital lobes was significantly higher on the left side than on the right side. In the nonautistic group, except for in the dorso-medio-lateral frontal lobes (left > right), there was no difference in the regional cerebral blood flow in either cerebrum or cerebellum. A positive correlationship between regional cerebral flow and development quotient (intelligence quotient) was observed in the left laterotemporal and both dorso-medio-lateral frontal areas, and a negative one was observed in the cerebellar vermis area. These results suggest that the regional cerebral blood flow decrease in the temporal and frontal areas relates to not only the brain mechanism of autism reported previously but also intelligence levels.

[Improvement of obstructive sleep apnea by uvulopalatopharyngoplasty and tonsillectomy in a case of Duchenne muscular dystrophy].

A 10-year-old boy with Duchenne muscular dystrophy (DMD) underwent uvulopalatopharyngoplasty and tonsillectomy for obstructive sleep apnea (OSA). He has snored loudly during nocturnal sleep since infancy, and OSA developed one and a half years after he was wheel chair-bound at 8 years. Magnetic resonance imaging (MRI), conventional spirometry and overnight polysomnography were performed before and after the surgery. MRI before surgery revealed moderate tonsillar hypertrophy and a long uvula which narrowed the upper airway. After the surgery, his vital capacity (VC) was not changed (% VC; from 77 to 78%), but forced expiratory volume (FEV) was improved (FEV 1.0%; from 75 to 86%). A preoperative apnea index of 32.8/hour decreased to 0.8/hour postoperatively. REM-related falls in HbSaO2 improved remarkably. The present case suggests that subjects with DMD with tonsillar hypertrophy and a redundant uvula tend to develop noctrurnal OSA earlier than DMD cases with a normal tonsil and uvula. Assessment of respiratory function, particularly FEV 1.0%, is important for determining surgical indication of OSA in patients with DMD.

Rapid eye movement sleep in breath holders.

One-night polysomnography was performed on seven subjects suffering from breath-holding spells, including one whose death was suggested to be a consequence of a breath-holding spell. The fatal case showed no rapid eye movements (REMs) during REM sleep, although he exhibited REMs during wakefulness. The average numbers of both REMs and bursts of REMs in REM sleep in the other six breath holders were significantly lower than those in age-matched controls. The breath holders showed no airway obstruction, desaturation, or sleep fragmentation. Since the rapid ocular activity in REM sleep is generated in the brain stem, we hypothesized that a functional brainstem disturbance is involved in the occurrence of breath-holding spells.

[Feeding function, blink reflex and MRI in the severely handicapped].

Blink reflexes were studied in 41 patients with severe handicaps, and were correlated with feeding problems and other lower brainstem symptoms such as drooling, an absent gag reflex and stridor. Ventrodorsal diameters of the pons and medulla oblongata on sagittal MRI were also studied in 29 of the cases. The patients were divided into three groups: tube feeding (25 cases), oral feeding (13 cases) and mixed feeding (3 cases). In the tube feeding group, all but three cases showed a prolonged or absent R1 component, and all cases showed prolonged or absent R2 and R2' components. These abnormalities were significantly more frequent in the tube than in the oral feeding group. The patients with drooling, stridor or an absent gag reflex more frequently showed prolonged or absent components than the patients without these symptoms. The brainstem size on MRI was not different between the tube and oral feeding group. These results suggest that the blink reflex, particularly its late components, is a useful indicator for evaluating feeding function and other lower brainstem functions.

Apneustic breathing in children with brainstem damage due to hypoxic-ischemic encephalopathy.

To confirm the presence of apneusis in patients with hypoxic-ischemic encephalopathy and to clarify which factors influence their respiratory patterns, polygraphic studies were performed on two patients. Apneusis was clinically suspected in both patients who had severe brainstem damage. In one subject, inputs of vagal afferents from the gastrointestinal tract and the urinary bladder often resulted in extreme tachypnea instead of apneusis. Lung inflation facilitated expiration during inspiratory arrest. Expiration preceded a periodic inhibition of rigospastic discharge in the right biceps muscle. In the other subject, prolonged inspiratory pauses with cyanosis occurred with or without preceding epileptic seizure. Both phenytoin dose reduction and treatment with tandospirone, a serotonin-1A agonist, were effective in improving the respiratory distress in this subject.

Polysomnographic studies of Lesch-Nyhan syndrome.

Three cases of Lesch-Nyhan syndrome (LNS) were examined by polysomnography to assess the brainstem function, and to determine the causes of the neurological manifestations and sudden death in this syndrome. In the two older cases, the amount of slow wave and rapid eye movement (REM) sleep, the REM density and the frequency of REM bursts were decreased. In the youngest case, symmetrical phasic movements of all four limbs were observed at all sleep stages other than REM sleep. Although movements other than these symmetrical body movements appeared to be normal in this case, the frequency of twitch movements showed an abnormal pattern in each sleep stage in the two older cases. These findings suggest that in the brainstems of younger cases with LNS the REM-non REM generator as well as multiple neurotransmitter systems influencing body movements during sleep remain relatively normal, but become progressively impaired in adult cases. Severe obstructive apnea was observed in one case with hypothyroidism, but there were no respiratory abnormalities in other two cases.

Video analysis of gross body movements during sleep.

Gross body movements (GM) during sleep, classified into four GM types by the involved parts of body, were evaluated using two-dimensional video analysis in five normal children aged 4-12 years. The rate of occurrence of all GM types showed apparent sleep stage dependency. Among four GM types, GM-1 (GM with axial rotation) was the most frequent. Averaged duration of GM-1 was the longest. A total of 77.2% of GM-1 started with the contraction of chin muscle and 35% of total sleep changes (tSC) were related to GM. A total of 5.6% of tSC following GM shifted to the deeper stage. Further evaluation is necessary in order to understand the physiological mechanism of GM.